Publications - Salk Institute for Biological Studies

selected Publications

Schafer, S.T., Mansour, A.A., Schlachetzki, J.C.M., Pena, M., Ghassemzadeh, S., Mitchell, L., Mar, A., Quang, D., Stumpf, S., Ortiz, I.S., Lana, A.J., Baek, C., Zaghal, R., Glass, C.K., Nimmerjahn, A., Gage, F.H. An in vivo neuroimmune organoid model to study human microglia phenotypes. (2023) Móvil. 186(10):2111-2126.e20. DOI: 10.1016/j.cell.2023.04.022

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Herdy, J.R., Traxler, L., Agarwal, R.K., Karbacher, L., Schlachetzki, J.C.M., Boehnke, L., Zangwill, D., Galasko, D., Glass, C.K., Mertens, J., Gage, F.H. Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer's disease. (2022) Cell Stem Cell. 29(12):1637-1652.e6. DOI: 10.1016/j.stem.2022.11.010

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Gage, F.H. Adult neurogenesis in mammals. (2019) Ciencia. 364(6443):827-828. DOI: 10.1126/science.aav6885

Marchetto, M.C., Hrvoj-Mihic, B., Kerman, B.E., Yu, D.X., Vadodaria, K.C., Linker, S.B., Narvaiza, I., Santos, R., Denli, A.M., Mendes, A.P., Oefner, R., Cook, J., McHenry, L., Grasmick, J.M., Heard, K., Fredlender, C., Randolph-Moore, L., Kshirsagar, R., Xenitopoulos, R., Chou, G., Hah, N., Muotri, A.R., Padmanabhan, K., Semendeferi, K., Gage, F.H. Species-specific maturation profiles of human, chimpanzee and bonobo neural cells. (2019) Elife. 8. DOI: 10.7554/eLife.37527

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Franks, T.M., Benner, C., Narvaiza, I., Marchetto, M.C., Young, J.M., Malik, H.S., Gage, F.H., Hetzer, M.W. Evolution of a transcriptional regulator from a transmembrane nucleoporin. (2016) Genes & Development. 30(10):1155-71. DOI: 10.1101/gad.280941.116

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Todas las publicaciones

Doludda, B., Barde, W., D'Egidio, F., Fitzsimons, C.P., Frisén, J., Gage, F.H., Jessberger, S., Lazarov, O., Lie, D.C., Lucassen, P.J., de Lucia, C., Salta, E., Song, H., Song, J., Thuret, S., Toda, T., Kempermann, G. Adult neurogenesis: New neurons, new opportunities. (2026) Cell Stem Cell. 33(3):382-392. DOI: 10.1016/j.stem.2026.01.014

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Kelsey, M.M.G., Chongtham, A., LaCava, J., Taylor, M.S., Boeke, J.D., Gage, F.H., Seluanov, A., Gorbunova, V., Pereira, A.C., Sedivy, J.M. Retrotransposon Activation in the Aged and Alzheimer's Disease Brain Examined by Nanopore Long-read DNA Sequencing. (2025) bioRxiv. DOI: 10.64898/2025.12.12.693943

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Pașca, S.P., Arlotta, P., Campbell, P., Charo, A., Evans, J.H., Farahany, N., Gage, F.H., Godfrey-Smith, P., Hyun, I., Kriegstein, A.R., Melloni, L., Ming, G.L., Moreno, J.D., Sugarman, J., Temple, S., Testa, G., Greely, H.T. The need for a global effort to attend to human neural organoid and assembloid research. (2025) Ciencia. 390(6773):574-577. DOI: 10.1126/science.aeb1510

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Farsheed, A.C., Makhoul, J.T., Chew-Martinez, D., Maldonado, E., Liu, J., Yu, L.T., Gorostieta-Salas, E., Jones, J.R., Gage, F.H., Hartgerink, J.D. Omnidirectional 3D Printing of Anisotropic Nanofibrous Peptide Hydrogels. (2025) bioRxiv. DOI: 10.1101/2025.11.06.687046

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Esparza-Moltó, P.B., Goswami, A.V., Bozkurt, S., Münch, C., Newman, L.E., Moyzis, A.G., Rojas, G.R., Guan, D., Jones, J.R., Gage, F.H., Shadel, G.S. ROS-dependent localization of glycolytic enzymes to mitochondria. (2025) Redox Biol. 86:103812. DOI: 10.1016/j.redox.2025.103812

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Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.

Baek, G.H., Kim, D., Son, G., Do, H., Yeon, G.B., Lee, M.J., Ji, M., Son, J.H., Ju, M., Ahn, I., Kang, C.S., Lee, H., Choi, S., Suh, J.M., Seo, J., Gage, F.H., Paik, M.J., Park, Y., Kim, D.S., Han, J. Differential effects of lithium on metabolic dysfunctions in astrocytes derived from bipolar disorder patients. (2025) Molecular Psychiatry. DOI: 10.1038/s41380-025-03176-w

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Metabolic alterations have been observed in the brains of patients with bipolar disorder (BD), a neuropsychiatric disorder characterized by alternating episodes of mania and depression. However, the specific contributions of glial cells to these metabolic changes remain largely unknown. Here, we investigate the metabolic characteristics of induced astrocytes (iAstrocytes) derived from induced pluripotent stem cells of BD patients-classified by lithium responsiveness-and healthy controls. Transcriptomic analyses revealed dysregulated expression of genes associated with metabolic diseases in BD iAstrocytes. Compared to control iAstrocytes, BD iAstrocytes showed decreased mitochondrial respiration, increased glycolysis, and elevated lactate secretion, indicating impaired mitochondrial function. These defects were further supported by downregulation of oxidative phosphorylation complex proteins and decreased reactive oxygen species levels. Notably, BD iAstrocytes showed substantial lipid droplet (LD) accumulation, potentially as a consequence of disrupted metabolic homeostasis. Lithium treatment reduced LD levels in lithium-responsive (Li-R) iAstrocytes but failed to restore mitochondrial respiration or normalize lactate secretion. In co-culture with human neurons, lithium-nonresponsive (Li-NR) iAstrocytes exhibited enhanced uptake of neuron-derived lipids and selectively increased neuronal excitability. Metabolomic profiling revealed distinct metabolite signatures between Li-R and Li-NR iAstrocytes, suggesting lithium responsiveness as a key axis of metabolic heterogeneity. Together, our findings identify astrocyte-specific metabolic dysfunction as a hallmark of BD and reveal divergent roles of Li-R and Li-NR iAstrocytes in modulating neuronal function. LD accumulation in Li-NR iAstrocytes may serve as a functional readout for drug screening to identify alternative treatments for patients unresponsive to lithium.

Da Silva, I.I.N., Ramirez, D., Parylak, S.L., Wallace, L.A., Tucker, J.K., Erberich, J.M., Katariya, R., McDonald, A.H., Gallina, I.S., Tucker, A.L., Burgado, J., Jaeger, B.N., Barron, J.J., Pratt, J.M., Pena, M., Racha, V., Lim, C.K., Fernandes, S., Benassi, S., Randolph-Moore, L., Vadodaria, K.C., Marchetto, M.C., Allen, N.J., Gage, F.H. CK2 inhibition suppresses glial inflammation in the brain. (2025) bioRxiv. DOI: 10.1101/2025.08.05.668554

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Liu, Y.N., Wang, Q.W., Lu, S.Y., Shen, W., Guo, C., Xing, Z., Li, C., Sun, S., Sui, S.F., Mi, S., Gage, F.H., Yao, J. Synaptotagmin-7 deficit causes insulin hypoactivity and contributes to behavioral alterations in mice. (2025) iScience. 28(5):112354. DOI: 10.1016/j.isci.2025.112354

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Tucker, J.K., Da Silva, I.I.N., Gage, F.H. Scaffold hopping and sidechain modification from a flavone scaffold lead to discovery of potent, selective CK2A2 inhibitors with favorable properties for CNS activity. (2025) Bioorganic & Medicinal Chemistry. 127:118196. DOI: 10.1016/j.bmc.2025.118196

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Gage, F.H. New neurons are born in the adult human brain. (2025) Nature Medicine. DOI: 10.1038/s41591-025-03497-x

Gage, F.H. Adult Neurogenesis in the Human Dentate Gyrus. (2025) Hippocampus. 35(1):e23655. DOI: 10.1002/hipo.23655

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Pașca, S.P., Arlotta, P., Bateup, H.S., Camp, J.G., Cappello, S., Gage, F.H., Knoblich, J.A., Kriegstein, A.R., Lancaster, M.A., Ming, G.L., Novarino, G., Okano, H., Parmar, M., Park, I.H., Reiner, O., Song, H., Studer, L., Takahashi, J., Temple, S., Testa, G., Treutlein, B., Vaccarino, F.M., Vanderhaeghen, P., Young-Pearse, T. A framework for neural organoids, assembloids and transplantation studies. (2024) Naturaleza. DOI: 10.1038/s41586-024-08487-6

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Son, G., Na, Y., Kim, Y., Son, J.H., Clemenson, G.D., Schafer, S.T., Yoo, J.Y., Parylak, S.L., Paquola, A., Do, H., Kim, D., Ahn, I., Ju, M., Kang, C.S., Ju, Y., Jung, E., McDonald, A.H., Park, Y., Kim, G., Paik, S.B., Hur, J., Kim, J., Han, Y.M., Lee, S.H., Gage, F.H., Kim, J.S., Han, J. miR-124 coordinates metabolic regulators acting at early stages of human neurogenesis. (2024) Communications Biology. 7(1):1393. DOI: 10.1038/s42003-024-07089-2

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Fernandes, S., Revanna, J., Pratt, J., Hayes, N., Marchetto, M.C., Gage, F.H. Modeling Alzheimer's disease using human cell derived brain organoids and 3D models. (2024) Frontiers in Neuroscience. 18:1434945. DOI: 10.3389/fnins.2024.1434945

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Minhas, P.S., Jones, J.R., Latif-Hernandez, A., Sugiura, Y., Durairaj, A.S., Wang, Q., Mhatre, S.D., Uenaka, T., Crapser, J., Conley, T., Ennerfelt, H., Jung, Y.J., Liu, L., Prasad, P., Jenkins, B.C., Ay, Y.A., Matrongolo, M., Goodman, R., Newmeyer, T., Heard, K., Kang, A., Wilson, E.N., Yang, T., Ullian, E.M., Serrano, G.E., Beach, T.G., Wernig, M., Rabinowitz, J.D., Suematsu, M., Longo, F.M., McReynolds, M.R., Gage, F.H., Andreasson, K.I. Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies. (2024) Ciencia. 385(6711):eabm6131. DOI: 10.1126/science.abm6131

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Perez Garcia, G., Bicak, M., Buros, J., Haure-Mirande, J.V., Perez, G.M., Otero-Pagan, A., Gama Sosa, M.A., De Gasperi, R., Sano, M., Gage, F.H., Barlow, C., Dudley, J.T., Glicksberg, B.S., Wang, Y., Readhead, B., Ehrlich, M.E., Elder, G.A., Gandy, S. Beneficial effects of physical exercise and an orally active mGluR2/3 antagonist pro-drug on neurogenesis and behavior in an Alzheimer's amyloidosis model. (2024) Front Dement. 2:1198006. DOI: 10.3389/frdem.2023.1198006

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Schmidt, T.T., Tyer, C., Rughani, P., Haggblom, C., Jones, J.R., Dai, X., Frazer, K.A., Gage, F.H., Juul, S., Hickey, S., Karlseder, J. High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer. (2024) Nature Communications. 15(1):5149. DOI: 10.1038/s41467-024-48917-7

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Phang, H.J., Heimler, S.R., Scandalis, L.M., Wing, D., Moran, R., Nichols, J.F., Moreno, D., Shadel, G.S., Gage, F.H., Molina, A.J.A. Protocol for the San Diego Nathan Shock Center Clinical Cohort: a new resource for studies of human aging. (2024) BMJ Open. 14(6):e082659. DOI: 10.1136/bmjopen-2023-082659

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Herdy, J.R., Mertens, J., Gage, F.H. Neuronal senescence may drive brain aging. LINK TO FREE FULL-TEXT https://www.science.org/stoken/author-tokens/ST-1962/full [Pubmed] (2024) Ciencia. 384(6703):1404-1406. DOI: 10.1126/science.adi3450

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Minhas, P.S., Jones, J.R., Latif-Hernandez, A., Sugiura, Y., Durairaj, A.S., Uenaka, T., Wang, Q., Mhatre, S.D., Liu, L., Conley, T., Ennerfelt, H., Jung, Y.J., Prasad, P., Jenkins, B.C., Goodman, R., Newmeyer, T., Heard, K., Kang, A., Wilson, E.N., Ullian, E.M., Serrano, G.E., Beach, T.G., Rabinowitz, J.D., Wernig, M., Suematsu, M., Longo, F.M., McReynolds, M.R., Gage, F.H., Andreasson, K.I. Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies. (2024) bioRxiv. DOI: 10.1101/2024.06.23.598940

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Stern, S., Zhang, L., Wang, M., Wright, R., Rosh, I., Hussein, Y., Stern, T., Choudhary, A., Tripathi, U., Reed, P., Sadis, H., Nayak, R., Shemen, A., Agarwal, K., Cordeiro, D., Peles, D., Hang, Y., Mendes, A.P.D., Baul, T.D., Roth, J.G., Coorapati, S., Boks, M.P., McCombie, W.R., Hulshoff Pol, H., Brennand, K.J., Réthelyi, J.M., Kahn, R.S., Marchetto, M.C., Gage, F.H. Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission. (2024) Molecular Psychiatry. DOI: 10.1038/s41380-024-02561-1

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Tripathi, U., Rosh, I., Ben Ezer, R., Nayak, R., Hussein, Y., Choudhary, A., Djamus, J., Manole, A., Houlden, H., Gage, F.H., Stern, S. Upregulated ECM genes and increased synaptic activity in Parkinson's human DA neurons with PINK1/ PRKN mutations. (2024) NPJ Parkinsons Dis. 10(1):103. DOI: 10.1038/s41531-024-00715-0

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Zocher, S., McCloskey, A., Karasinsky, A., Schulte, R., Friedrich, U., Lesche, M., Rund, N., Gage, F.H., Hetzer, M.W., Toda, T. Lifelong persistence of nuclear RNAs in the mouse brain. (2024) Ciencia. 384(6691):53-59. DOI: 10.1126/science.adf3481

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Podvin, S., Jones, J., Kang, A., Goodman, R., Reed, P., Lietz, C.B., Then, J., Lee, K.C., Eyler, L.T., Jeste, D.V., Gage, F.H., Hook, V. Human iN neuronal model of schizophrenia displays dysregulation of chromogranin B and related neuropeptide transmitter signatures. (2024) Molecular Psychiatry. DOI: 10.1038/s41380-024-02422-x

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Toda, T., Bedrosian, T.A., Schafer, S.T., Cuoco, M.S., Linker, S.B., Ghassemzadeh, S., Mitchell, L., Whiteley, J.T., Novaresi, N., McDonald, A.H., Gallina, I.S., Yoon, H., Hester, M.E., Pena, M., Lim, C., Suljic, E., AlFatah Mansour, A., Boulard, M., Parylak, S.L., Gage, F.H. Long interspersed nuclear elements safeguard neural progenitors from precocious differentiation. (2024) Cell Reports. 43(2):113774. DOI: 10.1016/j.celrep.2024.113774

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Rosh, I., Tripathi, U., Hussein, Y., Rike, W.A., Djamus, J., Shklyar, B., Manole, A., Houlden, H., Winkler, J., Gage, F.H., Stern, S. Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson's disease patients. (2024) NPJ Parkinsons Dis. 10(1):38. DOI: 10.1038/s41531-024-00653-x

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Miao, S., Fourgeaud, L., Burrola, P.G., Stern, S., Zhang, Y., Happonen, K.E., Novak, S.W., Gage, F.H., Lemke, G. Tyro3 promotes the maturation of glutamatergic synapses. (2024) Frontiers in Neuroscience. 18:1327423. DOI: 10.3389/fnins.2024.1327423

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Wang, M., Zhang, L., Novak, S.W., Yu, J., Gallina, I.S., Xu, L.L., Lim, C.K., Fernandes, S., Shokhirev, M.N., Williams, A.E., Saxena, M.D., Coorapati, S., Parylak, S.L., Quintero, C., Molina, E., Andrade, L.R., Manor, U., Gage, F.H. Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain. (2024) Nature Biotechnology. DOI: 10.1038/s41587-024-02157-8

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Garrison, M.A., Jang, Y., Bae, T., Cherskov, A., Emery, S.B., Fasching, L., Jones, A., Moldovan, J.B., Molitor, C., Pochareddy, S., Peters, M.A., Shin, J.H., Wang, Y., Yang, X., Akbarian, S., Chess, A., Gage, F.H., Gleeson, J.G., Kidd, J.M., McConnell, M., Mills, R.E., Moran, J.V., Park, P.J., Sestan, N., Urban, A.E., Vaccarino, F.M., Walsh, C.A., Weinberger, D.R., Wheelan, S.J., Abyzov, A. Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases. (2023) Sci Data. 10(1):813. DOI: 10.1038/s41597-023-02645-7

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Manole, A., Wong, T., Rhee, A., Novak, S., Chin, S.M., Tsimring, K., Paucar, A., Williams, A., Newmeyer, T.F., Schafer, S.T., Rosh, I., Kaushik, S., Hoffman, R., Chen, S., Wang, G., Snyder, M., Cuervo, A.M., Andrade, L., Manor, U., Lee, K., Jones, J.R., Stern, S., Marchetto, M.C., Gage, F.H. NGLY1 mutations cause protein aggregation in human neurons. (2023) Cell Reports. 42(12):113466. DOI: 10.1016/j.celrep.2023.113466

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Mizrahi, L., Choudhary, A., Ofer, P., Goldberg, G., Milanesi, E., Kelsoe, J.R., Gurwitz, D., Alda, M., Gage, F.H., Stern, S. Immunoglobulin genes expressed in lymphoblastoid cell lines discern and predict lithium response in bipolar disorder patients. (2023) Molecular Psychiatry. DOI: 10.1038/s41380-023-02183-z

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Traxler, L., Lucciola, R., Herdy, J.R., Jones, J.R., Mertens, J., Gage, F.H. Neural cell state shifts and fate loss in ageing and age-related diseases. (2023) Nat Rev Neurol. DOI: 10.1038/s41582-023-00815-0

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Arlotta, P., Gage, F.H. Neural Organoids and the Quest to Understand and Treat Psychiatric Disease. (2023) Biological Psychiatry. 93(7):588-589. DOI: 10.1016/j.biopsych.2023.01.021

Mishra, H.K., Wei, H., Rohr, K.E., Ko, I., Nievergelt, C.M., Maihofer, A.X., Shilling, P.D., Alda, M., Berrettini, W.H., Brennand, K.J., Calabrese, J.R., Coryell, W.H., Frye, M., Gage, F., Gershon, E., McInnis, M.G., Nurnberger, J., Oedegaard, K.J., Zandi, P.P., Kelsoe, J.R., McCarthy, M.J. Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder. (2023) Eur Neuropsychopharmacol. 74:1-14. DOI: 10.1016/j.euroneuro.2023.04.009

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Kempermann, G., Song, H., Gage, F.H. Adult neurogenesis in the hippocampus. (2023) Hippocampus. DOI: 10.1002/hipo.23525

Niemsiri, V., Rosenthal, S.B., Nievergelt, C.M., Maihofer, A.X., Marchetto, M.C., Santos, R., Shekhtman, T., Alliey-Rodriguez, N., Anand, A., Balaraman, Y., Berrettini, W.H., Bertram, H., Burdick, K.E., Calabrese, J.R., Calkin, C.V., Conroy, C., Coryell, W.H., DeModena, A., Eyler, L.T., Feeder, S., Fisher, C., Frazier, N., Frye, M.A., Gao, K., Garnham, J., Gershon, E.S., Goes, F.S., Goto, T., Harrington, G.J., Jakobsen, P., Kamali, M., Kelly, M., Leckband, S.G., Lohoff, F.W., McCarthy, M.J., McInnis, M.G., Craig, D., Millett, C.E., Mondimore, F., Morken, G., Nurnberger, J.I., Donovan, C.O., Øedegaard, K.J., Ryan, K., Schinagle, M., Shilling, P.D., Slaney, C., Stapp, E.K., Stautland, A., Tarwater, B., Zandi, P.P., Alda, M., Fisch, K.M., Gage, F.H., Kelsoe, J.R. Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis. (2023) Molecular Psychiatry. DOI: 10.1038/s41380-022-01909-9

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Parylak, S.L., Qiu, F., Linker, S.B., Gallina, I.S., Lim, C.K., Preciado, D., McDonald, A.H., Zhou, X., Gage, F.H. Neuronal activity-related transcription is blunted in immature compared to mature dentate granule cells. (2023) Hippocampus. DOI: 10.1002/hipo.23515

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Bermperidis, T., Schafer, S., Gage, F.H., Sejnowski, T., Torres, E.B. Dynamic Interrogation of Stochastic Transcriptome Trajectories Using Disease Associated Genes Reveals Distinct Origins of Neurological and Psychiatric Disorders. (2023) Frontiers in Neuroscience. 16:884707. DOI: 10.3389/fnins.2022.884707

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Perez-Garcia, G., Bicak, M., Haure-Mirande, J.V., Perez, G.M., Otero-Pagan, A., Gama Sosa, M.A., De Gasperi, R., Sano, M., Barlow, C., Gage, F.H., Readhead, B., Ehrlich, M.E., Gandy, S., Elder, G.A. BCI-838, an orally active mGluR2/3 receptor antagonist pro-drug, rescues learning behavior deficits in the PS19 MAPT mouse model of tauopathy. (2023) Neurosci Lett.:137080 DOI: 10.1016/j.neulet.2023.137080

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Wang, M., Gage, F.H., Schafer, S.T. Transplantation Strategies to Enhance Maturity and Cellular Complexity in Brain Organoids. (2023) Biological Psychiatry. DOI: 10.1016/j.biopsych.2023.01.004

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Fu, C., Ngo, J., Zhang, S., Lu, L., Miron, A., Schafer, S., Gage, F.H., Jin, F., Schumacher, F.R., Wynshaw-Boris, A. Novel correlative analysis identifies multiple genomic variations impacting ASD with macrocephaly. (2022) Human Molecular Genetics. DOI: 10.1093/hmg/ddac300

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Wilson, M.N., Thunemann, M., Liu, X., Lu, Y., Puppo, F., Adams, J.W., Kim, J.H., Ramezani, M., Pizzo, D.P., Djurovic, S., Andreassen, O.A., Mansour, A.A., Gage, F.H., Muotri, A.R., Devor, A., Kuzum, D. Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex. (2022) Nature Communications. 13(1):7945. DOI: 10.1038/s41467-022-35536-3

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Linker, S.B., Narvaiza, I., Hsu, J.Y., Wang, M., Qiu, F., Mendes, A.P.D., Oefner, R., Kottilil, K., Sharma, A., Randolph-Moore, L., Mejia, E., Santos, R., Marchetto, M.C., Gage, F.H. Human-specific regulation of neural maturation identified by cross-primate transcriptomics. (2022) Current Biology. DOI: 10.1016/j.cub.2022.09.028

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van den Hurk, M., Lau, S., Marchetto, M.C., Mertens, J., Stern, S., Corti, O., Brice, A., Winner, B., Winkler, J., Gage, F.H., Bardy, C. Druggable transcriptomic pathways revealed in Parkinson's patient-derived midbrain neurons. (2022) NPJ Parkinsons Dis. 8(1):134. DOI: 10.1038/s41531-022-00400-0

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Complex genetic predispositions accelerate the chronic degeneration of midbrain substantia nigra neurons in Parkinson's disease (PD). Deciphering the human molecular makeup of PD pathophysiology can guide the discovery of therapeutics to slow the disease progression. However, insights from human postmortem brain studies only portray the latter stages of PD, and there is a lack of data surrounding molecular events preceding the neuronal loss in patients. We address this gap by identifying the gene dysregulation of live midbrain neurons reprogrammed in vitro from the skin cells of 42 individuals, including sporadic and familial PD patients and matched healthy controls. To minimize bias resulting from neuronal reprogramming and RNA-seq methods, we developed an analysis pipeline integrating PD transcriptomes from different RNA-seq datasets (unsorted and sorted bulk vs. single-cell and Patch-seq) and reprogramming strategies (induced pluripotency vs. direct conversion). This PD cohort's transcriptome is enriched for human genes associated with known clinical phenotypes of PD, regulation of locomotion, bradykinesia and rigidity. Dysregulated gene expression emerges strongest in pathways underlying synaptic transmission, metabolism, intracellular trafficking, neural morphogenesis and cellular stress/immune responses. We confirmed a synaptic impairment with patch-clamping and identified pesticides and endoplasmic reticulum stressors as the most significant gene-chemical interactions in PD. Subsequently, we associated the PD transcriptomic profile with candidate pharmaceuticals in a large database and a registry of current clinical trials. This study highlights human transcriptomic pathways that can be targeted therapeutically before the irreversible neuronal loss. Furthermore, it demonstrates the preclinical relevance of unbiased large transcriptomic assays of reprogrammed patient neurons.

Pașca, S.P., Arlotta, P., Bateup, H.S., Camp, J.G., Cappello, S., Gage, F.H., Knoblich, J.A., Kriegstein, A.R., Lancaster, M.A., Ming, G.L., Muotri, A.R., Park, I.H., Reiner, O., Song, H., Studer, L., Temple, S., Testa, G., Treutlein, B., Vaccarino, F.M. A nomenclature consensus for nervous system organoids and assembloids. (2022) Naturaleza. 609(7929):907-910. DOI: 10.1038/s41586-022-05219-6

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Stern, S., Lau, S., Manole, A., Rosh, I., Percia, M.M., Ben Ezer, R., Shokhirev, M.N., Qiu, F., Schafer, S., Mansour, A.A., Mangan, K.P., Stern, T., Ofer, P., Stern, Y., Diniz Mendes, A.P., Djamus, J., Moore, L.R., Nayak, R., Laufer, S.H., Aicher, A., Rhee, A., Wong, T.L., Nguyen, T., Linker, S.B., Winner, B., Freitas, B.C., Jones, E., Sagi, I., Bardy, C., Brice, A., Winkler, J., Marchetto, M.C., Gage, F.H. Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson's disease patients. (2022) NPJ Parkinsons Dis. 8(1):103. DOI: 10.1038/s41531-022-00366-z

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Traxler, L., Herdy, J.R., Stefanoni, D., Eichhorner, S., Pelucchi, S., Szücs, A., Santagostino, A., Kim, Y., Agarwal, R.K., Schlachetzki, J.C.M., Glass, C.K., Lagerwall, J., Galasko, D., Gage, F.H., D'Alessandro, A., Mertens, J. Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease. (2022) Cell Metabolism. DOI: 10.1016/j.cmet.2022.07.014

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van Niekerk, E.A., Kawaguchi, R., Marques de Freria, C., Groeniger, K., Marchetto, M.C., Dupraz, S., Bradke, F., Geschwind, D.H., Gage, F.H., Tuszynski, M.H. Methods for culturing adult CNS neurons reveal a CNS conditioning effect. (2022) Cell Rep Methods. 2(7):100255. DOI: 10.1016/j.crmeth.2022.100255

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Bae, T., Fasching, L., Wang, Y., Shin, J.H., Suvakov, M., Jang, Y., Norton, S., Dias, C., Mariani, J., Jourdon, A., Wu, F., Panda, A., Pattni, R., Chahine, Y., Yeh, R., Roberts, R.C., Huttner, A., Kleinman, J.E., Hyde, T.M., Straub, R.E., Walsh, C.A., , Urban, A.E., Leckman, J.F., Weinberger, D.R., Vaccarino, F.M., Abyzov, A., Walsh, C.A., Park, P.J., Sestan, N., Weinberger, D., Moran, J.V., Gage, F.H., Vaccarino, F.M., Gleeson, J., Mathern, G., Courchesne, E., Roy, S., Chess, A.J., Akbarian, S., Bizzotto, S., Coulter, M., Dias, C., D'Gama, A., Ganz, J., Hill, R., Huang, A.Y., Khoshkhoo, S., Kim, S., Lee, A., Lodato, M., Maury, E.A., Miller, M., Borges-Monroy, R., Rodin, R., Zhou, Z., Bohrson, C., Chu, C., Cortes-Ciriano, I., Dou, Y., Galor, A., Gulhan, D., Kwon, M., Luquette, J., Sherman, M., Viswanadham, V., Jones, A., Rosenbluh, C., Cho, S., Langmead, B., Thorpe, J., Erwin, J., Jaffe, A., McConnell, M., Narurkar, R., Paquola, A., Shin, J., Straub, R., Abyzov, A., Bae, T., Jang, Y., Wang, Y., Molitor, C., Peters, M., Linker, S., Reed, P., Wang, M., Urban, A., Zhou, B., Zhu, X., Pattni, R., Serres Amero, A., Juan, D., Lobon, I., Marques-Bonet, T., Solis Moruno, M., Garcia Perez, R., Povolotskaya, I., Soriano, E., Antaki, D., Averbuj, D., Ball, L., Breuss, M., Yang, X., Chung, C., Emery, S.B., Flasch, D.A., Kidd, J.M., Kopera, H.C., Kwan, K.Y., Mills, R.E., Moldovan, J.B., Sun, C., Zhao, X., Zhou, W., Frisbie, T.J., Cherskov, A., Fasching, L., Jourdon, A., Pochareddy, S., Scuderi, S. Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability. (2022) Ciencia. 377(6605):511-517. DOI: 10.1126/science.abm6222

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Shi, Y., Evans, R.M., Gage, F.H. Oleic acid regulates hippocampal neurogenesis as a TLX ligand. (2022) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 119(15):e2203038119. DOI: 10.1073/pnas.2203038119

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Gage, F.H. Adult neurogenesis in neurological diseases. [Pubmed] (2021) Ciencia. 374(6571):1049-1050. DOI: 10.1126/science.abm7468

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Heard, K.J., Shokhirev, M.N., Becronis, C., Fredlender, C., Zahid, N., Le, A.T., Ji, Y., Skime, M., Nelson, T., Hall-Flavin, D., Weinshilboum, R., Gage, F.H., Vadodaria, K.C. Chronic cortisol differentially impacts stem cell-derived astrocytes from major depressive disorder patients. (2021) Transl Psychiatry. 11(1):608. DOI: 10.1038/s41398-021-01733-9

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Gorbunova, V., Seluanov, A., Mita, P., McKerrow, W., Fenyö, D., Boeke, J.D., Linker, S.B., Gage, F.H., Kreiling, J.A., Petrashen, A.P., Woodham, T.A., Taylor, J.R., Helfand, S.L., Sedivy, J.M. The role of retrotransposable elements in ageing and age-associated diseases. https://rdcu.be/ct1i3 Full-text provided by the Springer Nature SharedIt content-sharing initiative [Pubmed] (2021) Naturaleza. 596(7870):43-53. DOI: 10.1038/s41586-021-03542-y

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Shadel, G.S., Adams, P.D., Berggren, W.T., Diedrich, J.K., Diffenderfer, K.E., Gage, F.H., Hah, N., Hansen, M., Hetzer, M.W., Molina, A.J.A., Manor, U., Marek, K., O'Keefe, D.D., Pinto, A.F.M., Sacco, A., Sharpee, T.O., Shokriev, M.N., Zambetti, S. The San Diego Nathan Shock Center: tackling the heterogeneity of aging. (2021) Geroscience. DOI: 10.1007/s11357-021-00426-x

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Understanding basic mechanisms of aging holds great promise for developing interventions that prevent or delay many age-related declines and diseases simultaneously to increase human healthspan. However, a major confounding factor in aging research is the heterogeneity of the aging process itself. At the organismal level, it is clear that chronological age does not always predict biological age or susceptibility to frailty or pathology. While genetics and environment are major factors driving variable rates of aging, additional complexity arises because different organs, tissues, and cell types are intrinsically heterogeneous and exhibit different aging trajectories normally or in response to the stresses of the aging process (e.g., damage accumulation). Tackling the heterogeneity of aging requires new and specialized tools (e.g., single-cell analyses, mass spectrometry-based approaches, and advanced imaging) to identify novel signatures of aging across scales. Cutting-edge computational approaches are then needed to integrate these disparate datasets and elucidate network interactions between known aging hallmarks. There is also a need for improved, human cell-based models of aging to ensure that basic research findings are relevant to human aging and healthspan interventions. The San Diego Nathan Shock Center (SD-NSC) provides access to cutting-edge scientific resources to facilitate the study of the heterogeneity of aging in general and to promote the use of novel human cell models of aging. The center also has a robust Research Development Core that funds pilot projects on the heterogeneity of aging and organizes innovative training activities, including workshops and a personalized mentoring program, to help investigators new to the aging field succeed. Finally, the SD-NSC participates in outreach activities to educate the general community about the importance of aging research and promote the need for basic biology of aging research in particular.

Johnston, S., Parylak, S., Kim, S., Mac, N., Lim, C., Gallina, I., Bloyd, C., Newberry, A., Saavedra, C.D., Novak, O., Goncalves, J.T., Gage, F.H., Shtrahman, M. AAV ablates neurogenesis in the adult murine hippocampus. (2021) Elife. 10. DOI: 10.7554/eLife.59291

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Tan, K., Kim, M.E., Song, H.W., Skarbrevik, D., Babajanian, E., Bedrosian, T.A., Gage, F.H., Wilkinson, M.F. The Rhox gene cluster suppresses germline LINE1 transposition. (2021) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 118(23). DOI: 10.1073/pnas.2024785118

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Schafer, S.T., Gage, F.H. To eat, or not to eat, that is the question: Neural stem cells escape phagocytosis in autism with macrocephaly. (2021) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 118(19). DOI: 10.1073/pnas.2104888118

Dias, G.P., Murphy, T., Stangl, D., Ahmet, S., Morisse, B., Nix, A., Aimone, L.J., Aimone, J.B., Kuro-O, M., Gage, F.H., Thuret, S. Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho. (2021) Molecular Psychiatry. DOI: 10.1038/s41380-021-01102-4

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Reid, D.A., Reed, P.J., Schlachetzki, J.C.M., Nitulescu, I.I., Chou, G., Tsui, Chandran, S., Jones, J.R., Lu, A.T., McClain, C.A., Ooi, J.H., Wang, T.W., Lana, Linker, S.B., Ricciardulli, A.S., Lau, S., Schafer, S., Horvath, S., Dixon, J.R., Hah, N., Glass, C.K., Gage, F.H. Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons. (2021) Ciencia. 372(6537):91-94. DOI: 10.1126/science.abb9032

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Mertens, J., Herdy, J.R., Traxler, L., Schafer, S.T., Schlachetzki, J.C.M., Böhnke, L., Reid, D.A., Lee, H., Zangwill, D., Fernandes, D.P., Agarwal, R.K., Lucciola, R., Zhou-Yang, L., Karbacher, L., Edenhofer, F., Stern, S., Horvath, S., Paquola, A.C.M., Glass, C.K., Yuan, S.H., Ku, M., Szücs, A., Goldstein, L.S.B., Galasko, D., Gage, F.H. Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients. (2021) Cell Stem Cell. DOI: 10.1016/j.stem.2021.04.004

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Schafer, S.T., Gage, F.H. The When and Where: Molecular and Cellular Convergence in Autism. (2021) Biological Psychiatry. 89(5):419-420. DOI: 10.1016/j.biopsych.2020.12.016

Mishra, H.K., Ying, N.M., Luis, A., Wei, H., Nguyen, M., Nakhla, T., Vandenburgh, S., Alda, M., Berrettini, W.H., Brennand, K.J., Calabrese, J.R., Coryell, W.H., Frye, M.A., Gage, F.H., Gershon, E.S., McInnis, M.G., Nievergelt, C.M., Nurnberger, J.I., Shilling, P.D., Oedegaard, K.J., Zandi, P.P., , Kelsoe, J.R., Welsh, D.K., McCarthy, M.J. Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies. (2021) Molecular Psychiatry. DOI: 10.1038/s41380-021-01048-7

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Nakatsuka, N., Heard, K.J., Faillétaz, A., Momotenko, D., Vörös, J., Gage, F.H., Vadodaria, K.C. Sensing serotonin secreted from human serotonergic neurons using aptamer-modified nanopipettes. (2021) Molecular Psychiatry. DOI: 10.1038/s41380-021-01066-5

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Bedrosian, T.A., Houtman, J., Eguiguren, J.S., Ghassemzadeh, S., Rund, N., Novaresi, N.M., Hu, L., Parylak, S.L., Denli, A.M., Randolph-Moore, L., Namba, T., Gage, F.H., Toda, T. Lamin B1 decline underlies age-related loss of adult hippocampal neurogenesis. (2021) EMBO Journal. 40(3):e105819. DOI: 10.15252/embj.2020105819

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Fukuda, S., Varshney, A., Fowler, B.J., Wang, S.B., Narendran, S., Ambati, K., Yasuma, T., Magagnoli, J., Leung, H., Hirahara, S., Nagasaka, Y., Yasuma, R., Apicella, I., Pereira, F., Makin, R.D., Magner, E., Liu, X., Sun, J., Wang, M., Baker, K., Marion, K.M., Huang, X., Baghdasaryan, E., Ambati, M., Ambati, V.L., Pandey, A., Pandya, L., Cummings, T., Banerjee, D., Huang, P., Yerramothu, P., Tolstonog, G.V., Held, U., Erwin, J.A., Paquola, A.C.M., Herdy, J.R., Ogura, Y., Terasaki, H., Oshika, T., Darwish, S., Singh, R.K., Mozaffari, S., Bhattarai, D., Kim, K.B., Hardin, J.W., Bennett, C.L., Hinton, D.R., Hanson, T.E., Röver, C., Parang, K., Kerur, N., Liu, J., Werner, B.C., Sutton, S.S., Sadda, S.R., Schumann, G.G., Gelfand, B.D., Gage, F.H., Ambati, J. Cytoplasmic synthesis of endogenous complementary DNA via reverse transcription and implications in age-related macular degeneration. (2021) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 118(6). DOI: 10.1073/pnas.2022751118

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Vadodaria, K.C., Mendes, A.P.D., Mei, A., Racha, V., Erikson, G., Shokhirev, M.N., Oefner, R., Heard, K.J., McCarthy, M.J., Eyler, L., Kelsoe, J.R., Santos, R., Marchetto, M.C., Gage, F.H. Altered Neuronal Support and Inflammatory Response in Bipolar Disorder Patient-Derived Astrocytes. (2021) Stem Cell Reports. DOI: 10.1016/j.stemcr.2021.02.004

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Santos, R., Linker, S.B., Stern, S., Mendes, A.P.D., Shokhirev, M.N., Erikson, G., Randolph-Moore, L., Racha, V., Kim, Y., Kelsoe, J.R., Bang, A.G., Alda, M., Marchetto, M.C., Gage, F.H. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. (2021) Molecular Psychiatry. DOI: 10.1038/s41380-020-00981-3

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Wang, Q.W., Lu, S.Y., Liu, Y.N., Chen, Y., Wei, H., Shen, W., Chen, Y.F., Fu, C.L., Wang, Y.H., Dai, A., Huang, X., Gage, F.H., Xu, Q., Yao, J. Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity. (2020) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. DOI: 10.1073/pnas.2016416117

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Linker, S.B., Randolph-Moore, L., Kottilil, K., Qiu, F., Jaeger, B.N., Barron, J., Gage, F.H. Identification of bona fide B2 SINE retrotransposon transcription through single-nucleus RNA-seq of the mouse hippocampus. (2020) Genome Research. DOI: 10.1101/gr.262196.120

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Figueiredo, T., Mendes, A.P.D., Moreira, D.P., Goulart, E., Oliveira, D., Kobayashi, G.S., Stern, S., Kok, F., Marchetto, M.C., Santos, R., Gage, F.H., Zatz, M. Inositol monophosphatase 1 (IMPA1) mutation in intellectual disability patients impairs neurogenesis but not gliogenesis. (2020) Molecular Psychiatry. DOI: 10.1038/s41380-020-00862-9

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Kerman, B.E., Genoud, S., Kurt Vatandaslar, B., Denli, A.M., Ghosh, S.G., Xu, X., Yeo, G.W., Aimone, J.B., Gage, F.H. Motoneuron expression profiling identifies an association between an axonal splice variant of HDGF-related protein 3 and peripheral myelination. (2020) Revista de Química Biológica. DOI: 10.1074/jbc.RA120.014329

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Mansour, A.A., Schafer, S.T., Gage, F.H. Cellular complexity in brain organoids: Current progress and unsolved issues. (2020) Seminars in Cell & Developmental Biology. DOI: 10.1016/j.semcdb.2020.05.013

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Wenderski, W., Wang, L., Krokhotin, A., Walsh, J.J., Li, H., Shoji, H., Ghosh, S., George, R.D., Miller, E.L., Elias, L., Gillespie, M.A., Son, E.Y., Staahl, B.T., Baek, S.T., Stanley, V., Moncada, C., Shipony, Z., Linker, S.B., Marchetto, M.C.N., Gage, F.H., Chen, D., Sultan, T., Zaki, M.S., Ranish, J.A., Miyakawa, T., Luo, L., Malenka, R.C., Crabtree, G.R., Gleeson, J.G. Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism. (2020) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. DOI: 10.1073/pnas.1908238117

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Sun, G., Chiuppesi, F., Chen, X., Wang, C., Tian, E., Nguyen, J., Kha, M., Trinh, D., Zhang, H., Marchetto, M.C., Song, H., Ming, G.L., Gage, F.H., Diamond, D.J., Wussow, F., Shi, Y. Modeling Human Cytomegalovirus-Induced Microcephaly in Human iPSC-Derived Brain Organoids. (2020) Cell Reports Medicine. 1(1):100002. DOI: 10.1016/j.xcrm.2020.100002

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Shen, W., Wang, Q.W., Liu, Y.N., Marchetto, M.C., Linker, S., Lu, S.Y., Chen, Y., Liu, C., Guo, C., Xing, Z., Shi, W., Kelsoe, J.R., Alda, M., Wang, H., Zhong, Y., Sui, S.F., Zhao, M., Yang, Y., Mi, S., Cao, L., Gage, F.H., Yao, J. Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice. (2020) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. DOI: 10.1073/pnas.1918165117

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Stern, S., Sarkar, A., Galor, D., Stern, T., Mei, A., Stern, Y., Mendes, A.P.D., Randolph-Moore, L., Rouleau, G., Bang, A.G., Santos, R., Alda, M., Marchetto, M.C., Gage, F.H. A Physiological Instability Displayed in Hippocampal Neurons Derived From Lithium-Nonresponsive Bipolar Disorder Patients. (2020) Biological Psychiatry. DOI: 10.1016/j.biopsych.2020.01.020

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Wang, M., Wei, P.C., Lim, C.K., Gallina, I.S., Marshall, S., Marchetto, M.C., Alt, F.W., Gage, F.H. Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability. (2020) Cell Stem Cell. 26(2):221-233.e6 . DOI: 10.1016/j.stem.2019.12.013

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Zhu, Z., Mesci, P., Bernatchez, J.A., Gimple, R.C., Wang, X., Schafer, S.T., Wettersten, H.I., Beck, S., Clark, A.E., Wu, Q., Prager, B.C., Kim, L.J.Y., Dhanwani, R., Sharma, S., Garancher, A., Weis, S.M., Mack, S.C., Negraes, P.D., Trujillo, C.A., Penalva, L.O., Feng, J., Lan, Z., Zhang, R., Wessel, A.W., Dhawan, S., Diamond, M.S., Chen, C.C., Wechsler-Reya, R.J., Gage, F.H., Hu, H., Siqueira-Neto, J.L., Muotri, A.R., Cheresh, D.A., Rich, J.N. Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αβ Axis. (2019) Cell Stem Cell. 26(2):187-204. DOI: 10.1016/j.stem.2019.11.016

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Nott, A., Holtman, I.R., Coufal, N.G., Schlachetzki, J.C.M., Yu, M., Hu, R., Han, C.Z., Pena, M., Xiao, J., Wu, Y., Keulen, Z., Pasillas, M.P., O'Connor, C., Nickl, C.K., Schafer, S.T., Shen, Z., Rissman, R.A., Brewer, J.B., Gosselin, D., Gonda, D.D., Levy, M.L., Rosenfeld, M.G., McVicker, G., Gage, F.H., Ren, B., Glass, C.K. Brain cell type-specific enhancer-promoter interactome maps and disease risk association. (2019) Ciencia. 366(6469):1134-1139. DOI: 10.1126/science.aay0793

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Vadodaria, K.C., Jones, J.R., Linker, S., Gage, F.H. Modeling Brain Disorders Using Induced Pluripotent Stem Cells. (2019) Cold Spring Harbor Perspectives in Biology. DOI: 10.1101/cshperspect.a035659

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Stern, S., Sarkar, A., Stern, T., Mei, A., Mendes, A.P.D., Stern, Y., Goldberg, G., Galor, D., Nguyen, T., Randolph-Moore, L., Kim, Y., Rouleau, G., Bang, A., Alda, M., Santos, R., Marchetto, M.C., Gage, F.H. Mechanisms Underlying the Hyperexcitability of CA3 and Dentate Gyrus Hippocampal Neurons Derived From Patients With Bipolar Disorder. (2019) Biological Psychiatry. DOI: 10.1016/j.biopsych.2019.09.018

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Amatya, D.N., Linker, S.B., Mendes, A.P.D., Santos, R., Erikson, G., Shokhirev, M.N., Zhou, Y., Sharpee, T., Gage, F.H., Marchetto, M.C., Kim, Y. Dynamical Electrical Complexity Is Reduced during Neuronal Differentiation in Autism Spectrum Disorder. (2019) Stem Cell Reports. DOI: 10.1016/j.stemcr.2019.08.001

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Quraishi, I.H., Stern, S., Mangan, K.P., Zhang, Y., Ali, S.R., Mercier, M.R., Marchetto, M.C., McLachlan, M.J., Jones, E.M., Gage, F.H., Kaczmarek, L.K. An epilepsy-associated KCNT1 mutation enhances excitability of human iPSC-derived neurons by increasing Slack K currents. (2019) Journal of Neuroscience. DOI: 10.1523/JNEUROSCI.1628-18.2019

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Mutations in the KCNT1 (Slack, K1.1) sodium-activated potassium channel produce severe epileptic encephalopathies. Expression in heterologous systems has shown that the disease-causing mutations give rise to channels that have increased current amplitude. It is not known, however, whether such gain of function occurs in human neurons, nor whether such increased K current is expected to suppress or increase the excitability of cortical neurons. Using genetically-engineered human iPSC-derived neurons, we have now found that sodium-dependent potassium currents are increased several-fold in neurons bearing a homozygous P924L mutation. In current clamp recordings, the increased K current in neurons with the P924L mutation acts to shorten the duration of action potentials and to increase the amplitude of the afterhyperpolarization that follows each action potential. Strikingly, the number of action potentials that were evoked by depolarizing currents as well as maximal firing rates were increased in neurons expressing the mutant channel. In networks of spontaneously active neurons, the mean firing rate, the occurrence of rapid bursts of action potentials, and the intensity of firing during the burst were all increased in neurons with the P924L Slack mutation. The feasibility of an increased K current to increase firing rates independent of any compensatory changes was validated by numerical simulations. Our findings indicate that gain-of-function in Slack K channels causes hyperexcitability in both isolated neurons and in neural networks and occurs by a cell-autonomous mechanism that does not require network interactions.KCNT1 mutations lead to severe epileptic encephalopathies for which there are no effective treatments. This study is the first demonstration that a KCNT1 mutation increases the Slack current in neurons. It also provides the first explanation for how this increased potassium current induces hyperexcitability, which could be the underlining factor causing seizures.

Stern, S., Linker, S., Vadodaria, K.C., Marchetto, M.C., Gage, F.H. Prediction of Response to Drug Therapy in Psychiatric Disorders. (2019) Focus (American Psychiatric Publishing). 17(3):294-307. DOI: 10.1176/appi.focus.17304

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Vadodaria, K.C., Ji, Y., Skime, M., Paquola, A., Nelson, T., Hall-Flavin, D., Fredlender, C., Heard, K.J., Deng, Y., Le, A.T., Dave, S., Fung, L., Li, X., Marchetto, M.C., Weinshilboum, R., Gage, F.H. Studying treatment resistance in depression using patient derived neurons in vitro. (2019) Molecular Psychiatry. 24(6):775. DOI: 10.1038/s41380-019-0424-2

Sommer, A., Marxreiter, F., Krach, F., Fadler, T., Grosch, J., Maroni, M., Graef, D., Eberhardt, E., Riemenschneider, M.J., Yeo, G.W., Kohl, Z., Xiang, W., Gage, F.H., Winkler, J., Prots, I., Winner, B. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease. (2019) Cell Stem Cell. 24(6):1006. DOI: 10.1016/j.stem.2019.04.019

Herdy, J., Schafer, S., Kim, Y., Ansari, Z., Zangwill, D., Ku, M., Paquola, A., Lee, H., Mertens, J., Gage, F.H. Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons. (2019) Elife. 8. DOI: 10.7554/eLife.41356

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Wang, M., Zhang, L., Gage, F.H. Modeling neuropsychiatric disorders using human induced pluripotent stem cells. (2019) Protein & Cell. 11(1):45-59. DOI: 10.1007/s13238-019-0638-8

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Schafer, S.T., Gage, F.H. Nerve cells from the brain invade prostate tumours. (2019) Naturaleza. 569(7758):637-638. DOI: 10.1038/d41586-019-01461-7

Gage, F.H. Adult neurogenesis in mammals. (2019) Ciencia. 364(6443):827-828. DOI: 10.1126/science.aav6885

Nudell, V., Wei, H., Nievergelt, C., Maihofer, A.X., Shilling, P., Alda, M., Berrettini, W.H., Brennand, K.J., Calabrese, J.R., Coryell, W.H., Covault, J.M., Frye, M.A., Gage, F., Gershon, E., McInnis, M.G., Nurnberger, J.I., Oedegaard, K.J., Shekhtman, T., Zandi, P.P., Kelsoe, J.R., McCarthy, M.J. Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels. (2019) Molecular Neuropsychiatry. 5(2):115-124. DOI: 10.1159/000497354

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Wang, M., Zhang, L., Gage, F.H. Microglia, complement and schizophrenia. (2019) Nature Neuroscience. 22(3):333-334. DOI: 10.1038/s41593-019-0343-1

Farrelly, L.A., Thompson, R.E., Zhao, S., Lepack, A.E., Lyu, Y., Bhanu, N.V., Zhang, B., Loh, Y.E., Ramakrishnan, A., Vadodaria, K.C., Heard, K.J., Erikson, G., Nakadai, T., Bastle, R.M., Lukasak, B.J., Zebroski, H., Alenina, N., Bader, M., Berton, O., Roeder, R.G., Molina, H., Gage, F.H., Shen, L., Garcia, B.A., Li, H., Muir, T.W., Maze, I. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. (2019) Naturaleza. DOI: 10.1038/s41586-019-1024-7

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Vadodaria, K.C., Ji, Y., Skime, M., Paquola, A.C., Nelson, T., Hall-Flavin, D., Heard, K.J., Fredlender, C., Deng, Y., Elkins, J., Dani, K., Le, A.T., Marchetto, M.C., Weinshilboum, R., Gage, F.H. Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons. (2019) Molecular Psychiatry. DOI: 10.1038/s41380-019-0377-5

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Lucassen, P.J., Toni, N., Kempermann, G., Frisen, J., Gage, F.H., Swaab, D.F. Limits to human neurogenesis-really? (2019) Molecular Psychiatry. DOI: 10.1038/s41380-018-0337-5

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Schafer, S.T., Paquola, A.C.M., Stern, S., Gosselin, D., Ku, M., Pena, M., Kuret, T.J.M., Liyanage, M., Mansour, A.A., Jaeger, B.N., Marchetto, M.C., Glass, C.K., Mertens, J., Gage, F.H. Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons. (2019) Nature Neuroscience. DOI: 10.1038/s41593-018-0295-x

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Eftekharzadeh, B., Daigle, J.G., Kapinos, L.E., Coyne, A., Schiantarelli, J., Carlomagno, Y., Cook, C., Miller, S.J., Dujardin, S., Amaral, A.S., Grima, J.C., Bennett, R.E., Tepper, K., DeTure, M., Vanderburg, C.R., Corjuc, B.T., DeVos, S.L., Gonzalez, J.A., Chew, J., Vidensky, S., Gage, F.H., Mertens, J., Troncoso, J., Mandelkow, E., Salvatella, X., Lim, R.Y.H., Petrucelli, L., Wegmann, S., Rothstein, J.D., Hyman, B.T. Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. (2019) Neuron. 101(2):349. DOI: 10.1016/j.neuron.2018.12.031

Padmanabhan, K., Osakada, F., Tarabrina, A., Kizer, E., Callaway, E.M., Gage, F.H., Sejnowski, T.J. Centrifugal Inputs to the Main Olfactory Bulb Revealed Through Whole Brain Circuit-Mapping. (2019) Frontiers in Neuroanatomy. 12:115. DOI: 10.3389/fnana.2018.00115

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Vadodaria, K.C., Ji, Y., Skime, M., Paquola, A., Nelson, T., Hall-Flavin, D., Fredlender, C., Heard, K.J., Deng, Y., Le, A.T., Dave, S., Fung, L., Li, X., Marchetto, M.C., Weinshilboum, R., Gage, F.H. Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. (2019) Molecular Psychiatry. DOI: 10.1038/s41380-019-0363-y

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Kim, Y., Vadodaria, K.C., Lenkei, Z., Kato, T., Gage, F.H., Marchetto, M.C., Santos, R. MITOCHONDRIA, METABOLISM AND REDOX MECHANISMS IN PSYCHIATRIC DISORDERS. (2018) Antioxidants & Redox Signaling. DOI: 10.1089/ars.2018.7606

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McCarthy, M.J., Wei, H., Nievergelt, C.M., Stautland, A., Maihofer, A.X., Welsh, D.K., Shilling, P., Alda, M., Alliey-Rodriguez, N., Anand, A., Andreasson, O.A., Balaraman, Y., Berrettini, W.H., Bertram, H., Brennand, K.J., Calabrese, J.R., Calkin, C.V., Claasen, A., Conroy, C., Coryell, W.H., Craig, D.W., D'Arcangelo, N., Demodena, A., Djurovic, S., Feeder, S., Fisher, C., Frazier, N., Frye, M.A., Gage, F.H., Gao, K., Garnham, J., Gershon, E.S., Glazer, K., Goes, F., Goto, T., Harrington, G., Jakobsen, P., Kamali, M., Karberg, E., Kelly, M., Leckband, S.G., Lohoff, F., McInnis, M.G., Mondimore, F., Morken, G., Nurnberger, J.I., Obral, S., Oedegaard, K.J., Ortiz, A., Ritchey, M., Ryan, K., Schinagle, M., Schoeyen, H., Schwebel, C., Shaw, M., Shekhtman, T., Slaney, C., Stapp, E., Szelinger, S., Tarwater, B., Zandi, P.P., Kelsoe, J.R. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder. (2018) Neuropsychopharmacology . DOI: 10.1038/s41386-018-0273-8

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Suh, H., Zhou, Q.G., Fernandez-Carasa, I., Clemenson, G.D., Pons-Espinal, M., Ro, E.J., Marti, M., Raya, A., Gage, F.H., Consiglio, A. Long-Term Labeling of Hippocampal Neural Stem Cells by a Lentiviral Vector. (2018) Frontiers in Molecular Neuroscience. 11:415. DOI: 10.3389/fnmol.2018.00415

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Kuhn, H.G., Toda, T., Gage, F.H. Adult hippocampal neurogenesis: a coming-of-age story. (2018) Journal of Neuroscience. DOI: 10.1523/JNEUROSCI.2144-18.2018

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Eftekharzadeh, B., Daigle, J.G., Kapinos, L.E., Coyne, A., Schiantarelli, J., Carlomagno, Y., Cook, C., Miller, S.J., Dujardin, S., Amaral, A.S., Grima, J.C., Bennett, R.E., Tepper, K., DeTure, M., Vanderburgh, C.R., Corjuc, B.T., DeVos, S.L., Gonzalez, J.A., Chew, J., Vidensky, S., Gage, F.H., Mertens, J., Troncoso, J., Mandelkow, E., Salvatella, X., Lim, R.Y.H., Petrucelli, L., Wegmann, S., Rothstein, J.D., Hyman, B.T. Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. (2018) Neuron. 99(5):925-940.e7. DOI: 10.1016/j.neuron.2018.07.039

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Choi, S.H., Bylykbashi, E., Chatila, Z.K., Lee, S.W., Pulli, B., Clemenson, G.D., Kim, E., Rompala, A., Oram, M.K., Asselin, C., Aronson, J., Zhang, C., Miller, S.J., Lesinski, A., Chen, J.W., Kim, D.Y., van Praag, H., Spiegelman, B.M., Gage, F.H., Tanzi, R.E. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model. (2018) Ciencia. 361(6406). DOI: 10.1126/science.aan8821

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Mertens, J., Reid, D., Lau, S., Kim, Y., Gage, F.H. Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases. (2018) Annual Review of Genetics. 52:271-293. DOI: 10.1146/annurev-genet-120417-031534

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Jaeger, B.N., Linker, S.B., Parylak, S.L., Barron, J.J., Gallina, I.S., Saavedra, C.D., Fitzpatrick, C., Lim, C.K., Schafer, S.T., Lacar, B., Jessberger, S., Gage, F.H. A novel environment-evoked transcriptional signature predicts reactivity in single dentate granule neurons. (2018) Nature Communications. 9(1):3084. DOI: 10.1038/s41467-018-05418-8

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van den Hurk, M., Erwin, J.A., Yeo, G.W., Gage, F.H., Bardy, C. Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells. (2018) Frontiers in Molecular Neuroscience. 11:261. DOI: 10.3389/fnmol.2018.00261

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Sommer, A., Maxreiter, F., Krach, F., Fadler, T., Grosch, J., Maroni, M., Graef, D., Eberhardt, E., Riemenschneider, M.J., Yeo, G.W., Kohl, Z., Xiang, W., Gage, F.H., Winkler, J., Prots, I., Winner, B. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease. (2018) Cell Stem Cell. 23(1):123-131.e6. DOI: 10.1016/j.stem.2018.06.015

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Linker, S.B., Hsu, J.Y., Pfaff, A., Amatya, D., Ko, S.M., Voter, S., Wong, Q., Gage, F.H. BrainImageR: Spatiotemporal gene set analysis referencing the human brain. (2018) Bioinformatics. DOI: 10.1093/bioinformatics/bty618

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Kronenberg, Z.N., Fiddes, I.T., Gordon, D., Murali, S., Cantsilieris, S., Meyerson, O.S., Underwood, J.G., Nelson, B.J., Chaisson, M.J.P., Dougherty, M.L., Munson, K.M., Hastie, A.R., Diekhans, M., Hormozdiari, F., Lorusso, N., Hoekzema, K., Qiu, R., Clark, K., Raja, A., Welch, A.E., Sorensen, M., Baker, C., Fulton, R.S., Armstrong, J., Graves-Lindsay, T.A., Denli, A.M., Hoppe, E.R., Hsieh, P., Hill, C.M., Pang, A.W.C., Lee, J., Lam, E.T., Dutcher, S.K., Gage, F.H., Warren, W.C., Shendure, J., Haussler, D., Schneider, V.A., Cao, H., Ventura, M., Wilson, R.K., Paten, B., Pollen, A., Eichler, E.E. High-resolution comparative analysis of great ape genomes. (2018) Ciencia. 360(6393). DOI: 10.1126/science.aar6343

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Sarkar, A., Mei, A., Paquola, A.C.M., Stern, S., Bardy, C., Klug, J.R., Kim, S., Neshat, N., Kim, H.J., Ku, M., Shokhirev, M.N., Adamowicz, D.H., Marchetto, M.C., Jappelli, R., Erwin, J.A., Padmanabhan, K., Shtrahman, M., Jin, X., Gage, F.H. Efficient Generation of CA3 Neurons from Human Pluripotent Stem Cells Enables Modeling of Hippocampal Connectivity In Vitro. (2018) Cell Stem Cell. 22(5):684-697.e9. DOI: 10.1016/j.stem.2018.04.009

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Strnadel, J., Carromeu, C., Bardy, C., Navarro, M., Platoshyn, O., Glud, A.N., Marsala, S., Kafka, J., Miyanohara, A., Kato, T., Tadokoro, T., Hefferan, M.P., Kamizato, K., Yoshizumi, T., Juhas, S., Juhasova, J., Ho, C.S., Kheradmand, T., Chen, P., Bohaciakova, D., Hruska-Plochan, M., Todd, A.J., Driscoll, S.P., Glenn, T.D., Pfaff, S.L., Klima, J., Ciacci, J., Curtis, E., Gage, F.H., Bui, J., Yamada, K., Muotri, A.R., Marsala, M. Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs. (2018) Science Translational Medicine. 10(440). DOI: 10.1126/scitranslmed.aam6651

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Stern, S., Linker, S., Vadodaria, K.C., Marchetto, M.C., Gage, F.H. Prediction of response to drug therapy in psychiatric disorders. (2018) Open Biology. 8(5). DOI: 10.1098/rsob.180031

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Personalized medicine has become increasingly relevant to many medical fields, promising more efficient drug therapies and earlier intervention. The development of personalized medicine is coupled with the identification of biomarkers and classification algorithms that help predict the responses of different patients to different drugs. In the last 10 years, the Food and Drug Administration (FDA) has approved several genetically pre-screened drugs labelled as pharmacogenomics in the fields of oncology, pulmonary medicine, gastroenterology, haematology, neurology, rheumatology and even psychiatry. Clinicians have long cautioned that what may appear to be similar patient-reported symptoms may actually arise from different biological causes. With growing populations being diagnosed with different psychiatric conditions, it is critical for scientists and clinicians to develop precision medication tailored to individual conditions. Genome-wide association studies have highlighted the complicated nature of psychiatric disorders such as schizophrenia, bipolar disorder, major depression and autism spectrum disorder. Following these studies, association studies are needed to look for genomic markers of responsiveness to available drugs of individual patients within the population of a specific disorder. In addition to GWAS, the advent of new technologies such as brain imaging, cell reprogramming, sequencing and gene editing has given us the opportunity to look for more biomarkers that characterize a therapeutic response to a drug and to use all these biomarkers for determining treatment options. In this review, we discuss studies that were performed to find biomarkers of responsiveness to different available drugs for four brain disorders: bipolar disorder, schizophrenia, major depression and autism spectrum disorder. We provide recommendations for using an integrated method that will use available techniques for a better prediction of the most suitable drug.

Kim, Y., Zheng, X., Ansari, Z., Bunnell, M.C., Herdy, J.R., Traxler, L., Lee, H., Paquola, A.C.M., Blithikioti, C., Ku, M., Schlachetzki, J.C.M., Winkler, J., Edenhofer, F., Glass, C.K., Paucar, A.A., Jaeger, B.N., Pham, S., Boyer, L., Campbell, B.C., Hunter, T., Mertens, J., Gage, F.H. Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile. (2018) Cell Reports. 23(9):2550-2558. DOI: 10.1016/j.celrep.2018.04.105

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Mansour, A.A., Gonçalves, J.T., Bloyd, C.W., Li, H., Fernandes, S., Quang, D., Johnston, S., Parylak, S.L., Jin, X., Gage, F.H. An in vivo model of functional and vascularized human brain organoids. (2018) Nature Biotechnology. DOI: 10.1038/nbt.4127

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Toda, T., Parylak, S.L., Linker, S.B., Gage, F.H. The role of adult hippocampal neurogenesis in brain health and disease. (2018) Molecular Psychiatry. DOI: 10.1038/s41380-018-0036-2

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Kempermann, G., Gage, F.H., Aigner, L., Song, H., Curtis, M.A., Thuret, S., Kuhn, H.G., Jessberger, S., Frankland, P.W., Cameron, H.A., Gould, E., Hen, R., Abrous, D.N., Toni, N., Schinder, A.F., Zhao, X., Lucassen, P.J., Frisén, J. Human Adult Neurogenesis: Evidence and Remaining Questions. (2018) Cell Stem Cell. DOI: 10.1016/j.stem.2018.04.004

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Bedrosian, T.A., Quayle, C., Novaresi, N., Gage, F.H. Early life experience drives structural variation of neural genomes in mice. (2018) Ciencia. 359(6382):1395-1399. DOI: 10.1126/science.aah3378

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Zheng, Y., Shen, W., Zhang, J., Yang, B., Liu, Y.N., Qi, H., Yu, X., Lu, S.Y., Chen, Y., Xu, Y.Z., Li, Y., Gage, F.H., Mi, S., Yao, J. CRISPR interference-based specific and efficient gene inactivation in the brain. (2018) Nature Neuroscience. DOI: 10.1038/s41593-018-0077-5

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Vadodaria, K.C., Amatya, D.N., Marchetto, M.C., Gage, F.H. Modeling psychiatric disorders using patient stem cell-derived neurons: a way forward. (2018) Genome Medicine. 10(1):1. DOI: 10.1186/s13073-017-0512-3

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Jaeger, B.N., Parylak, S.L., Gage, F.H. Mechanisms of dietary flavonoid action in neuronal function and neuroinflammation. (2017) Molecular Aspects of Medicine. DOI: 10.1016/j.mam.2017.11.003

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Toda, T., Gage, F.H. Review: adult neurogenesis contributes to hippocampal plasticity. (2017) Cell and Tissue Research. DOI: 10.1007/s00441-017-2735-4

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Snijders, C., de Nijs, L., Baker, D.G., Hauger, R.L., van den Hove, D., Kenis, G., Nievergelt, C.M., Boks, M.P., Vermetten, E., Gage, F.H., Rutten, B.P.F. MicroRNAs in Post-traumatic Stress Disorder. (2017) Current Topics in Behavioral Neurosciences. DOI: 10.1007/7854_2017_32

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Topol, A., Zhu, S., Hartley, B.J., English, J., Hauberg, M.E., Tran, N., Rittenhouse, C.A., Simone, A., Ruderfer, D.M., Johnson, J., Readhead, B., Hadas, Y., Gochman, P.A., Wang, Y.C., Shah, H., Cagney, G., Rapoport, J., Gage, F.H., Dudley, J.T., Sklar, P., Mattheisen, M., Cotter, D., Fang, G., Brennand, K.J. Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. (2017) Cell Reports. 20(10):2525. DOI: 10.1016/j.celrep.2017.08.073

Toda, T., Hsu, J.Y., Linker, S.B., Hu, L., Schafer, S.T., Mertens, J., Jacinto, F.V., Hetzer, M.W., Gage, F.H. Nup153 Interacts with Sox2 to Enable Bimodal Gene Regulation and Maintenance of Neural Progenitor Cells. (2017) Cell Stem Cell. 21:618–634. DOI: 10.1016/j.stem.2017.08.012

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Shahsavani, M., Pronk, R.J., Falk, R., Lam, M., Moslem, M., Linker, S.B., Salma, J., Day, K., Schuster, J., Anderlid, B.M., Dahl, N., Gage, F.H., Falk, A. An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis. (2017) Molecular Psychiatry. DOI: 10.1038/mp.2017.175

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Vadodaria, K.C., Stern, S., Marchetto, M.C., Gage, F.H. Serotonin in psychiatry: in vitro disease modeling using patient-derived neurons. (2017) Cell and Tissue Research. DOI: 10.1007/s00441-017-2670-4

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Linker, S.B., Marchetto, M.C., Narvaiza, I., Denli, A.M., Gage, F.H. Examining non-LTR retrotransposons in the context of the evolving primate brain. (2017) BMC Biology. 15(1):68. DOI: 10.1186/s12915-017-0409-z

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Newkirk, S.J., Lee, S., Grandi, F.C., Gaysinskaya, V., Rosser, J.M., Vanden Berg, N., Hogarth, C.A., Marchetto, M.C.N., Muotri, A.R., Griswold, M.D., Ye, P., Bortvin, A., Gage, F.H., Boeke, J.D., An, W. Intact piRNA pathway prevents L1 mobilization in male meiosis. (2017) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 114(28):E5635-E5644. DOI: 10.1073/pnas.1701069114

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Santos, R., Vadodaria, K.C., Jaeger, B.N., Mei, A., Lefcochilos-Fogelquist, S., Mendes, A.P.D., Erikson, G., Shokhirev, M., Randolph-Moore, L., Fredlender, C., Dave, S., Oefner, R., Fitzpatrick, C., Pena, M., Barron, J.J., Ku, M., Denli, A.M., Kerman, B.E., Charnay, P., Kelsoe, J.R., Marchetto, M.C., Gage, F.H. Differentiation of Inflammation-Responsive Astrocytes from Glial Progenitors Generated from Human Induced Pluripotent Stem Cells. (2017) Stem Cell Reports. 8(6):1757-1769. DOI: 10.1016/j.stemcr.2017.05.011

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Gosselin, D., Skola, D., Coufal, N.G., Holtman, I.R., Schlachetzki, J.C.M., Sajti, E., Jaeger, B.N., O'Connor, C., Fitzpatrick, C., Pasillas, M.P., Pena, M., Adair, A., Gonda, D.D., Levy, M.L., Ransohoff, R.M., Gage, F.H., Glass, C.K. An environment-dependent transcriptional network specifies human microglia identity. (2017) Ciencia. 356(6344). DOI: 10.1126/science.aal3222

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Marchetto, M.C., Belinson, H., Tian, Y., Freitas, B.C., Fu, C., Vadodaria, K., Beltrao-Braga, P., Trujillo, C.A., Mendes, A.P.D., Padmanabhan, K., Nunez, Y., Ou, J., Ghosh, H., Wright, R., Brennand, K., Pierce, K., Eichenfield, L., Pramparo, T., Eyler, L., Barnes, C.C., Courchesne, E., Geschwind, D.H., Gage, F.H., Wynshaw-Boris, A., Muotri, A.R. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. (2017) Molecular Psychiatry. 22(6):820-835. DOI: 10.1038/mp.2016.95

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Ishii, S., Torii, M., Son, A.I., Rajendraprasad, M., Morozov, Y.M., Kawasawa, Y.I., Salzberg, A.C., Fujimoto, M., Brennand, K., Nakai, A., Mezger, V., Gage, F.H., Rakic, P., Hashimoto-Torii, K. Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling. (2017) Nature Communications. 8:15157. DOI: 10.1038/ncomms15157

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McConnell, M.J., Moran, J.V., Abyzov, A., Akbarian, S., Bae, T., Cortes-Ciriano, I., Erwin, J.A., Fasching, L., Flasch, D.A., Freed, D., Ganz, J., Jaffe, A.E., Kwan, K.Y., Kwon, M., Lodato, M.A., Mills, R.E., Paquola, A.C.M., Rodin, R.E., Rosenbluh, C., Sestan, N., Sherman, M.A., Shin, J.H., Song, S., Straub, R.E., Thorpe, J., Weinberger, D.R., Urban, A.E., Zhou, B., Gage, F.H., Lehner, T., Senthil, G., Walsh, C.A., Chess, A., Courchesne, E., Gleeson, J.G., Kidd, J.M., Park, P.J., Pevsner, J., Vaccarino, F.M. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. (2017) Ciencia. 356(6336). DOI: 10.1126/science.aal1641

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Kim, Y., Santos, R., Gage, F.H., Marchetto, M.C. Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges. (2017) Frontiers in Cellular Neuroscience. 11:30. DOI: 10.3389/fncel.2017.00030

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Ramsay, L., Marchetto, M.C., Caron, M., Chen, S.H., Busche, S., Kwan, T., Pastinen, T., Gage, F.H., Bourque, G. Conserved expression of transposon-derived non-coding transcripts in primate stem cells. (2017) BMC Genomics. 18(1):214. DOI: 10.1186/s12864-017-3568-y

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Stern, S., Santos, R., Marchetto, M.C., Mendes, A.P., Rouleau, G.A., Biesmans, S., Wang, Q.W., Yao, J., Charnay, P., Bang, A.G., Alda, M., Gage, F.H. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. (2017) Molecular Psychiatry. DOI: 10.1038/mp.2016.260

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Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.Molecular Psychiatry advance online publication, 28 February 2017; doi:10.1038/mp.2016.260.

Adamowicz, D.H., Roy, S., Salmon, D.P., Galasko, D.R., Hansen, L.A., Masliah, E., Gage, F.H. Hippocampal α-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology. (2017) Journal of Neuroscience. 37(7):1675-1684. DOI: 10.1523/JNEUROSCI.3047-16.2016

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Despite considerable research to uncover them, the anatomic and neuropathologic correlates of memory impairment in dementia with Lewy bodies (DLB) remain unclear. While some studies have implicated Lewy bodies in the neocortex, others have pointed to α-synuclein pathology in the hippocampus. We systematically examined hippocampal Lewy pathology and its distribution in hippocampal subfields in 95 clinically and neuropathologically characterized human cases of DLB, finding that α-synuclein pathology was highest in two hippocampal-related subregions: the CA2 subfield and the entorhinal cortex (EC). While the EC had numerous classic somatic Lewy bodies, CA2 contained mainly Lewy neurites in presumed axon terminals, suggesting the involvement of the EC → CA2 circuitry in the pathogenesis of DLB symptoms. Clinicopathological correlations with measures of verbal and visual memory supported a role for EC Lewy pathology, but not CA2, in causing these memory deficits. Lewy pathology in CA1-the main output region for CA2-correlated best with results from memory testing despite a milder pathology. This result indicates that CA1 may be more functionally relevant than CA2 in the context of memory impairment in DLB. These correlations remained significant after controlling for several factors, including concurrent Alzheimer's pathology (neuritic plaques and neurofibrillary tangles) and the interval between time of testing and time of death. Our data suggest that although hippocampal Lewy pathology in DLB is predominant in CA2 and EC, memory performance correlates most strongly with CA1 burden.SIGNIFICANCE STATEMENT This study provides a detailed neuropathologic analysis of hippocampal Lewy pathology in human patients with autopsy-confirmed dementia with Lewy bodies. The approach-informed by regional molecular markers, concurrent Alzheimer's pathology analysis, and relevant clinical data-helps tease out the relative contribution of Lewy pathology to memory dysfunction in the disease. Levels of Lewy pathology were found to be highest in the hippocampal CA2 subregion and entorhinal cortex, implicating a potentially overlooked circuit in disease pathogenesis. However, correlation with memory performance was strongest with CA1. This unexpected finding suggests that Lewy pathology must reach a critical burden across hippocampal circuitry to contribute to memory dysfunction beyond that related to other factors, notably coexisting Alzheimer's disease tau pathology.

Sarkar, A., Marchetto, M.C., Gage, F.H. Synaptic activity: An emerging player in schizophrenia. (2017) Brain Research. 1656:68-75. DOI: 10.1016/j.brainres.2015.12.028

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Paquola, A.C.M., Erwin, J.A., Gage, F.H. Insights into the role of somatic mosaicism in the brain. (2017) Current Opinion in Systems Biology. 1:90-94. DOI: 10.1016/j.coisb.2016.12.004

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Han, J., Gage, F.H. A role for miR-19 in the migration of adult-born neurons and schizophrenia. (2016) Neurogenesis. 3(1):e1251873. DOI: 10.1080/23262133.2016.1251873

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Erwin, J.A., Paquola, A.C., Singer, T., Gallina, I., Novotny, M., Quayle, C., Bedrosian, T.A., Alves, F.I., Butcher, C.R., Herdy, J.R., Sarkar, A., Lasken, R.S., Muotri, A.R., Gage, F.H. L1-associated genomic regions are deleted in somatic cells of the healthy human brain. (2016) Nature Neuroscience. 19(12):1583-1591. DOI: 10.1038/nn.4388

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Gonçalves, J.T., Schafer, S.T., Gage, F.H. Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. (2016) Móvil. 167(4):897-914. DOI: 10.1016/j.cell.2016.10.021

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Vadodaria, K.C., Marchetto, M.C., Mertens, J., Gage, F.H. Generating human serotonergic neurons in vitro: Methodological advances. (2016) Bioessays. 38(11):1123-1129. DOI: 10.1002/bies.201600127

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Bardy, C., van den Hurk, M., Kakaradov, B., Erwin, J.A., Jaeger, B.N., Hernandez, R.V., Eames, T., Paucar, A.A., Gorris, M., Marchand, C., Jappelli, R., Barron, J., Bryant, A.K., Kellogg, M., Lasken, R.S., Rutten, B.P., Steinbusch, H.W., Yeo, G.W., Gage, F.H. Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology. (2016) Molecular Psychiatry. 21(11):1573-1588. DOI: 10.1038/mp.2016.158

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Du, H., Deng, W., Aimone, J.B., Ge, M., Parylak, S., Walch, K., Zhang, W., Cook, J., Song, H., Wang, L., Gage, F.H., Mu, Y. Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding. (2016) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 113(37):E5501-10. DOI: 10.1073/pnas.1606951113

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van den Hurk, M., Kenis, G., Bardy, C., van den Hove, D.L., Gage, F.H., Steinbusch, H.W., Rutten, B.P. Transcriptional and epigenetic mechanisms of cellular reprogramming to induced pluripotency. (2016) Epigenomics. 8(8):1131-49. DOI: 10.2217/epi-2016-0032

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Gage, F.H., Guarente, L.P., Wagers, A.J. Aging and Rejuvenation: Insights from Rusty Gage, Leonard Guarente, and Amy Wagers. (2016) Trends in Molecular Medicine. 22(8):633-4. DOI: 10.1016/j.molmed.2016.06.011

Chailangkarn, T., Trujillo, C.A., Freitas, B.C., Hrvoj-Mihic, B., Herai, R.H., Yu, D.X., Brown, T.T., Marchetto, M.C., Bardy, C., McHenry, L., Stefanacci, L., Järvinen, A., Searcy, Y.M., DeWitt, M., Wong, W., Lai, P., Ard, M.C., Hanson, K.L., Romero, S., Jacobs, B., Dale, A.M., Dai, L., Korenberg, J.R., Gage, F.H., Bellugi, U., Halgren, E., Semendeferi, K., Muotri, A.R. A human neurodevelopmental model for Williams syndrome. (2016) Naturaleza. 536(7616):338-43. DOI: 10.1038/nature19067

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Nuttle, X., Giannuzzi, G., Duyzend, M.H., Schraiber, J.G., Narvaiza, I., Sudmant, P.H., Penn, O., Chiatante, G., Malig, M., Huddleston, J., Benner, C., Camponeschi, F., Ciofi-Baffoni, S., Stessman, H.A., Marchetto, M.C., Denman, L., Harshman, L., Baker, C., Raja, A., Penewit, K., Janke, N., Tang, W.J., Ventura, M., Banci, L., Antonacci, F., Akey, J.M., Amemiya, C.T., Gage, F.H., Reymond, A., Eichler, E.E. Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. (2016) Naturaleza. 536(7615):205-9. DOI: 10.1038/nature19075

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Padmanabhan, K., Osakada, F., Tarabrina, A., Kizer, E., Callaway, E.M., Gage, F.H., Sejnowski, T.J. Diverse Representations of Olfactory Information in Centrifugal Feedback Projections. (2016) Journal of Neuroscience. 36(28):7535-45. DOI: 10.1523/JNEUROSCI.3358-15.2016

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Han, J., Kim, H.J., Schafer, S.T., Paquola, A., Clemenson, G.D., Toda, T., Oh, J., Pankonin, A.R., Lee, B.S., Johnston, S.T., Sarkar, A., Denli, A.M., Gage, F.H. Functional Implications of miR-19 in the Migration of Newborn Neurons in the Adult Brain. (2016) Neuron. 91(1):79-89. DOI: 10.1016/j.neuron.2016.05.034

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Mertens, J., Marchetto, M.C., Bardy, C., Gage, F.H. Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. (2016) Nature Reviews Neuroscience. 17(7):424-37. DOI: 10.1038/nrn.2016.46

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Ettle, B., Kerman, B.E., Valera, E., Gillmann, C., Schlachetzki, J.C., Reiprich, S., Büttner, C., Ekici, A.B., Reis, A., Wegner, M., Bäuerle, T., Riemenschneider, M.J., Masliah, E., Gage, F.H., Winkler, J. α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy. (2016) Acta Neuropathologica. 132(1):59-75. DOI: 10.1007/s00401-016-1572-y

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Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.

Zheng, X., Boyer, L., Jin, M., Mertens, J., Kim, Y., Ma, L., Ma, L., Hamm, M., Gage, F.H., Hunter, T. Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. (2016) Elife. 5. DOI: 10.7554/eLife.13374

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Gonçalves, J.T., Bloyd, C.W., Shtrahman, M., Johnston, S.T., Schafer, S.T., Parylak, S.L., Tran, T., Chang, T., Gage, F.H. In vivo imaging of dendritic pruning in dentate granule cells. (2016) Nature Neuroscience. 19(6):788-91. DOI: 10.1038/nn.4301

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Bedrosian, T.A., Linker, S., Gage, F.H. Environment-driven somatic mosaicism in brain disorders. (2016) Genome Medicine. 8(1):58. DOI: 10.1186/s13073-016-0317-9

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Poo, M.M., Pignatelli, M., Ryan, T.J., Tonegawa, S., Bonhoeffer, T., Martin, K.C., Rudenko, A., Tsai, L.H., Tsien, R.W., Fishell, G., Mullins, C., Gonçalves, J.T., Shtrahman, M., Johnston, S.T., Gage, F.H., Dan, Y., Long, J., Buzsáki, G., Stevens, C. What is memory? The present state of the engram. (2016) BMC Biology. 14:40. DOI: 10.1186/s12915-016-0261-6

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Oedegaard, K.J., Alda, M., Anand, A., Andreassen, O.A., Balaraman, Y., Berrettini, W.H., Bhattacharjee, A., Brennand, K.J., Burdick, K.E., Calabrese, J.R., Calkin, C.V., Claasen, A., Coryell, W.H., Craig, D., DeModena, A., Frye, M., Gage, F.H., Gao, K., Garnham, J., Gershon, E., Jakobsen, P., Leckband, S.G., McCarthy, M.J., McInnis, M.G., Maihofer, A.X., Mertens, J., Morken, G., Nievergelt, C.M., Nurnberger, J., Pham, S., Schoeyen, H., Shekhtman, T., Shilling, P.D., Szelinger, S., Tarwater, B., Yao, J., Zandi, P.P., Kelsoe, J.R. The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample. (2016) BMC Psychiatry. 16:129. DOI: 10.1186/s12888-016-0732-x

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Topol, A., Zhu, S., Hartley, B.J., English, J., Hauberg, M.E., Tran, N., Rittenhouse, C.A., Simone, A., Ruderfer, D.M., Johnson, J., Readhead, B., Hadas, Y., Gochman, P.A., Wang, Y.C., Shah, H., Cagney, G., Rapoport, J., Gage, F.H., Dudley, J.T., Sklar, P., Mattheisen, M., Cotter, D., Fang, G., Brennand, K.J. Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. (2016) Cell Reports. 15(5):1024-1036. DOI: 10.1016/j.celrep.2016.03.090

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Lacar, B., Linker, S.B., Jaeger, B.N., Krishnaswami, S., Barron, J., Kelder, M., Parylak, S., Paquola, A., Venepally, P., Novotny, M., O'Connor, C., Fitzpatrick, C., Erwin, J., Hsu, J.Y., Husband, D., McConnell, M.J., Lasken, R., Gage, F.H. Nuclear RNA-seq of single neurons reveals molecular signatures of activation. (2016) Nature Communications. 7:11022. DOI: 10.1038/ncomms11022

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Harrison, B.J., Venkat, G., Lamb, J.L., Hutson, T.H., Drury, C., Rau, K.K., Bunge, M.B., Mendell, L.M., Gage, F.H., Johnson, R.D., Hill, C.E., Rouchka, E.C., Moon, L.D., Petruska, J.C. The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity. (2016) Journal of Neuroscience. 36(15):4259-75. DOI: 10.1523/JNEUROSCI.2423-15.2016

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Otani, T., Marchetto, M.C., Gage, F.H., Simons, B.D., Livesey, F.J. 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size. (2016) Cell Stem Cell. 18(4):467-80. DOI: 10.1016/j.stem.2016.03.003

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Zheng, X., Boyer, L., Jin, M., Kim, Y., Fan, W., Bardy, C., Berggren, T., Evans, R.M., Gage, F.H., Hunter, T. Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration. (2016) Elife. 5. DOI: 10.7554/eLife.13378

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Mishra, H.K., Prots, I., Havlicek, S., Kohl, Z., Perez-Branguli, F., Boerstler, T., Anneser, L., Minakaki, G., Wend, H., Hampl, M., Leone, M., Brückner, M., Klucken, J., Reis, A., Boyer, L., Schuierer, G., Behrens, J., Lampert, A., Engel, F.B., Gage, F.H., Winkler, J., Winner, B. GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient iPSC model. (2016) Ann. Neurol. DOI: 10.1002/ana.24633

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Krishnaswami, S.R., Grindberg, R.V., Novotny, M., Venepally, P., Lacar, B., Bhutani, K., Linker, S.B., Pham, S., Erwin, J.A., Miller, J.A., Hodge, R., McCarthy, J.K., Kelder, M., McCorrison, J., Aevermann, B.D., Fuertes, F.D., Scheuermann, R.H., Lee, J., Lein, E.S., Schork, N., McConnell, M.J., Gage, F.H., Lasken, R.S. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. (2016) Nature Protocols. 11(3):499-524. DOI: 10.1038/nprot.2016.015

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Johnston, S.T., Shtrahman, M., Parylak, S., Gonçalves, J.T., Gage, F.H. Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness. (2016) Neurobiology of Learning and Memory. 129:60-8. DOI: 10.1016/j.nlm.2015.10.013

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Weissman, I.L., Gage, F.H. A Mechanism for Somatic Brain Mosaicism. (2016) Móvil. 164(4):593-5. DOI: 10.1016/j.cell.2016.01.048

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Agre, P., Bertozzi, C., Bissell, M., Campbell, K.P., Cummings, R.D., Desai, U.R., Estes, M., Flotte, T., Fogleman, G., Gage, F., Ginsburg, D., Gordon, J.I., Hart, G., Hascall, V., Kiessling, L., Kornfeld, S., Lowe, J., Magnani, J., Mahal, L.K., Medzhitov, R., Roberts, R.J., Sackstein, R., Sarkar, R., Schnaar, R., Schwartz, N., Varki, A., Walt, D., Weissman, I. Training the next generation of biomedical investigators in glycosciences. (2016) Journal of Clinical Investigation. 126(2):405-8. DOI: 10.1172/JCI85905

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Tang, X., Kim, J., Zhou, L., Wengert, E., Zhang, L., Wu, Z., Carromeu, C., Muotri, A.R., Marchetto, M.C., Gage, F.H., Chen, G. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. (2016) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 113(3):751-6. DOI: 10.1073/pnas.1524013113

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Vadodaria, K.C., Mertens, J., Paquola, A., Bardy, C., Li, X., Jappelli, R., Fung, L., Marchetto, M.C., Hamm, M., Gorris, M., Koch, P., Gage, F.H. The different moods of human serotonergic neurons. (2016) Molecular Psychiatry. 21(1):3. DOI: 10.1038/mp.2015.202

Duricki, D.A., Hutson, T.H., Kathe, C., Soleman, S., Gonzalez-Carter, D., Petruska, J.C., Shine, H.D., Chen, Q., Wood, T.C., Bernanos, M., Cash, D., Williams, S.C., Gage, F.H., Moon, L.D. Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke. (2016) Brain. 139(Pt 1):259-75. DOI: 10.1093/brain/awv341

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Vadodaria, K.C., Mertens, J., Paquola, A., Bardy, C., Li, X., Jappelli, R., Fung, L., Marchetto, M.C., Hamm, M., Gorris, M., Koch, P., Gage, F.H. Generation of functional human serotonergic neurons from fibroblasts. (2016) Molecular Psychiatry. 21(1):49-61. DOI: 10.1038/mp.2015.161

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Harrison, B.J., Venkat, G., Hutson, T., Rau, K.K., Bunge, M.B., Mendell, L.M., Gage, F.H., Johnson, R.D., Hill, C., Rouchka, E.C., Moon, L., Petruska, J.C. Transcriptional changes in sensory ganglia associated with primary afferent axon collateral sprouting in spared dermatome model. (2015) Genomics Data. 6:249-52. DOI: 10.1016/j.gdata.2015.10.005

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Brennand, K.J., Marchetto, M.C., Benvenisty, N., Brüstle, O., Ebert, A., Izpisua Belmonte, J.C., Kaykas, A., Lancaster, M.A., Livesey, F.J., McConnell, M.J., McKay, R.D., Morrow, E.M., Muotri, A.R., Panchision, D.M., Rubin, L.L., Sawa, A., Soldner, F., Song, H., Studer, L., Temple, S., Vaccarino, F.M., Wu, J., Vanderhaeghen, P., Gage, F.H., Jaenisch, R. Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders. (2015) Stem Cell Reports. 5(6):933-45. DOI: 10.1016/j.stemcr.2015.10.011

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Mertens, J., Paquola, A.C., Ku, M., Hatch, E., Böhnke, L., Ladjevardi, S., McGrath, S., Campbell, B., Lee, H., Herdy, J.R., Gonçalves, J.T., Toda, T., Kim, Y., Winkler, J., Yao, J., Hetzer, M.W., Gage, F.H. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. (2015) Cell Stem Cell. 17(6):705-18. DOI: 10.1016/j.stem.2015.09.001

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Kim, H.J., Denli, A.M., Wright, R., Baul, T.D., Clemenson, G.D., Morcos, A.S., Zhao, C., Schafer, S.T., Gage, F.H., Kagalwala, M.N. REST Regulates Non-Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II. (2015) Journal of Neuroscience. 35(44):14872-84. DOI: 10.1523/JNEUROSCI.4286-14.2015

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Mertens, J., Wang, Q.W., Kim, Y., Yu, D.X., Pham, S., Yang, B., Zheng, Y., Diffenderfer, K.E., Zhang, J., Soltani, S., Eames, T., Schafer, S.T., Boyer, L., Marchetto, M.C., Nurnberger, J.I., Calabrese, J.R., Ødegaard, K.J., McCarthy, M.J., Zandi, P.P., Alda, M., Alba, M., Nievergelt, C.M., , Mi, S., Brennand, K.J., Kelsoe, J.R., Gage, F.H., Yao, J. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. (2015) Naturaleza. 527(7576):95-9. DOI: 10.1038/nature15526

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Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

Denli, A.M., Narvaiza, I., Kerman, B.E., Pena, M., Benner, C., Marchetto, M.C., Diedrich, J.K., Aslanian, A., Ma, J., Moresco, J.J., Moore, L., Hunter, T., Saghatelian, A., Gage, F.H. Primate-specific ORF0 contributes to retrotransposon-mediated diversity. (2015) Móvil. 163(3):583-93. DOI: 10.1016/j.cell.2015.09.025

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Mu, Y., Zhao, C., Toni, N., Yao, J., Gage, F.H. Distinct roles of NMDA receptors at different stages of granule cell development in the adult brain. (2015) Elife. 4:e07871. DOI: 10.7554/eLife.07871

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Tashiro, A., Zhao, C., Suh, H., Gage, F.H. Preparation and Use of Retroviral Vectors for Labeling, Imaging, and Genetically Manipulating Cells. (2015) Cold Spring Harbor Protocols. 2015(10):883-8. DOI: 10.1101/pdb.top086363

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Tashiro, A., Zhao, C., Suh, H., Gage, F.H. Analysis of Spine Motility of Newborn Granule Cells in Acute Brain Slices. (2015) Cold Spring Harbor Protocols. 2015(10):934-6. DOI: 10.1101/pdb.prot086397

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Tashiro, A., Zhao, C., Suh, H., Gage, F.H. Imaging Newborn Granule Cells in Fixed Sections. (2015) Cold Spring Harbor Protocols. 2015(10):932-3. DOI: 10.1101/pdb.prot086389

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Tashiro, A., Zhao, C., Suh, H., Gage, F.H. Purification and Injection of Retroviral Vectors. (2015) Cold Spring Harbor Protocols. 2015(10):925-31. DOI: 10.1101/pdb.prot086371

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Prescott, S.L., Srinivasan, R., Marchetto, M.C., Grishina, I., Narvaiza, I., Selleri, L., Gage, F.H., Swigut, T., Wysocka, J. Enhancer divergence and cis-regulatory evolution in the human and chimp neural crest. (2015) Móvil. 163(1):68-83. DOI: 10.1016/j.cell.2015.08.036

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Kempermann, G., Song, H., Gage, F.H. Neurogenesis in the Adult Hippocampus. (2015) Cold Spring Harbor Perspectives in Biology. 7(9):a018812. DOI: 10.1101/cshperspect.a018812

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Jovičić, A., Mertens, J., Boeynaems, S., Bogaert, E., Chai, N., Yamada, S.B., Paul, J.W., Sun, S., Herdy, J.R., Bieri, G., Kramer, N.J., Gage, F.H., Van Den Bosch, L., Robberecht, W., Gitler, A.D. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. (2015) Nature Neuroscience. 18(9):1226-9. DOI: 10.1038/nn.4085

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Firth, A.L., Menon, T., Parker, G.S., Qualls, S.J., Lewis, B.M., Ke, E., Dargitz, C.T., Wright, R., Khanna, A., Gage, F.H., Verma, I.M. Functional Gene Correction for Cystic Fibrosis in Lung Epithelial Cells Generated from Patient iPSCs. (2015) Cell Reports. 12(9):1385-90. DOI: 10.1016/j.celrep.2015.07.062

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Deng, W., Gage, F.H. The effect of immature adult-born dentate granule cells on hyponeophagial behavior is related to their roles in learning and memory. (2015) Frontiers in Systems Neuroscience. 9:34. DOI: 10.3389/fnsys.2015.00034

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Han, J., Sarkar, A., Gage, F.H. MIR137: big impacts from small changes. (2015) Nature Neuroscience. 18(7):931-3. DOI: 10.1038/nn.4045

Zhao, C., Jou, J., Wolff, L.J., Sun, H., Gage, F.H. Spine morphogenesis in newborn granule cells is differentially regulated in the outer and middle molecular layers. (2015) Journal of Comparative Neurology. 523(10):1588. DOI: 10.1002/cne.23800

Krzisch, M., Temprana, S.G., Mongiat, L.A., Armida, J., Schmutz, V., Virtanen, M.A., Kocher-Braissant, J., Kraftsik, R., Vutskits, L., Conzelmann, K.K., Bergami, M., Gage, F.H., Schinder, A.F., Toni, N. Pre-existing astrocytes form functional perisynaptic processes on neurons generated in the adult hippocampus. (2015) Brain Structure & Function. 220(4):2027-42. DOI: 10.1007/s00429-014-0768-y

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Kerman, B.E., Kim, H.J., Padmanabhan, K., Mei, A., Georges, S., Joens, M.S., Fitzpatrick, J.A., Jappelli, R., Chandross, K.J., August, P., Gage, F.H. In vitro myelin formation using embryonic stem cells. (2015) Development. 142(12):2213-25. DOI: 10.1242/dev.116517

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Bardy, C., van den Hurk, M., Eames, T., Marchand, C., Hernandez, R.V., Kellogg, M., Gorris, M., Galet, B., Palomares, V., Brown, J., Bang, A.G., Mertens, J., Böhnke, L., Boyer, L., Simon, S., Gage, F.H. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. (2015) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 112(20):E2725-34. DOI: 10.1073/pnas.1504393112

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Pei, L., Mu, Y., Leblanc, M., Alaynick, W., Barish, G.D., Pankratz, M., Tseng, T.W., Kaufman, S., Liddle, C., Yu, R.T., Downes, M., Pfaff, S.L., Auwerx, J., Gage, F.H., Evans, R.M. Dependence of hippocampal function on ERRγ-regulated mitochondrial metabolism. (2015) Cell Metabolism. 21(4):628-36. DOI: 10.1016/j.cmet.2015.03.004

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Adamowicz, D.H., Mertens, J., Gage, F.H. Alzheimer's disease: distinct stages in neurogenic decline? (2015) Biological Psychiatry. 77(8):680-2. DOI: 10.1016/j.biopsych.2015.02.021

Amador-Arjona, A., Cimadamore, F., Huang, C.T., Wright, R., Lewis, S., Gage, F.H., Terskikh, A.V. SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. (2015) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 112(15):E1936-45. DOI: 10.1073/pnas.1421480112

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Schafer, S.T., Han, J., Pena, M., von Bohlen Und Halbach, O., Peters, J., Gage, F.H. The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis. (2015) Journal of Neuroscience. 35(12):4983-98. DOI: 10.1523/JNEUROSCI.4130-14.2015

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Clemenson, G.D., Lee, S.W., Deng, W., Barrera, V.R., Iwamoto, K.S., Fanselow, M.S., Gage, F.H. Enrichment rescues contextual discrimination deficit associated with immediate shock. (2015) Hippocampus. 25(3):385-92. DOI: 10.1002/hipo.22380

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Brennand, K., Savas, J.N., Kim, Y., Tran, N., Simone, A., Hashimoto-Torii, K., Beaumont, K.G., Kim, H.J., Topol, A., Ladran, I., Abdelrahim, M., Matikainen-Ankney, B., Chao, S.H., Mrksich, M., Rakic, P., Fang, G., Zhang, B., Yates, J.R., Gage, F.H. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. (2015) Molecular Psychiatry. 20(3):361-8. DOI: 10.1038/mp.2014.22

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Pankevich, D.E., Altevogt, B.M., Dunlop, J., Gage, F.H., Hyman, S.E. Improving and accelerating drug development for nervous system disorders. (2014) Neuron. 84(3):546-53. DOI: 10.1016/j.neuron.2014.10.007

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Kim, S.H., Steele, J.W., Lee, S.W., Clemenson, G.D., Carter, T.A., Treuner, K., Gadient, R., Wedel, P., Glabe, C., Barlow, C., Ehrlich, M.E., Gage, F.H., Gandy, S. Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse. (2014) Molecular Psychiatry. 19(11):1235-42. DOI: 10.1038/mp.2014.87

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Hook, V., Brennand, K.J., Kim, Y., Toneff, T., Funkelstein, L., Lee, K.C., Ziegler, M., Gage, F.H. Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. (2014) Stem Cell Reports. 3(4):531-8. DOI: 10.1016/j.stemcr.2014.08.001

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Aimone, J.B., Li, Y., Lee, S.W., Clemenson, G.D., Deng, W., Gage, F.H. Regulation and function of adult neurogenesis: from genes to cognition. (2014) Physiological Reviews. 94(4):991-1026. DOI: 10.1152/physrev.00004.2014

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Jessberger, S., Gage, F.H. Adult neurogenesis: bridging the gap between mice and humans. (2014) Trends in Cell Biology. 24(10):558-63. DOI: 10.1016/j.tcb.2014.07.003

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Winner, B., Marchetto, M.C., Winkler, J., Gage, F.H. Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease. (2014) Human Molecular Genetics. 23(R1):R27-34. DOI: 10.1093/hmg/ddu205

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Gage, F., Nair, P. QnAs with Fred Gage. (2014) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 111(36):12958-9. DOI: 10.1073/pnas.1412625111

Erwin, J.A., Marchetto, M.C., Gage, F.H. Mobile DNA elements in the generation of diversity and complexity in the brain. (2014) Nature Reviews Neuroscience. 15(8):497-506. DOI: 10.1038/nrn3730

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Gage, F., Pariente, N. On jumping genes and other things: Interview with Fred Gage, Adler Professor at the Salk Institute. (2014) EMBO Reports. 15(8):822-6. DOI: 10.15252/embr.201439088

Zhao, C., Jou, J., Wolff, L.J., Sun, H., Gage, F.H. Spine morphogenesis in newborn granule cells is differentially regulated in the outer and middle molecular layers. (2014) Journal of Comparative Neurology. 522(12):2756-66. DOI: 10.1002/cne.23581

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Bekinschtein, P., Kent, B.A., Oomen, C.A., Clemenson, G.D., Gage, F.H., Saksida, L.M., Bussey, T.J. Brain-derived neurotrophic factor interacts with adult-born immature cells in the dentate gyrus during consolidation of overlapping memories. (2014) Hippocampus. 24(8):905-11. DOI: 10.1002/hipo.22304

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Stein, J.L., de la Torre-Ubieta, L., Tian, Y., Parikshak, N.N., Hernández, I.A., Marchetto, M.C., Baker, D.K., Lu, D., Hinman, C.R., Lowe, J.K., Wexler, E.M., Muotri, A.R., Gage, F.H., Kosik, K.S., Geschwind, D.H. A quantitative framework to evaluate modeling of cortical development by neural stem cells. (2014) Neuron. 83(1):69-86. DOI: 10.1016/j.neuron.2014.05.035

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Yu, D.X., Marchetto, M.C., Gage, F.H. How to make a hippocampal dentate gyrus granule neuron. (2014) Development. 141(12):2366-75. DOI: 10.1242/dev.096776

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Lacar, B., Parylak, S.L., Vadodaria, K.C., Sarkar, A., Gage, F.H. Increasing the resolution of the adult neurogenesis picture. (2014) F1000 Prime Reports. 6:8. DOI: 10.12703/P6-8

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Hrvoj-Mihic, B., Marchetto, M.C., Gage, F.H., Semendeferi, K., Muotri, A.R. Novel tools, classic techniques: evolutionary studies using primate pluripotent stem cells. (2014) Biological Psychiatry. 75(12):929-35. DOI: 10.1016/j.biopsych.2013.08.007

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Hashimoto-Torii, K., Torii, M., Fujimoto, M., Nakai, A., El Fatimy, R., Mezger, V., Ju, M.J., Ishii, S., Chao, S.H., Brennand, K.J., Gage, F.H., Rakic, P. Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. (2014) Neuron. 82(3):560-72. DOI: 10.1016/j.neuron.2014.03.002

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Rockenstein, E., Nuber, S., Overk, C.R., Ubhi, K., Mante, M., Patrick, C., Adame, A., Trejo-Morales, M., Gerez, J., Picotti, P., Jensen, P.H., Campioni, S., Riek, R., Winkler, J., Gage, F.H., Winner, B., Masliah, E. Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. (2014) Brain. 137(Pt 5):1496-513. DOI: 10.1093/brain/awu057

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In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.

Havlicek, S., Kohl, Z., Mishra, H.K., Prots, I., Eberhardt, E., Denguir, N., Wend, H., Plötz, S., Boyer, L., Marchetto, M.C., Aigner, S., Sticht, H., Groemer, T.W., Hehr, U., Lampert, A., Schlötzer-Schrehardt, U., Winkler, J., Gage, F.H., Winner, B. Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons. (2014) Human Molecular Genetics. 23(10):2527-41. DOI: 10.1093/hmg/ddt644

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Firth, A.L., Dargitz, C.T., Qualls, S.J., Menon, T., Wright, R., Singer, O., Gage, F.H., Khanna, A., Verma, I.M. Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells. (2014) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 111(17):E1723-30. DOI: 10.1073/pnas.1403470111

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Pao, G.M., Zhu, Q., Perez-Garcia, C.G., Chou, S.J., Suh, H., Gage, F.H., O'Leary, D.D., Verma, I.M. Role of BRCA1 in brain development. (2014) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 111(13):E1240-8. DOI: 10.1073/pnas.1400783111

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Crotti, A., Benner, C., Kerman, B.E., Gosselin, D., Lagier-Tourenne, C., Zuccato, C., Cattaneo, E., Gage, F.H., Cleveland, D.W., Glass, C.K. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. (2014) Nature Neuroscience. 17(4):513-21. DOI: 10.1038/nn.3668

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Yu, D.X., Di Giorgio, F.P., Yao, J., Marchetto, M.C., Brennand, K., Wright, R., Mei, A., McHenry, L., Lisuk, D., Grasmick, J.M., Silberman, P., Silberman, G., Jappelli, R., Gage, F.H. Modeling hippocampal neurogenesis using human pluripotent stem cells. (2014) Stem Cell Reports. 2(3):295-310. DOI: 10.1016/j.stemcr.2014.01.009

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Wright, R., Réthelyi, J.M., Gage, F.H. Enhancing induced pluripotent stem cell models of schizophrenia. (2014) JAMA Psychiatry. 71(3):334-5. DOI: 10.1001/jamapsychiatry.2013.4239

Vadodaria, K.C., Gage, F.H. SnapShot: adult hippocampal neurogenesis. (2014) Móvil. 156(5):1114-1114.e1. DOI: 10.1016/j.cell.2014.02.029

Rangel, L.M., Alexander, A.S., Aimone, J.B., Wiles, J., Gage, F.H., Chiba, A.A., Quinn, L.K. Temporally selective contextual encoding in the dentate gyrus of the hippocampus. (2014) Nature Communications. 5:3181. DOI: 10.1038/ncomms4181

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Parylak, S.L., Deng, W., Gage, F.H. Mother's milk programs offspring's cognition. (2014) Nature Neuroscience. 17(1):8-9. DOI: 10.1038/nn.3611

Marchetto, M.C., Gage, F.H. Your brain under the microscope: the promise of stem cells. (2014) Cerebrum. 2014:1.

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Grindberg, R.V., Yee-Greenbaum, J.L., McConnell, M.J., Novotny, M., O'Shaughnessy, A.L., Lambert, G.M., Araúzo-Bravo, M.J., Lee, J., Fishman, M., Robbins, G.E., Lin, X., Venepally, P., Badger, J.H., Galbraith, D.W., Gage, F.H., Lasken, R.S. RNA-sequencing from single nuclei. (2013) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 110(49):19802-7. DOI: 10.1073/pnas.1319700110

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Reilly, M.T., Faulkner, G.J., Dubnau, J., Ponomarev, I., Gage, F.H. The role of transposable elements in health and diseases of the central nervous system. (2013) Journal of Neuroscience. 33(45):17577-86. DOI: 10.1523/JNEUROSCI.3369-13.2013

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McConnell, M.J., Lindberg, M.R., Brennand, K.J., Piper, J.C., Voet, T., Cowing-Zitron, C., Shumilina, S., Lasken, R.S., Vermeesch, J.R., Hall, I.M., Gage, F.H. Mosaic copy number variation in human neurons. (2013) Ciencia. 342(6158):632-7. DOI: 10.1126/science.1243472

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Marchetto, M.C.N., Narvaiza, I., Denli, A.M., Benner, C., Lazzarini, T.A., Nathanson, J.L., Paquola, A.C.M., Desai, K.N., Herai, R.H., Weitzman, M.D., Yeo, G.W., Muotri, A.R., Gage, F.H. Differential L1 regulation in pluripotent stem cells of humans and apes. (2013) Naturaleza. 503(7477):525-529. DOI: 10.1038/nature12686

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Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). However, these tissue samples do not fairly represent the distinctive traits of live cell behaviour and are not amenable to genetic manipulation. We propose that induced pluripotent stem (iPS) cells could be a unique biological resource to determine relevant phenotypical differences between human and NHPs, and that those differences could have potential adaptation and speciation value. Here we describe the generation and initial characterization of iPS cells from chimpanzees and bonobos as new tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPS cells revealed differences in the regulation of long interspersed element-1 (L1, also known as LINE-1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (also known as A3B) and PIWIL2 (ref. 7) in NHP iPS cells correlated with increased L1 mobility and endogenous L1 messenger RNA levels. Moreover, results from the manipulation of A3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPS cells in culture and may have also occurred in the germ line or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have continuing adaptive significance.

Bekinschtein, P., Kent, B.A., Oomen, C.A., Clemenson, G.D., Gage, F.H., Saksida, L.M., Bussey, T.J. BDNF in the dentate gyrus is required for consolidation of "pattern-separated" memories. (2013) Cell Reports. 5(3):759-68. DOI: 10.1016/j.celrep.2013.09.027

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Miller, J.A., Nathanson, J., Franjic, D., Shim, S., Dalley, R.A., Shapouri, S., Smith, K.A., Sunkin, S.M., Bernard, A., Bennett, J.L., Lee, C.K., Hawrylycz, M.J., Jones, A.R., Amaral, D.G., Šestan, N., Gage, F.H., Lein, E.S. Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. (2013) Development. 140(22):4633-44. DOI: 10.1242/dev.097212

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Gage, F.H., Temple, S. Neural stem cells: generating and regenerating the brain. (2013) Neuron. 80(3):588-601. DOI: 10.1016/j.neuron.2013.10.037

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Deshmukh, V.A., Tardif, V., Lyssiotis, C.A., Green, C.C., Kerman, B., Kim, H.J., Padmanabhan, K., Swoboda, J.G., Ahmad, I., Kondo, T., Gage, F.H., Theofilopoulos, A.N., Lawson, B.R., Schultz, P.G., Lairson, L.L. A regenerative approach to the treatment of multiple sclerosis. (2013) Naturaleza. 502(7471):327-332. DOI: 10.1038/nature12647

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Herzog, C.D., Brown, L., Kruegel, B.R., Wilson, A., Tansey, M.G., Gage, F.H., Johnson, E.M., Bartus, R.T. Enhanced neurotrophic distribution, cell signaling and neuroprotection following substantia nigral versus striatal delivery of AAV2-NRTN (CERE-120). (2013) Neurobiol. Dis. 58:38-48. DOI: 10.1016/j.nbd.2013.04.011

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This paper reassesses the currently accepted viewpoint that targeting the terminal fields (i.e. striatum) of degenerating nigrostriatal dopamine neurons with neurotrophic factors in Parkinson's disease (PD) is sufficient for achieving an optimal neurotrophic response. Recent insight indicating that PD is an axonopathy characterized by axonal transport deficits prompted this effort. We tested whether a significantly greater neurotrophic response might be induced in SN neurons when the neurotrophic factor neurturin (NRTN) is also targeted to the substantia nigra (SN), compared to the more conventional, striatum-only target. While recognizing the importance of maintaining the integrity of nigrostriatal fibers and terminals (especially for achieving optimal function), we refocused attention to the fate of SN neurons. Under conditions of axonal degeneration and neuronal transport deficits, this component of the nigrostriatal system is most vulnerable to the lack of neurotrophic exposure following striatal-only delivery. Given the location of repair genes induced by neurotrophic factors, achieving adequate neurotrophic exposure to the SN neurons is essential for an optimal neurotrophic response, while the survival of these neurons is essential to the very survival of the fibers. Two separate studies were performed using the 6-OHDA model of nigrostriatal degeneration, in conjunction with delivery of the viral vector AAV2-NRTN (CERE-120) to continuously express NRTN to either striatum or nigra alone or combined striatal/nigral exposure, including conditions of ongoing axonopathy. These studies provide additional insight for reinterpreting past animal neurotrophic/6-OHDA studies conducted under conditions where axon transport deficiencies were generally not accounted for, which suggested that targeting the striatum was both necessary and sufficient. The current data demonstrate that delivering NRTN directly to the SN produces 1) expanded NRTN distribution within the terminal field and cell bodies of targeted nigrostriatal neurons, 2) enhanced intracellular neurotrophic factor signaling in the nigrostriatal neurons, and 3) produced greater numbers of surviving dopamine neurons against 6-OHDA-induced toxicity, particularly under the conditions of active axonopathy. Thus, these data provide empirical support that targeting the SN with neurotrophic factors (in addition to striatum) may help enhance the neurotrophic response in midbrain neurons, particularly under conditions of active neurodegeneration which occurs in PD patients.

Tang, X., Zhou, L., Wagner, A.M., Marchetto, M.C., Muotri, A.R., Gage, F.H., Chen, G. Astroglial cells regulate the developmental timeline of human neurons differentiated from induced pluripotent stem cells. (2013) Stem Cell Research. 11(2):743-57. DOI: 10.1016/j.scr.2013.05.002

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Sung, T.C., Chen, Z., Thuret, S., Vilar, M., Gage, F.H., Riek, R., Lee, K.F. P45 forms a complex with FADD and promotes neuronal cell survival following spinal cord injury. (2013) PLOS One. 8(7):e69286. DOI: 10.1371/journal.pone.0069286

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Yu, D.X., Marchetto, M.C., Gage, F.H. Therapeutic translation of iPSCs for treating neurological disease. (2013) Cell Stem Cell. 12(6):678-88. DOI: 10.1016/j.stem.2013.05.018

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Vilchez, D., Boyer, L., Lutz, M., Merkwirth, C., Morantte, I., Tse, C., Spencer, B., Page, L., Masliah, E., Berggren, W.T., Gage, F.H., Dillin, A. FOXO4 is necessary for neural differentiation of human embryonic stem cells. (2013) Aging Cell. 12(3):518-22. DOI: 10.1111/acel.12067

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Egawa, N., Kitaoka, S., Tsukita, K., Naitoh, M., Takahashi, K., Yamamoto, T., Adachi, F., Kondo, T., Okita, K., Asaka, I., Aoi, T., Watanabe, A., Yamada, Y., Morizane, A., Takahashi, J., Ayaki, T., Ito, H., Yoshikawa, K., Yamawaki, S., Suzuki, S., Watanabe, D., Hioki, H., Kaneko, T., Makioka, K., Okamoto, K., Takuma, H., Tamaoka, A., Hasegawa, K., Nonaka, T., Hasegawa, M., Kawata, A., Yoshida, M., Nakahata, T., Takahashi, R., Marchetto, M.C., Gage, F.H., Yamanaka, S., Inoue, H. Response to comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells". (2013) Science Translational Medicine. 5(188):188lr2. DOI: 10.1126/scitranslmed.3005697

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Li, Y., Stam, F.J., Aimone, J.B., Goulding, M., Callaway, E.M., Gage, F.H. Molecular layer perforant path-associated cells contribute to feed-forward inhibition in the adult dentate gyrus. (2013) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 110(22):9106-11. DOI: 10.1073/pnas.1306912110

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Rangel, L.M., Quinn, L.K., Chiba, A.A., Gage, F.H., Aimone, J.B. A hypothesis for temporal coding of young and mature granule cells. (2013) Frontiers in Neuroscience. 7:75. DOI: 10.3389/fnins.2013.00075

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Wang, X., Zhao, Y., Zhang, X., Badie, H., Zhou, Y., Mu, Y., Loo, L.S., Cai, L., Thompson, R.C., Yang, B., Chen, Y., Johnson, P.F., Wu, C., Bu, G., Mobley, W.C., Zhang, D., Gage, F.H., Ranscht, B., Zhang, Y.W., Lipton, S.A., Hong, W., Xu, H. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome. (2013) Nature Medicine. 19(4):473-80. DOI: 10.1038/nm.3117

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Deng, W., Mayford, M., Gage, F.H. Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice. (2013) Elife. 2:e00312. DOI: 10.7554/eLife.00312

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Liang, Y., Franks, T.M., Marchetto, M.C., Gage, F.H., Hetzer, M.W. Dynamic association of NUP98 with the human genome. (2013) PLOS Genetics. 9(2):e1003308. DOI: 10.1371/journal.pgen.1003308

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Shimozaki, K., Clemenson, G.D., Gage, F.H. Paired related homeobox protein 1 is a regulator of stemness in adult neural stem/progenitor cells. (2013) Journal of Neuroscience. 33(9):4066-75. DOI: 10.1523/JNEUROSCI.4586-12.2013

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Kurian, L., Sancho-Martinez, I., Nivet, E., Aguirre, A., Moon, K., Pendaries, C., Volle-Challier, C., Bono, F., Herbert, J.M., Pulecio, J., Xia, Y., Li, M., Montserrat, N., Ruiz, S., Dubova, I., Rodriguez, C., Denli, A.M., Boscolo, F.S., Thiagarajan, R.D., Gage, F.H., Loring, J.F., Laurent, L.C., Izpisua Belmonte, J.C. Conversion of human fibroblasts to angioblast-like progenitor cells. (2013) Nature Methods. 10(1):77-83. DOI: 10.1038/nmeth.2255

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Brennand, K.J., Simone, A., Tran, N., Gage, F.H. Modeling psychiatric disorders at the cellular and network levels. (2012) Molecular Psychiatry. 17(12):1239-53. DOI: 10.1038/mp.2012.20

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Fava, M., Targum, S.D., Nierenberg, A.A., Bleicher, L.S., Carter, T.A., Wedel, P.C., Hen, R., Gage, F.H., Barlow, C. An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. (2012) J Psychiatr Res. 46(12):1553-63. DOI: 10.1016/j.jpsychires.2012.08.013

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Winner, B., Regensburger, M., Schreglmann, S., Boyer, L., Prots, I., Rockenstein, E., Mante, M., Zhao, C., Winkler, J., Masliah, E., Gage, F.H. Role of α-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. (2012) Journal of Neuroscience. 32(47):16906-16. DOI: 10.1523/JNEUROSCI.2723-12.2012

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Bellin, M., Marchetto, M.C., Gage, F.H., Mummery, C.L. Induced pluripotent stem cells: the new patient? (2012) Nature Reviews Molecular Cell Biology. 13(11):713-26. DOI: 10.1038/nrm3448

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Vilchez, D., Boyer, L., Morantte, I., Lutz, M., Merkwirth, C., Joyce, D., Spencer, B., Page, L., Masliah, E., Berggren, W.T., Gage, F.H., Dillin, A. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. (2012) Naturaleza. 489(7415):304-8. DOI: 10.1038/nature11468

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Boyer, L.F., Campbell, B., Larkin, S., Mu, Y., Gage, F.H. Dopaminergic differentiation of human pluripotent cells. (2012) Curr Protoc Stem Cell Biol. Chapter 1:Unit1H.6. DOI: 10.1002/9780470151808.sc01h06s22

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Egawa, N., Kitaoka, S., Tsukita, K., Naitoh, M., Takahashi, K., Yamamoto, T., Adachi, F., Kondo, T., Okita, K., Asaka, I., Aoi, T., Watanabe, A., Yamada, Y., Morizane, A., Takahashi, J., Ayaki, T., Ito, H., Yoshikawa, K., Yamawaki, S., Suzuki, S., Watanabe, D., Hioki, H., Kaneko, T., Makioka, K., Okamoto, K., Takuma, H., Tamaoka, A., Hasegawa, K., Nonaka, T., Hasegawa, M., Kawata, A., Yoshida, M., Nakahata, T., Takahashi, R., Marchetto, M.C., Gage, F.H., Yamanaka, S., Inoue, H. Drug screening for ALS using patient-specific induced pluripotent stem cells. (2012) Science Translational Medicine. 4(145):145ra104. DOI: 10.1126/scitranslmed.3004052

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Giorgetti, A., Marchetto, M.C., Li, M., Yu, D., Fazzina, R., Mu, Y., Adamo, A., Paramonov, I., Cardoso, J.C., Monasterio, M.B., Bardy, C., Cassiani-Ingoni, R., Liu, G.H., Gage, F.H., Izpisua Belmonte, J.C. Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc. (2012) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 109(31):12556-61. DOI: 10.1073/pnas.1209523109

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Marchetto, M.C., Gage, F.H. Modeling brain disease in a dish: really? (2012) Cell Stem Cell. 10(6):642-5. DOI: 10.1016/j.stem.2012.05.008

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Zhao, C., Warner-Schmidt, J., Duman, R.S., Gage, F.H. Electroconvulsive seizure promotes spine maturation in newborn dentate granule cells in adult rat. (2012) Developmental Neurobiology. 72(6):937-42. DOI: 10.1002/dneu.20986

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Yao, J., Mu, Y., Gage, F.H. Neural stem cells: mechanisms and modeling. (2012) Protein & Cell. 3(4):251-61. DOI: 10.1007/s13238-012-2033-6

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Gage, F.H. Transplantation in the future. (2012) Progress in Brain Research. 200:7-13. DOI: 10.1016/B978-0-444-59575-1.00001-6

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Gage, F.H., Muotri, A.R. What makes each brain unique. (2012) Sci. Am. 306(3):26-31.

Li, Y., Aimone, J.B., Xu, X., Callaway, E.M., Gage, F.H. Development of GABAergic inputs controls the contribution of maturing neurons to the adult hippocampal network. (2012) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 109(11):4290-5. DOI: 10.1073/pnas.1120754109

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Ge, W.P., Miyawaki, A., Gage, F.H., Jan, Y.N., Jan, L.Y. Local generation of glia is a major astrocyte source in postnatal cortex. (2012) Naturaleza. 484(7394):376-80. DOI: 10.1038/nature10959

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Bracko, O., Singer, T., Aigner, S., Knobloch, M., Winner, B., Ray, J., Clemenson, G.D., Suh, H., Couillard-Despres, S., Aigner, L., Gage, F.H., Jessberger, S. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. (2012) Journal of Neuroscience. 32(10):3376-87. DOI: 10.1523/JNEUROSCI.4248-11.2012

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Thuret, S., Thallmair, M., Horky, L.L., Gage, F.H. Enhanced functional recovery in MRL/MpJ mice after spinal cord dorsal hemisection. (2012) PLOS One. 7(2):e30904. DOI: 10.1371/journal.pone.0030904

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Shimozaki, K., Zhang, C.L., Suh, H., Denli, A.M., Evans, R.M., Gage, F.H. SRY-box-containing gene 2 regulation of nuclear receptor tailless (Tlx) transcription in adult neural stem cells. (2012) Revista de Química Biológica. 287(8):5969-78. DOI: 10.1074/jbc.M111.290403

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Lee, S.W., Clemenson, G.D., Gage, F.H. New neurons in an aged brain. (2012) Behavioural Brain Research. 227(2):497-507. DOI: 10.1016/j.bbr.2011.10.009

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Vivar, C., Potter, M.C., Choi, J., Lee, J.Y., Stringer, T.P., Callaway, E.M., Gage, F.H., Suh, H., van Praag, H. Monosynaptic inputs to new neurons in the dentate gyrus. (2012) Nature Communications. 3:1107. DOI: 10.1038/ncomms2101

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Gage, F.H. ISSCR: beginning the next chapter. (2012) Cell Stem Cell. 10(1):29-31. DOI: 10.1016/j.stem.2011.12.009

Han, J., Denli, A.M., Gage, F.H. The enemy within: intronic miR-26b represses its host gene, ctdsp2, to regulate neurogenesis. (2012) Genes & Development. 26(1):6-10. DOI: 10.1101/gad.184416.111

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Brennand, K.J., Gage, F.H. Modeling psychiatric disorders through reprogramming. (2012) Dis Model Mech. 5(1):26-32. DOI: 10.1242/dmm.008268

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Israel, M.A., Yuan, S.H., Bardy, C., Reyna, S.M., Mu, Y., Herrera, C., Hefferan, M.P., Van Gorp, S., Nazor, K.L., Boscolo, F.S., Carson, C.T., Laurent, L.C., Marsala, M., Gage, F.H., Remes, A.M., Koo, E.H., Goldstein, L.S. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. (2012) Naturaleza. 482(7384):216-20. DOI: 10.1038/nature10821

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Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.

Boyce, V.S., Park, J., Gage, F.H., Mendell, L.M. Differential effects of brain-derived neurotrophic factor and neurotrophin-3 on hindlimb function in paraplegic rats. (2012) Eur. J. Neurosci. 35(2):221-32. DOI: 10.1111/j.1460-9568.2011.07950.x

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We compared the effect of viral administration of brain-derived neurotrophic factor (BDNF) or neurotrophin 3 (NT-3) on locomotor recovery in adult rats with complete thoracic (T10) spinal cord transection injuries, in order to determine the effect of chronic neurotrophin expression on spinal plasticity. At the time of injury, BDNF, NT-3 or green fluorescent protein (GFP) (control) was delivered to the lesion via adeno-associated virus (AAV) constructs. AAV-BDNF was significantly more effective than AAV-NT-3 in eliciting locomotion. In fact, AAV-BDNF-treated rats displayed plantar, weight-supported hindlimb stepping on a stationary platform, that is, without the assistance of a moving treadmill and without step training. Rats receiving AAV-NT-3 or AAV-GFP were incapable of hindlimb stepping during this task, despite provision of balance support. AAV-NT-3 treatment did promote the recovery of treadmill-assisted stepping, but this required continuous perineal stimulation. In addition, AAV-BDNF-treated rats were sensitized to noxious heat, whereas AAV-NT-3-treated and AAV-GFP-treated rats were not. Notably, AAV-BDNF-treated rats also developed hindlimb spasticity, detracting from its potential clinical applicability via the current viral delivery method. Intracellular recording from triceps surae motoneurons revealed that AAV-BDNF significantly reduced motoneuron rheobase, suggesting that AAV-BDNF promoted the recovery of over-ground stepping by enhancing neuronal excitability. Elevated nuclear c-Fos expression in interneurons located in the L2 intermediate zone after AAV-BDNF treatment indicated increased activation of interneurons in the vicinity of the locomotor central pattern generator. AAV-NT-3 treatment reduced motoneuron excitability, with little change in c-Fos expression. These results support the potential for BDNF delivery at the lesion site to reorganize locomotor circuits.

Mu, Y., Gage, F.H. Adult hippocampal neurogenesis and its role in Alzheimer's disease. (2011) Mol Neurodegener. 6:85. DOI: 10.1186/1750-1326-6-85

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Coufal, N.G., Garcia-Perez, J.L., Peng, G.E., Marchetto, M.C., Muotri, A.R., Mu, Y., Carson, C.T., Macia, A., Moran, J.V., Gage, F.H. Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells. (2011) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 108(51):20382-7. DOI: 10.1073/pnas.1100273108

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Brennand, K.J., Gage, F.H. Concise review: the promise of human induced pluripotent stem cell-based studies of schizophrenia. (2011) Stem Cells. 29(12):1915-22. DOI: 10.1002/stem.762

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Kuwabara, T., Kagalwala, M.N., Onuma, Y., Ito, Y., Warashina, M., Terashima, K., Sanosaka, T., Nakashima, K., Gage, F.H., Asashima, M. Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. (2011) EMBO Molecular Medicine. 3(12):742-54. DOI: 10.1002/emmm.201100177

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Marchetto, M.C., Brennand, K.J., Boyer, L.F., Gage, F.H. Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises. (2011) Human Molecular Genetics. 20(R2):R109-15. DOI: 10.1093/hmg/ddr336

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Hester, M.E., Murtha, M.J., Song, S., Rao, M., Miranda, C.J., Meyer, K., Tian, J., Boulting, G., Schaffer, D.V., Zhu, M.X., Pfaff, S.L., Gage, F.H., Kaspar, B.K. Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. (2011) Mol. Ther. 19(10):1905-12. DOI: 10.1038/mt.2011.135

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Zhu, Q., Pao, G.M., Huynh, A.M., Suh, H., Tonnu, N., Nederlof, P.M., Gage, F.H., Verma, I.M. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. (2011) Naturaleza. 477(7363):179-84. DOI: 10.1038/nature10371

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Shen, B., Xiang, Z., Miller, B., Louie, G., Wang, W., Noel, J.P., Gage, F.H., Wang, L. Genetically encoding unnatural amino acids in neural stem cells and optically reporting voltage-sensitive domain changes in differentiated neurons. (2011) Stem Cells. 29(8):1231-40. DOI: 10.1002/stem.679

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Woods, N.B., Parker, A.S., Moraghebi, R., Lutz, M.K., Firth, A.L., Brennand, K.J., Berggren, W.T., Raya, A., Izpisúa Belmonte, J.C., Gage, F.H., Verma, I.M. Brief report: efficient generation of hematopoietic precursors and progenitors from human pluripotent stem cell lines. (2011) Stem Cells. 29(7):1158-64. DOI: 10.1002/stem.657

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Aimone, J.B., Deng, W., Gage, F.H. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. (2011) Neuron. 70(4):589-96. DOI: 10.1016/j.neuron.2011.05.010

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Brennand, K.J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., McCarthy, S., Sebat, J., Gage, F.H. Modelling schizophrenia using human induced pluripotent stem cells. (2011) Naturaleza. 473(7346):221-5. DOI: 10.1038/nature09915

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Mu, Y., Zhao, C., Gage, F.H. Dopaminergic modulation of cortical inputs during maturation of adult-born dentate granule cells. (2011) Journal of Neuroscience. 31(11):4113-23. DOI: 10.1523/JNEUROSCI.4913-10.2011

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Aimone, J.B., Gage, F.H. Modeling new neuron function: a history of using computational neuroscience to study adult neurogenesis. (2011) European Journal of Neuroscience. 33(6):1160-9. DOI: 10.1111/j.1460-9568.2011.07615.x

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Winner, B., Kohl, Z., Gage, F.H. Neurodegenerative disease and adult neurogenesis. (2011) Eur. J. Neurosci. 33(6):1139-51. DOI: 10.1111/j.1460-9568.2011.07613.x

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Winner, B., Jappelli, R., Maji, S.K., Desplats, P.A., Boyer, L., Aigner, S., Hetzer, C., Loher, T., Vilar, M., Campioni, S., Tzitzilonis, C., Soragni, A., Jessberger, S., Mira, H., Consiglio, A., Pham, E., Masliah, E., Gage, F.H., Riek, R. In vivo demonstration that alpha-synuclein oligomers are toxic. (2011) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 108(10):4194-9. DOI: 10.1073/pnas.1100976108

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Winner, B., Melrose, H.L., Zhao, C., Hinkle, K.M., Yue, M., Kent, C., Braithwaite, A.T., Ogholikhan, S., Aigner, R., Winkler, J., Farrer, M.J., Gage, F.H. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. (2011) Neurobiol. Dis. 41(3):706-16. DOI: 10.1016/j.nbd.2010.12.008

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Yuan, S.H., Martin, J., Elia, J., Flippin, J., Paramban, R.I., Hefferan, M.P., Vidal, J.G., Mu, Y., Killian, R.L., Israel, M.A., Emre, N., Marsala, S., Marsala, M., Gage, F.H., Goldstein, L.S., Carson, C.T. Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells. (2011) PLOS One. 6(3):e17540. DOI: 10.1371/journal.pone.0017540

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Kim, J.E., O'Sullivan, M.L., Sanchez, C.A., Hwang, M., Israel, M.A., Brennand, K., Deerinck, T.J., Goldstein, L.S., Gage, F.H., Ellisman, M.H., Ghosh, A. Investigating synapse formation and function using human pluripotent stem cell-derived neurons. (2011) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 108(7):3005-10. DOI: 10.1073/pnas.1007753108

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Meng, X., Arocena, M., Penninger, J., Gage, F.H., Zhao, M., Song, B. PI3K mediated electrotaxis of embryonic and adult neural progenitor cells in the presence of growth factors. (2011) Exp. Neurol. 227(1):210-7. DOI: 10.1016/j.expneurol.2010.11.002

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Ruiz, S., Brennand, K., Panopoulos, A.D., Herrerías, A., Gage, F.H., Izpisua-Belmonte, J.C. High-efficient generation of induced pluripotent stem cells from human astrocytes. (2010) PLOS One. 5(12):e15526. DOI: 10.1371/journal.pone.0015526

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Marchetto, M.C., Carromeu, C., Acab, A., Yu, D., Yeo, G.W., Mu, Y., Chen, G., Gage, F.H., Muotri, A.R. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. (2010) Móvil. 143(4):527-39. DOI: 10.1016/j.cell.2010.10.016

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Mathews, E.A., Morgenstern, N.A., Piatti, V.C., Zhao, C., Jessberger, S., Schinder, A.F., Gage, F.H. A distinctive layering pattern of mouse dentate granule cells is generated by developmental and adult neurogenesis. (2010) Journal of Comparative Neurology. 518(22):4479-90. DOI: 10.1002/cne.22489

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Muotri, A.R., Marchetto, M.C., Coufal, N.G., Oefner, R., Yeo, G., Nakashima, K., Gage, F.H. L1 retrotransposition in neurons is modulated by MeCP2. (2010) Naturaleza. 468(7322):443-6. DOI: 10.1038/nature09544

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Long interspersed nuclear elements-1 (LINE-1 or L1s) are abundant retrotransposons that comprise approximately 20% of mammalian genomes. Active L1 retrotransposons can impact the genome in a variety of ways, creating insertions, deletions, new splice sites or gene expression fine-tuning. We have shown previously that L1 retrotransposons are capable of mobilization in neuronal progenitor cells from rodents and humans and evidence of massive L1 insertions was observed in adult brain tissues but not in other somatic tissues. In addition, L1 mobility in the adult hippocampus can be influenced by the environment. The neuronal specificity of somatic L1 retrotransposition in neural progenitors is partially due to the transition of a Sox2/HDAC1 repressor complex to a Wnt-mediated T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activator. The transcriptional switch accompanies chromatin remodelling during neuronal differentiation, allowing a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can have an impact on gene expression and neuronal function, thereby increasing brain-specific genetic mosaicism. Further understanding of the molecular mechanisms that regulate L1 expression should provide new insights into the role of L1 retrotransposition during brain development. Here we show that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of methyl-CpG-binding protein 2 (MeCP2), a protein involved in global DNA methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that patients with Rett syndrome (RTT), carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. Our findings add a new level of complexity to the molecular events that can lead to neurological disorders.

Ma, D.K., Marchetto, M.C., Guo, J.U., Ming, G.L., Gage, F.H., Song, H. Epigenetic choreographers of neurogenesis in the adult mammalian brain. (2010) Nature Neuroscience. 13(11):1338-44. DOI: 10.1038/nn.2672

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Aimone, J.B., Deng, W., Gage, F.H. Put them out to pasture? What are old granule cells good for, anyway...? (2010) Hippocampus. 20(10):1124-5. DOI: 10.1002/hipo.20867

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Liu, D., Ou, L., Clemenson, G.D., Chao, C., Lutske, M.E., Zambetti, G.P., Gage, F.H., Xu, Y. Puma is required for p53-induced depletion of adult stem cells. (2010) Naturaleza y Biología Celular. 12(10):993-8. DOI: 10.1038/ncb2100

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Petruska, J.C., Kitay, B., Boyce, V.S., Kaspar, B.K., Pearse, D.D., Gage, F.H., Mendell, L.M. Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats. (2010) Eur. J. Neurosci. 32(6):997-1005. DOI: 10.1111/j.1460-9568.2010.07392.x

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Mu, Y., Lee, S.W., Gage, F.H. Signaling in adult neurogenesis. (2010) Current Opinion in Neurobiology. 20(4):416-23. DOI: 10.1016/j.conb.2010.04.010

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Singer, T., McConnell, M.J., Marchetto, M.C., Coufal, N.G., Gage, F.H. LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? (2010) Trends in Neurosciences. 33(8):345-54. DOI: 10.1016/j.tins.2010.04.001

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Valdez, G., Tapia, J.C., Kang, H., Clemenson, G.D., Gage, F.H., Lichtman, J.W., Sanes, J.R. Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. (2010) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 107(33):14863-8. DOI: 10.1073/pnas.1002220107

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Mira, H., Andreu, Z., Suh, H., Lie, D.C., Jessberger, S., Consiglio, A., San Emeterio, J., Hortigüela, R., Marqués-Torrejón, M.A., Nakashima, K., Colak, D., Götz, M., Fariñas, I., Gage, F.H. Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus. (2010) Cell Stem Cell. 7(1):78-89. DOI: 10.1016/j.stem.2010.04.016

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Aimone, J.B., Deng, W., Gage, F.H. Adult neurogenesis: integrating theories and separating functions. (2010) Trends in Cognitive Sciences. 14(7):325-37. DOI: 10.1016/j.tics.2010.04.003

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Deng, W., Aimone, J.B., Gage, F.H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? (2010) Nature Reviews Neuroscience. 11(5):339-50. DOI: 10.1038/nrn2822

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Marchetto, M.C., Winner, B., Gage, F.H. Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases. (2010) Human Molecular Genetics. 19(R1):R71-6. DOI: 10.1093/hmg/ddq159

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Tronel, S., Fabre, A., Charrier, V., Oliet, S.H., Gage, F.H., Abrous, D.N. Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons. (2010) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 107(17):7963-8. DOI: 10.1073/pnas.0914613107

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Gage, F.H. Molecular and cellular mechanisms contributing to the regulation, proliferation and differentiation of neural stem cells in the adult dentate gyrus. (2010) Keio J Med. 59(3):79-83.

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Glass, C.K., Saijo, K., Winner, B., Marchetto, M.C., Gage, F.H. Mechanisms underlying inflammation in neurodegeneration. (2010) Móvil. 140(6):918-34. DOI: 10.1016/j.cell.2010.02.016

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Gage, F. The promise and the challenge of modelling human disease in a dish. (2010) EMBO Molecular Medicine. 2(3):77-8. DOI: 10.1002/emmm.201000060

Qu, Q., Sun, G., Li, W., Yang, S., Ye, P., Zhao, C., Yu, R.T., Gage, F.H., Evans, R.M., Shi, Y. Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. (2010) Naturaleza y Biología Celular. 12(1):31-40; sup pp 1-9. DOI: 10.1038/ncb2001

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Nakashima, K., Kohyama, J., Namihira, M., Gage, F.H., Okano, H., Sawamoto, K. [Epigenetic mechanisms regulating neural cell fate determination]. (2009) No To Hattatsu. 41(6):411-4.

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Jessberger, S., Gage, F.H., Eisch, A.J., Lagace, D.C. Making a neuron: Cdk5 in embryonic and adult neurogenesis. (2009) Trends in Neurosciences. 32(11):575-82. DOI: 10.1016/j.tins.2009.07.002

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Deng, W., Saxe, M.D., Gallina, I.S., Gage, F.H. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. (2009) Journal of Neuroscience. 29(43):13532-42. DOI: 10.1523/JNEUROSCI.3362-09.2009

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Muotri, A.R., Zhao, C., Marchetto, M.C., Gage, F.H. Environmental influence on L1 retrotransposons in the adult hippocampus. (2009) Hippocampus. 19(10):1002-7. DOI: 10.1002/hipo.20564

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Marchetto, M.C., Yeo, G.W., Kainohana, O., Marsala, M., Gage, F.H., Muotri, A.R. Transcriptional signature and memory retention of human-induced pluripotent stem cells. (2009) PLOS One. 4(9):e7076. DOI: 10.1371/journal.pone.0007076

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Tamaki, S.J., Jacobs, Y., Dohse, M., Capela, A., Cooper, J.D., Reitsma, M., He, D., Tushinski, R., Belichenko, P.V., Salehi, A., Mobley, W., Gage, F.H., Huhn, S., Tsukamoto, A.S., Weissman, I.L., Uchida, N. Neuroprotection of host cells by human central nervous system stem cells in a mouse model of infantile neuronal ceroid lipofuscinosis. (2009) Cell Stem Cell. 5(3):310-9. DOI: 10.1016/j.stem.2009.05.022

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Kuwabara, T., Hsieh, J., Muotri, A., Yeo, G., Warashina, M., Lie, D.C., Moore, L., Nakashima, K., Asashima, M., Gage, F.H. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. (2009) Nature Neuroscience. 12(9):1097-105. DOI: 10.1038/nn.2360

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Coufal, N.G., Garcia-Perez, J.L., Peng, G.E., Yeo, G.W., Mu, Y., Lovci, M.T., Morell, M., O'Shea, K.S., Moran, J.V., Gage, F.H. L1 retrotransposition in human neural progenitor cells. (2009) Naturaleza. 460(7259):1127-31. DOI: 10.1038/nature08248

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Overall, R.W., Kempermann, G., Peirce, J., Lu, L., Goldowitz, D., Gage, F.H., Goodwin, S., Smit, A.B., Airey, D.C., Rosen, G.D., Schalkwyk, L.C., Sutter, T.R., Nowakowski, R.S., Whatley, S., Williams, R.W. Genetics of the hippocampal transcriptome in mouse: a systematic survey and online neurogenomics resource. (2009) Frontiers in Neuroscience. 3:55. DOI: 10.3389/neuro.15.003.2009

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Clelland, C.D., Choi, M., Romberg, C., Clemenson, G.D., Fragniere, A., Tyers, P., Jessberger, S., Saksida, L.M., Barker, R.A., Gage, F.H., Bussey, T.J. A functional role for adult hippocampal neurogenesis in spatial pattern separation. (2009) Ciencia. 325(5937):210-3. DOI: 10.1126/science.1173215

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Thuret, S., Toni, N., Aigner, S., Yeo, G.W., Gage, F.H. Hippocampus-dependent learning is associated with adult neurogenesis in MRL/MpJ mice. (2009) Hippocampus. 19(7):658-69. DOI: 10.1002/hipo.20550

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Fortun, J., Puzis, R., Pearse, D.D., Gage, F.H., Bunge, M.B. Muscle injection of AAV-NT3 promotes anatomical reorganization of CST axons and improves behavioral outcome following SCI. (2009) J. Neurotrauma. 26(7):941-53. DOI: 10.1089/neu.2008.0807

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Jagasia, R., Steib, K., Englberger, E., Herold, S., Faus-Kessler, T., Saxe, M., Gage, F.H., Song, H., Lie, D.C. GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. (2009) Journal of Neuroscience. 29(25):7966-77. DOI: 10.1523/JNEUROSCI.1054-09.2009

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Li, Y., Mu, Y., Gage, F.H. Development of neural circuits in the adult hippocampus. (2009) Current Topics in Developmental Biology. 87:149-74. DOI: 10.1016/S0070-2153(09)01205-8

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Suh, H., Deng, W., Gage, F.H. Signaling in adult neurogenesis. (2009) Annual Review of Cell and Developmental Biology. 25:253-75. DOI: 10.1146/annurev.cellbio.042308.113256

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Andrews, M.R., Czvitkovich, S., Dassie, E., Vogelaar, C.F., Faissner, A., Blits, B., Gage, F.H., ffrench-Constant, C., Fawcett, J.W. Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration. (2009) Journal of Neuroscience. 29(17):5546-57. DOI: 10.1523/JNEUROSCI.0759-09.2009

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Saijo, K., Winner, B., Carson, C.T., Collier, J.G., Boyer, L., Rosenfeld, M.G., Gage, F.H., Glass, C.K. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. (2009) Móvil. 137(1):47-59. DOI: 10.1016/j.cell.2009.01.038

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Denli, A.M., Cao, X., Gage, F.H. miR-9 and TLX: chasing tails in neural stem cells. (2009) Nature Structural & Molecular Biology. 16(4):346-7. DOI: 10.1038/nsmb0409-346

Zhao, C., Suh, H., Gage, F.H. Notch keeps ependymal cells in line. (2009) Nature Neuroscience. 12(3):243-5. DOI: 10.1038/nn0309-243

Jessberger, S., Clark, R.E., Broadbent, N.J., Clemenson, G.D., Consiglio, A., Lie, D.C., Squire, L.R., Gage, F.H. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. (2009) Learn. Mem. 16(2):147-54. DOI: 10.1101/lm.1172609

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Yeo, G.W., Coufal, N.G., Liang, T.Y., Peng, G.E., Fu, X.D., Gage, F.H. An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells. (2009) Nature Structural & Molecular Biology. 16(2):130-7. DOI: 10.1038/nsmb.1545

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Jessberger, S., Gage, F.H. Fate plasticity of adult hippocampal progenitors: biological relevance and therapeutic use. (2009) Tendencias en Ciencias Farmacológicas. 30(2):61-5. DOI: 10.1016/j.tips.2008.11.003

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Aimone, J.B., Wiles, J., Gage, F.H. Computational influence of adult neurogenesis on memory encoding. (2009) Neuron. 61(2):187-202. DOI: 10.1016/j.neuron.2008.11.026

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Marumoto, T., Tashiro, A., Friedmann-Morvinski, D., Scadeng, M., Soda, Y., Gage, F.H., Verma, I.M. Development of a novel mouse glioma model using lentiviral vectors. (2009) Nature Medicine. 15(1):110-6. DOI: 10.1038/nm.1863

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Rose, J.B., Crews, L., Rockenstein, E., Adame, A., Mante, M., Hersh, L.B., Gage, F.H., Spencer, B., Potkar, R., Marr, R.A., Masliah, E. Neuropeptide Y fragments derived from neprilysin processing are neuroprotective in a transgenic model of Alzheimer's disease. (2009) Journal of Neuroscience. 29(4):1115-25. DOI: 10.1523/JNEUROSCI.4220-08.2009

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Marchetto, M.C., Muotri, A.R., Mu, Y., Smith, A.M., Cezar, G.G., Gage, F.H. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. (2008) Cell Stem Cell. 3(6):649-57. DOI: 10.1016/j.stem.2008.10.001

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Cao, X., Pfaff, S.L., Gage, F.H. YAP regulates neural progenitor cell number via the TEA domain transcription factor. (2008) Genes & Development. 22(23):3320-34. DOI: 10.1101/gad.1726608

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Jessberger, S., Gage, F.H. Stem-cell-associated structural and functional plasticity in the aging hippocampus. (2008) Psychol Aging. 23(4):684-91. DOI: 10.1037/a0014188

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Thompson, C.L., Pathak, S.D., Jeromin, A., Ng, L.L., MacPherson, C.R., Mortrud, M.T., Cusick, A., Riley, Z.L., Sunkin, S.M., Bernard, A., Puchalski, R.B., Gage, F.H., Jones, A.R., Bajic, V.B., Hawrylycz, M.J., Lein, E.S. Genomic anatomy of the hippocampus. (2008) Neuron. 60(6):1010-21. DOI: 10.1016/j.neuron.2008.12.008

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Jessberger, S., Aigner, S., Clemenson, G.D., Toni, N., Lie, D.C., Karalay, O., Overall, R., Kempermann, G., Gage, F.H. Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus. (2008) PLOS Biology. 6(11):e272. DOI: 10.1371/journal.pbio.0060272

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Spencer, B., Marr, R.A., Rockenstein, E., Crews, L., Adame, A., Potkar, R., Patrick, C., Gage, F.H., Verma, I.M., Masliah, E. Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice. (2008) BMC Neurosci. 9:109. DOI: 10.1186/1471-2202-9-109

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Kohyama, J., Kojima, T., Takatsuka, E., Yamashita, T., Namiki, J., Hsieh, J., Gage, F.H., Namihira, M., Okano, H., Sawamoto, K., Nakashima, K. Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain. (2008) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 105(46):18012-7. DOI: 10.1073/pnas.0808417105

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Li, X., Barkho, B.Z., Luo, Y., Smrt, R.D., Santistevan, N.J., Liu, C., Kuwabara, T., Gage, F.H., Zhao, X. Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells. (2008) Revista de Química Biológica. 283(41):27644-52. DOI: 10.1074/jbc.M804899200

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Gage, F.H., Selzer, M.E. Experts provide insights into emerging field of brain and spine repair. Interview by Bridget M. Kuehn. (2008) JAMA. 300(9):1013-4. DOI: 10.1001/jama.300.9.1013

Toni, N., Laplagne, D.A., Zhao, C., Lombardi, G., Ribak, C.E., Gage, F.H., Schinder, A.F. Neurons born in the adult dentate gyrus form functional synapses with target cells. (2008) Nature Neuroscience. 11(8):901-7. DOI: 10.1038/nn.2156

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Jessberger, S., Toni, N., Clemenson, G.D., Ray, J., Gage, F.H. Directed differentiation of hippocampal stem/progenitor cells in the adult brain. (2008) Nature Neuroscience. 11(8):888-93. DOI: 10.1038/nn.2148

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Yeo, G.W., Coufal, N., Aigner, S., Winner, B., Scolnick, J.A., Marchetto, M.C., Muotri, A.R., Carson, C., Gage, F.H. Multiple layers of molecular controls modulate self-renewal and neuronal lineage specification of embryonic stem cells. (2008) Human Molecular Genetics. 17(R1):R67-75. DOI: 10.1093/hmg/ddn065

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Zhao, C., Deng, W., Gage, F.H. Mechanisms and functional implications of adult neurogenesis. (2008) Móvil. 132(4):645-60. DOI: 10.1016/j.cell.2008.01.033

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Zhang, C.L., Zou, Y., He, W., Gage, F.H., Evans, R.M. A role for adult TLX-positive neural stem cells in learning and behaviour. (2008) Naturaleza. 451(7181):1004-7. DOI: 10.1038/nature06562

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Cezar, G.G., Quam, J.A., Smith, A.M., Rosa, G.J., Piekarczyk, M.S., Brown, J.F., Gage, F.H., Muotri, A.R. Identification of small molecules from human embryonic stem cells using metabolomics. (2007) Stem Cells Dev. 16(6):869-82. DOI: 10.1089/scd.2007.0022

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Yao, W., Nathanson, J., Lian, I., Gage, F.H., Sung, L.A. Mouse erythrocyte tropomodulin in the brain reported by lacZ knocked-in downstream from the E1 promoter. (2007) Gene Expr. Patterns. 8(1):36-46. DOI: 10.1016/j.modgep.2007.08.002

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Suh, H., Consiglio, A., Ray, J., Sawai, T., D'Amour, K.A., Gage, F.H. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. (2007) Cell Stem Cell. 1(5):515-28. DOI: 10.1016/j.stem.2007.09.002

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Yeo, G.W., Xu, X., Liang, T.Y., Muotri, A.R., Carson, C.T., Coufal, N.G., Gage, F.H. Alternative splicing events identified in human embryonic stem cells and neural progenitors. (2007) PLOS Computational Biology. 3(10):1951-67. DOI: 10.1371/journal.pcbi.0030196

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Human embryonic stem cells (hESCs) and neural progenitor (NP) cells are excellent models for recapitulating early neuronal development in vitro, and are key to establishing strategies for the treatment of degenerative disorders. While much effort had been undertaken to analyze transcriptional and epigenetic differences during the transition of hESC to NP, very little work has been performed to understand post-transcriptional changes during neuronal differentiation. Alternative RNA splicing (AS), a major form of post-transcriptional gene regulation, is important in mammalian development and neuronal function. Human ESC, hESC-derived NP, and human central nervous system stem cells were compared using Affymetrix exon arrays. We introduced an outlier detection approach, REAP (Regression-based Exon Array Protocol), to identify 1,737 internal exons that are predicted to undergo AS in NP compared to hESC. Experimental validation of REAP-predicted AS events indicated a threshold-dependent sensitivity ranging from 56% to 69%, at a specificity of 77% to 96%. REAP predictions significantly overlapped sets of alternative events identified using expressed sequence tags and evolutionarily conserved AS events. Our results also reveal that focusing on differentially expressed genes between hESC and NP will overlook 14% of potential AS genes. In addition, we found that REAP predictions are enriched in genes encoding serine/threonine kinase and helicase activities. An example is a REAP-predicted alternative exon in the SLK (serine/threonine kinase 2) gene that is differentially included in hESC, but skipped in NP as well as in other differentiated tissues. Lastly, comparative sequence analysis revealed conserved intronic cis-regulatory elements such as the FOX1/2 binding site GCAUG as being proximal to candidate AS exons, suggesting that FOX1/2 may participate in the regulation of AS in NP and hESC. In summary, a new methodology for exon array analysis was introduced, leading to new insights into the complexity of AS in human embryonic stem cells and their transition to neural stem cells.

Muotri, A.R., Marchetto, M.C., Coufal, N.G., Gage, F.H. The necessary junk: new functions for transposable elements. (2007) Human Molecular Genetics. 16 Spec No:R159-67. DOI: 10.1093/hmg/ddm196

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Jessberger, S., Zhao, C., Toni, N., Clemenson, G.D., Li, Y., Gage, F.H. Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling. (2007) Journal of Neuroscience. 27(35):9400-7. DOI: 10.1523/JNEUROSCI.2002-07.2007

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Lanctot, P.M., Gage, F.H., Varki, A.P. The glycans of stem cells. (2007) Current Opinion in Chemical Biology. 11(4):373-80. DOI: 10.1016/j.cbpa.2007.05.032

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Aigner, S., Denli, A.M., Gage, F.H. A novel model for an older remodeler: the BAF swap in neurogenesis. (2007) Neuron. 55(2):171-3. DOI: 10.1016/j.neuron.2007.07.004

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Smrt, R.D., Eaves-Egenes, J., Barkho, B.Z., Santistevan, N.J., Zhao, C., Aimone, J.B., Gage, F.H., Zhao, X. Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. (2007) Neurobiol. Dis. 27(1):77-89. DOI: 10.1016/j.nbd.2007.04.005

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Garcia-Perez, J.L., Marchetto, M.C., Muotri, A.R., Coufal, N.G., Gage, F.H., O'Shea, K.S., Moran, J.V. LINE-1 retrotransposition in human embryonic stem cells. (2007) Human Molecular Genetics. 16(13):1569-77. DOI: 10.1093/hmg/ddm105

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Toni, N., Teng, E.M., Bushong, E.A., Aimone, J.B., Zhao, C., Consiglio, A., van Praag, H., Martone, M.E., Ellisman, M.H., Gage, F.H. Synapse formation on neurons born in the adult hippocampus. (2007) Nature Neuroscience. 10(6):727-34. DOI: 10.1038/nn1908

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El-Amouri, S.S., Zhu, H., Yu, J., Gage, F.H., Verma, I.M., Kindy, M.S. Neprilysin protects neurons against Abeta peptide toxicity. (2007) Brain Research. 1152:191-200. DOI: 10.1016/j.brainres.2007.03.072

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Parent, J.M., Jessberger, S., Gage, F.H., Gong, C. Is neurogenesis reparative after status epilepticus? (2007) Epilepsia. 48 Suppl 8:69-71.

Jessberger, S., Nakashima, K., Clemenson, G.D., Mejia, E., Mathews, E., Ure, K., Ogawa, S., Sinton, C.M., Gage, F.H., Hsieh, J. Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. (2007) Journal of Neuroscience. 27(22):5967-75. DOI: 10.1523/JNEUROSCI.0110-07.2007

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van Praag, H., Lucero, M.J., Yeo, G.W., Stecker, K., Heivand, N., Zhao, C., Yip, E., Afanador, M., Schroeter, H., Hammerstone, J., Gage, F.H. Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in mice. (2007) Journal of Neuroscience. 27(22):5869-78. DOI: 10.1523/JNEUROSCI.0914-07.2007

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Laplagne, D.A., Kamienkowski, J.E., Espósito, M.S., Piatti, V.C., Zhao, C., Gage, F.H., Schinder, A.F. Similar GABAergic inputs in dentate granule cells born during embryonic and adult neurogenesis. (2007) European Journal of Neuroscience. 25(10):2973-81. DOI: 10.1111/j.1460-9568.2007.05549.x

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Jessberger, S., Clemenson, G.D., Gage, F.H. Spontaneous fusion and nonclonal growth of adult neural stem cells. (2007) Stem Cells. 25(4):871-4. DOI: 10.1634/stemcells.2006-0620

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Tashiro, A., Makino, H., Gage, F.H. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. (2007) Journal of Neuroscience. 27(12):3252-9. DOI: 10.1523/JNEUROSCI.4941-06.2007

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Leingärtner, A., Thuret, S., Kroll, T.T., Chou, S.J., Leasure, J.L., Gage, F.H., O'Leary, D.D. Cortical area size dictates performance at modality-specific behaviors. (2007) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 104(10):4153-8. DOI: 10.1073/pnas.0611723104

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Cao, X., Pfaff, S.L., Gage, F.H. A functional study of miR-124 in the developing neural tube. (2007) Genes & Development. 21(5):531-6. DOI: 10.1101/gad.1519207

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Pereira, A.C., Huddleston, D.E., Brickman, A.M., Sosunov, A.A., Hen, R., McKhann, G.M., Sloan, R., Gage, F.H., Brown, T.R., Small, S.A. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. (2007) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 104(13):5638-43. DOI: 10.1073/pnas.0611721104

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Suzuki, S., Gerhold, L.M., Böttner, M., Rau, S.W., Dela Cruz, C., Yang, E., Zhu, H., Yu, J., Cashion, A.B., Kindy, M.S., Merchenthaler, I., Gage, F.H., Wise, P.M. Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. (2007) Journal of Comparative Neurology. 500(6):1064-75. DOI: 10.1002/cne.21240

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Jessberger, S., Gage, F.H. ZOOMING IN: a new high-resolution gene expression atlas of the brain. (2007) Mol. Syst. Biol. 3:75. DOI: 10.1038/msb4100122

Miller, T.M., Kim, S.H., Yamanaka, K., Hester, M., Umapathi, P., Arnson, H., Rizo, L., Mendell, J.R., Gage, F.H., Cleveland, D.W., Kaspar, B.K. Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis. (2006) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 103(51):19546-51. DOI: 10.1073/pnas.0609411103

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Suhonen, J., Ray, J., Blömer, U., Gage, F.H., Kaspar, B. Ex vivo and in vivo gene delivery to the brain. (2006) Current Protocols in Human Genetics. Chapter 13:Unit 13.3. DOI: 10.1002/0471142905.hg1303s51

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Thallmair, M., Ray, J., Stallcup, W.B., Gage, F.H. Functional and morphological effects of NG2 proteoglycan deletion on hippocampal neurogenesis. (2006) Exp. Neurol. 202(1):167-78. DOI: 10.1016/j.expneurol.2006.05.025

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NG2-expressing cells are the largest proliferating cell population in the adult central nervous system. The function of NG2 proteoglycan or NG2-expressing cells in the adult brain, however, is unknown. So far, NG2-positive cells are thought to be mainly oligodendrocyte precursor cells. This view was recently challenged when NG2+/CNP-EGFP-positive cells were identified as multipotent progenitor cells in the postnatal and adult CNS (e.g., [Belachew, S., Chittajallu, R., Aguirre, A.A., Yuan, X., Kirby, M., Anderson, S., Gallo, V., 2003. Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J. Cell Biol. 161, 169-186]). In addition, purified NG2-expressing progenitor cells, were shown to differentiate into neurons and astrocytes in vitro [Sellers, D.L., Horner, P.J., 2005. Instructive niches: environmental instructions that confound NG2 proteoglycan expression and the fate-restriction of CNS progenitors J. Anat. 207, 727-734]. In this study, we focus on the influence of NG2 ablation on neurogenesis in the hippocampus, where putative multipotent NG2-positive cells reside, and on hippocampus-dependent behavior using NG2 knockout mice. Using the thymidine analogue bromodeoxyuridine (BrdU) to label dividing cells in vivo we show that the number of BrdU-positive cells was unchanged in the hippocampus of NG2 knockout mice 1 day after a series of BrdU injections. This finding suggests that the proliferation rate of hippocampal progenitor cells is not influenced by NG2. A few BrdU-positive cells were found in deeper layers of the granule zone 1 day after a series of BrdU injections, which is different from the wild type. The presence and the phenotype of newborn hippocampal cells were studied 4 weeks after a series of BrdU injections. The survival and differentiation of BrdU-positive cells in NG2 knockout hippocampus did not significantly differ from wild-type mice. Concurrently, the water maze task did not reveal obvious differences compared to wild-type animals. These results suggest that the null mutation for NG2 does not influence adult hippocampal neurogenesis or hippocampal-dependent behavioral tasks.

Borrell, V., Kaspar, B.K., Gage, F.H., Callaway, E.M. In vivo evidence for radial migration of neurons by long-distance somal translocation in the developing ferret visual cortex. (2006) Cereb. Cortex. 16(11):1571-83. DOI: 10.1093/cercor/bhj094

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Ramirez-Amaya, V., Marrone, D.F., Gage, F.H., Worley, P.F., Barnes, C.A. Integration of new neurons into functional neural networks. (2006) Journal of Neuroscience. 26(47):12237-41. DOI: 10.1523/JNEUROSCI.2195-06.2006

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Although it is established that new granule cells can be born and can survive in the adult mammalian hippocampus, there remains some question concerning the functional integration of these neurons into behaviorally relevant neural networks. By using high-resolution confocal microscopy, we have applied a new strategy to address the question of functional integration of newborn neurons into networks that mediate spatial information processing and memory formation. Exploration-induced expression of the immediate-early gene Arc in hippocampal cells has been linked to cellular activity observed in electrophysiological recordings under the same behavioral conditions. We investigated whether mature (5-month-old), newborn granule cells express Arc in response to a discrete spatial experience by detecting the expression of Arc in combination with NeuN (neuron-specific nuclear protein)-positive and bromodeoxyuridine-positive cells. We found that mature new granule cells do indeed express Arc in response to an exploration experience, supporting the idea that these cells are well integrated into hippocampal circuits. The proportion of mature newborn neurons that expressed Arc in response to exploration, however, was significantly higher (approximately 2.8%) than the proportion of cells that expressed Arc in the already existing population of granule cells (approximately 1.6%; p < 0.01). This finding extends previous data suggesting that the cellular physiology of newborn granule neurons differs from that of the existing population by indicating that these properties are retained in mature adult-generated neurons. Thus, these data have interesting implications for network models of spatial information processing and the role of hippocampal circuits in memory, indicating that mature new neurons are selectively recruited into hippocampal cell assemblies in higher proportions than older cells.

Laplagne, D.A., Espósito, M.S., Piatti, V.C., Morgenstern, N.A., Zhao, C., van Praag, H., Gage, F.H., Schinder, A.F. Functional convergence of neurons generated in the developing and adult hippocampus. (2006) PLOS Biology. 4(12):e409. DOI: 10.1371/journal.pbio.0040409

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Carson, C.T., Aigner, S., Gage, F.H. Stem cells: the good, bad and barely in control. (2006) Nature Medicine. 12(11):1237-8. DOI: 10.1038/nm1106-1237

Horky, L.L., Galimi, F., Gage, F.H., Horner, P.J. Fate of endogenous stem/progenitor cells following spinal cord injury. (2006) Journal of Comparative Neurology. 498(4):525-38. DOI: 10.1002/cne.21065

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Jagasia, R., Song, H., Gage, F.H., Lie, D.C. New regulators in adult neurogenesis and their potential role for repair. (2006) Trends in Molecular Medicine. 12(9):400-5. DOI: 10.1016/j.molmed.2006.07.006

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Tashiro, A., Sandler, V.M., Toni, N., Zhao, C., Gage, F.H. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. (2006) Naturaleza. 442(7105):929-33. DOI: 10.1038/nature05028

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Bhardwaj, R.D., Curtis, M.A., Spalding, K.L., Buchholz, B.A., Fink, D., Björk-Eriksson, T., Nordborg, C., Gage, F.H., Druid, H., Eriksson, P.S., Frisén, J. Neocortical neurogenesis in humans is restricted to development. (2006) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 103(33):12564-8. DOI: 10.1073/pnas.0605177103

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Thuret, S., Moon, L.D., Gage, F.H. Therapeutic interventions after spinal cord injury. (2006) Nature Reviews Neuroscience. 7(8):628-43. DOI: 10.1038/nrn1955

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Suzuki, A., Raya, A., Kawakami, Y., Morita, M., Matsui, T., Nakashima, K., Gage, F.H., Rodríguez-Esteban, C., Izpisúa Belmonte, J.C. Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. (2006) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 103(27):10294-9. DOI: 10.1073/pnas.0506945103

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Tashiro, A., Zhao, C., Gage, F.H. Retrovirus-mediated single-cell gene knockout technique in adult newborn neurons in vivo. (2006) Nature Protocols. 1(6):3049-55. DOI: 10.1038/nprot.2006.473

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Muotri, A.R., Gage, F.H. Generation of neuronal variability and complexity. (2006) Naturaleza. 441(7097):1087-93. DOI: 10.1038/nature04959

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Cao, X., Yeo, G., Muotri, A.R., Kuwabara, T., Gage, F.H. Noncoding RNAs in the mammalian central nervous system. (2006) Annual Review of Neuroscience. 29:77-103. DOI: 10.1146/annurev.neuro.29.051605.112839

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Aimone, J.B., Wiles, J., Gage, F.H. Potential role for adult neurogenesis in the encoding of time in new memories. (2006) Nature Neuroscience. 9(6):723-7. DOI: 10.1038/nn1707

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Barkho, B.Z., Song, H., Aimone, J.B., Smrt, R.D., Kuwabara, T., Nakashima, K., Gage, F.H., Zhao, X. Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation. (2006) Stem Cells Dev. 15(3):407-21. DOI: 10.1089/scd.2006.15.407

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Zhang, C.L., Zou, Y., Yu, R.T., Gage, F.H., Evans, R.M. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. (2006) Genes & Development. 20(10):1308-20. DOI: 10.1101/gad.1413606

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Jacobs, S., Lie, D.C., DeCicco, K.L., Shi, Y., DeLuca, L.M., Gage, F.H., Evans, R.M. Retinoic acid is required early during adult neurogenesis in the dentate gyrus. (2006) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 103(10):3902-7. DOI: 10.1073/pnas.0511294103

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Suzuki, A., Raya, A., Kawakami, Y., Morita, M., Matsui, T., Nakashima, K., Gage, F.H., Rodríguez-Esteban, C., Izpisúa Belmonte, J.C. Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification. (2006) Nature Clinical Practice. Cardiovascular Medicine. 3 Suppl 1:S114-22. DOI: 10.1038/ncpcardio0442

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Ray, J., Gage, F.H. Differential properties of adult rat and mouse brain-derived neural stem/progenitor cells. (2006) Molecular and Cellular Neurosciences. 31(3):560-73. DOI: 10.1016/j.mcn.2005.11.010

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Yang, H., Lu, P., McKay, H.M., Bernot, T., Keirstead, H., Steward, O., Gage, F.H., Edgerton, V.R., Tuszynski, M.H. Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury. (2006) Journal of Neuroscience. 26(8):2157-66. DOI: 10.1523/JNEUROSCI.4070-05.2005

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Zhao, C., Teng, E.M., Summers, R.G., Ming, G.L., Gage, F.H. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. (2006) Journal of Neuroscience. 26(1):3-11. DOI: 10.1523/JNEUROSCI.3648-05.2006

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Battista, D., Ferrari, C.C., Gage, F.H., Pitossi, F.J. Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus. (2006) European Journal of Neuroscience. 23(1):83-93. DOI: 10.1111/j.1460-9568.2005.04539.x

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Alisch, R.S., Garcia-Perez, J.L., Muotri, A.R., Gage, F.H., Moran, J.V. Unconventional translation of mammalian LINE-1 retrotransposons. (2006) Genes & Development. 20(2):210-24. DOI: 10.1101/gad.1380406

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Kempermann, G., Chesler, E.J., Lu, L., Williams, R.W., Gage, F.H. Natural variation and genetic covariance in adult hippocampal neurogenesis. (2006) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 103(3):780-5. DOI: 10.1073/pnas.0510291103

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Warashina, M., Min, K.H., Kuwabara, T., Huynh, A., Gage, F.H., Schultz, P.G., Ding, S. A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells. (2006) Angew. Chem. Int. Ed. Engl. 45(4):591-3. DOI: 10.1002/anie.200503089

Pizzo, D.P., Coufal, N.G., Lortie, M.J., Gage, F.H., Thal, L.J. Regulatable acetylcholine-producing fibroblasts enhance cognitive performance. (2006) Mol. Ther. 13(1):175-82. DOI: 10.1016/j.ymthe.2005.08.001

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Moon, L.D., Leasure, J.L., Gage, F.H., Bunge, M.B. Motor enrichment sustains hindlimb movement recovered after spinal cord injury and glial transplantation. (2006) Restorative Neurology and Neuroscience. 24(3):147-61.

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Muotri, A.R., Nakashima, K., Toni, N., Sandler, V.M., Gage, F.H. Development of functional human embryonic stem cell-derived neurons in mouse brain. (2005) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 102(51):18644-8. DOI: 10.1073/pnas.0509315102

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Hsieh, J., Gage, F.H. Chromatin remodeling in neural development and plasticity. (2005) Current Opinion in Cell Biology. 17(6):664-71. DOI: 10.1016/j.ceb.2005.09.002

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Genoud, S., Maricic, I., Kumar, V., Gage, F.H. Targeted expression of IGF-1 in the central nervous system fails to protect mice from experimental autoimmune encephalomyelitis. (2005) Journal of Neuroimmunology. 168(1-2):40-5. DOI: 10.1016/j.jneuroim.2005.06.033

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Lie, D.C., Colamarino, S.A., Song, H.J., Désiré, L., Mira, H., Consiglio, A., Lein, E.S., Jessberger, S., Lansford, H., Dearie, A.R., Gage, F.H. Wnt signalling regulates adult hippocampal neurogenesis. (2005) Naturaleza. 437(7063):1370-5. DOI: 10.1038/nature04108

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Singer, O., Marr, R.A., Rockenstein, E., Crews, L., Coufal, N.G., Gage, F.H., Verma, I.M., Masliah, E. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. (2005) Nature Neuroscience. 8(10):1343-9. DOI: 10.1038/nn1531

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Gage, F.H., McAllister, A.K. Neuronal and glial cell biology. (2005) Current Opinion in Neurobiology. 15(5):497-9. DOI: 10.1016/j.conb.2005.08.010

van Praag, H., Shubert, T., Zhao, C., Gage, F.H. Exercise enhances learning and hippocampal neurogenesis in aged mice. (2005) Journal of Neuroscience. 25(38):8680-5. DOI: 10.1523/JNEUROSCI.1731-05.2005

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Cummings, B.J., Uchida, N., Tamaki, S.J., Salazar, D.L., Hooshmand, M., Summers, R., Gage, F.H., Anderson, A.J. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. (2005) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 102(39):14069-74. DOI: 10.1073/pnas.0507063102

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Aigner, S., Gage, F.H. A small gem with great powers: geminin keeps neural progenitors thriving. (2005) Developmental Cell. 9(2):171-2. DOI: 10.1016/j.devcel.2005.07.005

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Zupanc, G.K., Hinsch, K., Gage, F.H. Proliferation, migration, neuronal differentiation, and long-term survival of new cells in the adult zebrafish brain. (2005) Journal of Comparative Neurology. 488(3):290-319. DOI: 10.1002/cne.20571

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Muotri, A.R., Chu, V.T., Marchetto, M.C., Deng, W., Moran, J.V., Gage, F.H. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. (2005) Naturaleza. 435(7044):903-10. DOI: 10.1038/nature03663

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Kuwabara, T., Hsieh, J., Nakashima, K., Warashina, M., Taira, K., Gage, F.H. The NRSE smRNA specifies the fate of adult hippocampal neural stem cells. (2005) Nucleic Acids Symp Ser (Oxf).(49):87-8 DOI: 10.1093/nass/49.1.87

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Lin, W., Dominguez, B., Yang, J., Aryal, P., Brandon, E.P., Gage, F.H., Lee, K.F. Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. (2005) Neuron. 46(4):569-79. DOI: 10.1016/j.neuron.2005.04.002

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Kaspar, B.K., Frost, L.M., Christian, L., Umapathi, P., Gage, F.H. Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis. (2005) Ann. Neurol. 57(5):649-55. DOI: 10.1002/ana.20451

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Scheel, J.R., Ray, J., Gage, F.H., Barlow, C. Quantitative analysis of gene expression in living adult neural stem cells by gene trapping. (2005) Nature Methods. 2(5):363-70. DOI: 10.1038/nmeth755

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Miller, T.M., Kaspar, B.K., Kops, G.J., Yamanaka, K., Christian, L.J., Gage, F.H., Cleveland, D.W. Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. (2005) Ann. Neurol. 57(5):773-6. DOI: 10.1002/ana.20453

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Lilley, C.E., Carson, C.T., Muotri, A.R., Gage, F.H., Weitzman, M.D. DNA repair proteins affect the lifecycle of herpes simplex virus 1. (2005) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 102(16):5844-9. DOI: 10.1073/pnas.0501916102

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Myers, C.P., Lewcock, J.W., Hanson, M.G., Gosgnach, S., Aimone, J.B., Gage, F.H., Lee, K.F., Landmesser, L.T., Pfaff, S.L. Cholinergic input is required during embryonic development to mediate proper assembly of spinal locomotor circuits. (2005) Neuron. 46(1):37-49. DOI: 10.1016/j.neuron.2005.02.022

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Lein, E.S., Callaway, E.M., Albright, T.D., Gage, F.H. Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. (2005) Journal of Comparative Neurology. 485(1):1-10. DOI: 10.1002/cne.20426

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Galimi, F., Summers, R.G., van Praag, H., Verma, I.M., Gage, F.H. A role for bone marrow-derived cells in the vasculature of noninjured CNS. (2005) Blood. 105(6):2400-2. DOI: 10.1182/blood-2004-02-0612

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Martin, M.J., Muotri, A., Gage, F., Varki, A. Human embryonic stem cells express an immunogenic nonhuman sialic acid. (2005) Nature Medicine. 11(2):228-32. DOI: 10.1038/nm1181

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Hashimoto, M., Rockenstein, E., Mante, M., Crews, L., Bar-On, P., Gage, F.H., Marr, R., Masliah, E. An antiaggregation gene therapy strategy for Lewy body disease utilizing beta-synuclein lentivirus in a transgenic model. (2004) Gene Therapy. 11(23):1713-23. DOI: 10.1038/sj.gt.3302349

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Hsieh, J., Nakashima, K., Kuwabara, T., Mejia, E., Gage, F.H. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. (2004) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 101(47):16659-64. DOI: 10.1073/pnas.0407643101

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Chin, V.I., Taupin, P., Sanga, S., Scheel, J., Gage, F.H., Bhatia, S.N. Microfabricated platform for studying stem cell fates. (2004) Biotechnol. Bioeng. 88(3):399-415. DOI: 10.1002/bit.20254

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Platforms that allow parallel, quantitative analysis of single cells will be integral to realizing the potential of postgenomic biology. In stem cell biology, the study of clonal stem cells in multiwell formats is currently both inefficient and time-consuming. Thus, to investigate low-frequency events of interest, large sample sizes must be interrogated. We report a simple, versatile, and efficient micropatterned arraying system conducive to the culture and dynamic monitoring of stem cell proliferation. This platform enables: 1) parallel, automated, long-term ( approximately days to weeks), live-cell microscopy of single cells in culture; 2) tracking of individual cell fates over time (proliferation, apoptosis); and 3) correlation of differentiated progeny with founder clones. To achieve these goals, we used microfabrication techniques to create an array of approximately 10,000 microwells on a glass coverslip. The dimensions of the wells are tunable, ranging from 20 to >500 microm in diameter and 10-500 microm in height. The microarray can be coated with adhesive proteins and is integrated into a culture chamber that permits rapid (approximately min), addressable monitoring of each well using a standard programmable microscope stage. All cells share the same media (including paracrine survival signals), as opposed to cells in multiwell formats. The incorporation of a coverslip as a substrate also renders the platform compatible with conventional, high-magnification light and fluorescent microscopy. We validated this approach by analyzing the proliferation dynamics of a heterogeneous adult rat neural stem cell population. Using this platform, one can further interrogate the response of distinct stem cell subpopulations to microenvironmental cues (mitogens, cell-cell interactions, and cell-extracellular matrix interactions) that govern their behavior. In the future, the platform may also be adapted for the study of other cell types by tailoring the surface coatings, microwell dimensions, and culture environment, thereby enabling parallel investigation of many distinct cellular responses.

Shihabuddin, L.S., Numan, S., Huff, M.R., Dodge, J.C., Clarke, J., Macauley, S.L., Yang, W., Taksir, T.V., Parsons, G., Passini, M.A., Gage, F.H., Stewart, G.R. Intracerebral transplantation of adult mouse neural progenitor cells into the Niemann-Pick-A mouse leads to a marked decrease in lysosomal storage pathology. (2004) Journal of Neuroscience. 24(47):10642-51. DOI: 10.1523/JNEUROSCI.3584-04.2004

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Hsieh, J., Gage, F.H. Epigenetic control of neural stem cell fate. (2004) Current Opinion in Genetics & Development. 14(5):461-9. DOI: 10.1016/j.gde.2004.07.006

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Consiglio, A., Gritti, A., Dolcetta, D., Follenzi, A., Bordignon, C., Gage, F.H., Vescovi, A.L., Naldini, L. Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors. (2004) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 101(41):14835-40. DOI: 10.1073/pnas.0404180101

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Schinder, A.F., Gage, F.H. A hypothesis about the role of adult neurogenesis in hippocampal function. (2004) Physiology (Bethesda). 19:253-61. DOI: 10.1152/physiol.00012.2004

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Aimone, J.B., Leasure, J.L., Perreau, V.M., Thallmair, M., Gage Spatial and temporal gene expression profiling of the contused rat spinal cord. (2004) Exp. Neurol. 189(2):204-21. DOI: 10.1016/j.expneurol.2004.05.042

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Wurmser, A.E., Nakashima, K., Summers, R.G., Toni, N., D'Amour, K.A., Lie, D.C., Gage, F.H. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. (2004) Naturaleza. 430(6997):350-6. DOI: 10.1038/nature02604

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Pizzo, D.P., Paban, V., Coufal, N.G., Gage, F.H., Thal, L.J. Long-term production of choline acetyltransferase in the CNS after transplantation of fibroblasts modified with a regulatable vector. (2004) Brain Research. Molecular Brain Research. 126(1):1-13. DOI: 10.1016/j.molbrainres.2004.03.006

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Farmer, J., Zhao, X., van Praag, H., Wodtke, K., Gage, F.H., Christie, B.R. Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. (2004) Neuroscience. 124(1):71-9. DOI: 10.1016/j.neuroscience.2003.09.029

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Brandon, E.P., Mellott, T., Pizzo, D.P., Coufal, N., D'Amour, K.A., Gobeske, K., Lortie, M., López-Coviella, I., Berse, B., Thal, L.J., Gage, F.H., Blusztajn, J.K. Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency. (2004) Journal of Neuroscience. 24(24):5459-66. DOI: 10.1523/JNEUROSCI.1106-04.2004

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Gage, F.H. Structural plasticity of the adult brain. (2004) Dialogues Clin Neurosci. 6(2):135-41.

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Lie, D.C., Song, H., Colamarino, S.A., Ming, G.L., Gage, F.H. Neurogenesis in the adult brain: new strategies for central nervous system diseases. (2004) Annual Review of Pharmacology and Toxicology. 44:399-421. DOI: 10.1146/annurev.pharmtox.44.101802.121631

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Marr, R.A., Guan, H., Rockenstein, E., Kindy, M., Gage, F.H., Verma, I., Masliah, E., Hersh, L.B. Neprilysin regulates amyloid Beta peptide levels. (2004) J. Mol. Neurosci. 22(1-2):5-11. DOI: 10.1385/JMN:22:1-2:5

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Schaffer, D.V., Gage, F.H. Neurogenesis and neuroadaptation. (2004) Neuromolecular Med. 5(1):1-9. DOI: 10.1385/NMM:5:1:001

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Wurmser, A.E., Palmer, T.D., Gage, F.H. Neuroscience. Cellular interactions in the stem cell niche. (2004) Ciencia. 304(5675):1253-5. DOI: 10.1126/science.1099344

Aimone, J.B., Gage, F.H. Unbiased characterization of high-density oligonucleotide microarrays using probe-level statistics. (2004) Journal of Neuroscience Methods. 135(1-2):27-33. DOI: 10.1016/j.jneumeth.2003.11.016

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Lein, E.S., Zhao, X., Gage, F.H. Defining a molecular atlas of the hippocampus using DNA microarrays and high-throughput in situ hybridization. (2004) Journal of Neuroscience. 24(15):3879-89. DOI: 10.1523/JNEUROSCI.4710-03.2004

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Kempermann, G., Wiskott, L., Gage, F.H. Functional significance of adult neurogenesis. (2004) Current Opinion in Neurobiology. 14(2):186-91. DOI: 10.1016/j.conb.2004.03.001

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Kuwabara, T., Hsieh, J., Nakashima, K., Taira, K., Gage, F.H. A small modulatory dsRNA specifies the fate of adult neural stem cells. (2004) Móvil. 116(6):779-93.

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Markakis, E.A., Palmer, T.D., Randolph-Moore, L., Rakic, P., Gage, F.H. Novel neuronal phenotypes from neural progenitor cells. (2004) Journal of Neuroscience. 24(12):2886-97. DOI: 10.1523/JNEUROSCI.4161-03.2004

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Hsieh, J., Aimone, J.B., Kaspar, B.K., Kuwabara, T., Nakashima, K., Gage, F.H. IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. (2004) Journal of Cell Biology. 164(1):111-22. DOI: 10.1083/jcb.200308101

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Shi, Y., Chichung Lie, D., Taupin, P., Nakashima, K., Ray, J., Yu, R.T., Gage, F.H., Evans, R.M. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. (2004) Naturaleza. 427(6969):78-83. DOI: 10.1038/nature02211

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Nakashima, K., Colamarino, S., Gage, F.H. Embryonic stem cells: staying plastic on plastic. (2004) Nature Medicine. 10(1):23-4. DOI: 10.1038/nm0104-23

Muotri, A.R., Gage, F.H. Vibrating in the background. (2003) Nature Genetics. 35(3):205-7. DOI: 10.1038/ng1103-205

Rhodes, J.S., van Praag, H., Jeffrey, S., Girard, I., Mitchell, G.S., Garland, T., Gage, F.H. Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. (2003) Behavioral Neuroscience. 117(5):1006-16. DOI: 10.1037/0735-7044.117.5.1006

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Dziewczapolski, G., Lie, D.C., Ray, J., Gage, F.H., Shults, C.W. Survival and differentiation of adult rat-derived neural progenitor cells transplanted to the striatum of hemiparkinsonian rats. (2003) Exp. Neurol. 183(2):653-64.

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Gage, F.H. Brain, repair yourself. (2003) Sci. Am. 289(3):46-53.

D'Amour, K.A., Gage, F.H. Genetic and functional differences between multipotent neural and pluripotent embryonic stem cells. (2003) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 100 Suppl :11866-72. DOI: 10.1073/pnas.1834200100

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Gage, F.H., Verma, I.M. Stem cells at the dawn of the 21st century. (2003) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 100 Suppl :11817-8. DOI: 10.1073/pnas.1834433100

Aberg, M.A., Aberg, N.D., Palmer, T.D., Alborn, A.M., Carlsson-Skwirut, C., Bang, P., Rosengren, L.E., Olsson, T., Gage, F.H., Eriksson, P.S. IGF-I has a direct proliferative effect in adult hippocampal progenitor cells. (2003) Molecular and Cellular Neurosciences. 24(1):23-40.

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Arvanian, V.L., Horner, P.J., Gage, F.H., Mendell, L.M. Chronic neurotrophin-3 strengthens synaptic connections to motoneurons in the neonatal rat. (2003) Journal of Neuroscience. 23(25):8706-12.

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Kaspar, B.K., Lladó, J., Sherkat, N., Rothstein, J.D., Gage, F.H. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. (2003) Ciencia. 301(5634):839-42. DOI: 10.1126/science.1086137

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Dickinson-Anson, H., Winkler, J., Fisher, L.J., Song, H.J., Poo, M.m., Gage, F.H. Acetylcholine-secreting cells improve age-induced memory deficits. (2003) Molecular Therapy. 8(1):51-61.

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South, S.M., Kohno, T., Kaspar, B.K., Hegarty, D., Vissel, B., Drake, C.T., Ohata, M., Jenab, S., Sailer, A.W., Malkmus, S., Masuyama, T., Horner, P., Bogulavsky, J., Gage, F.H., Yaksh, T.L., Woolf, C.J., Heinemann, S.F., Inturrisi, C.E. A conditional deletion of the NR1 subunit of the NMDA receptor in adult spinal cord dorsal horn reduces NMDA currents and injury-induced pain. (2003) Journal of Neuroscience. 23(12):5031-40.

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Zhao, X., Ueba, T., Christie, B.R., Barkho, B., McConnell, M.J., Nakashima, K., Lein, E.S., Eadie, B.D., Willhoite, A.R., Muotri, A.R., Summers, R.G., Chun, J., Lee, K.F., Gage, F.H. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. (2003) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 100(11):6777-82. DOI: 10.1073/pnas.1131928100

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Scheel, J.R., Garrett, L.J., Allen, D.M., Carter, T.A., Randolph-Moore, L., Gambello, M.J., Gage, F.H., Wynshaw-Boris, A., Barlow, C. An inbred 129SvEv GFPCre transgenic mouse that deletes loxP-flanked genes in all tissues. (2003) Investigación de Ácidos Nucleicos. 31(10):e57.

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Klassen, H.J., Imfeld, K.L., Kirov, I.I., Tai, L., Gage, F.H., Young, M.J., Berman, M.A. Expression of cytokines by multipotent neural progenitor cells. (2003) Cytokine. 22(3-4):101-6.

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Brown, J., Cooper-Kuhn, C.M., Kempermann, G., Van Praag, H., Winkler, J., Gage, F.H., Kuhn, H.G. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. (2003) European Journal of Neuroscience. 17(10):2042-6.

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Brivanlou, A.H., Gage, F.H., Jaenisch, R., Jessell, T., Melton, D., Rossant, J. Stem cells. Setting standards for human embryonic stem cells. (2003) Ciencia. 300(5621):913-6. DOI: 10.1126/science.1082940

Klassen, H., Imfeld, K.L., Ray, J., Young, M.J., Gage, F.H., Berman, M.A. The immunological properties of adult hippocampal progenitor cells. (2003) Vision Research. 43(8):947-56.

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Marr, R.A., Rockenstein, E., Mukherjee, A., Kindy, M.S., Hersh, L.B., Gage, F.H., Verma, I.M., Masliah, E. Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. (2003) Journal of Neuroscience. 23(6):1992-6.

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Brandon, E.P., Lin, W., D'Amour, K.A., Pizzo, D.P., Dominguez, B., Sugiura, Y., Thode, S., Ko, C.P., Thal, L.J., Gage, F.H., Lee, K.F. Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. (2003) Journal of Neuroscience. 23(2):539-49.

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Lai, K., Kaspar, B.K., Gage, F.H., Schaffer, D.V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. (2003) Nature Neuroscience. 6(1):21-7. DOI: 10.1038/nn983

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Kempermann, G., Gast, D., Kronenberg, G., Yamaguchi, M., Gage, F.H. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. (2003) Development. 130(2):391-9.

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Horner, P.J., Gage, F.H. Regeneration in the adult and aging brain. (2002) Archives of Neurology. 59(11):1717-20.

Zhao, X., Gage, F.H. Expressing the central nervous system. (2002) Neurochem. Res. 27(10):953-4.

Taupin, P., Gage, F.H. Adult neurogenesis and neural stem cells of the central nervous system in mammals. (2002) Journal of Neuroscience Research. 69(6):745-9. DOI: 10.1002/jnr.10378

Tamaki, S., Eckert, K., He, D., Sutton, R., Doshe, M., Jain, G., Tushinski, R., Reitsma, M., Harris, B., Tsukamoto, A., Gage, F., Weissman, I., Uchida, N. Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. (2002) Journal of Neuroscience Research. 69(6):976-86. DOI: 10.1002/jnr.10412

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Direct isolation of human central nervous system stem cells (CNS-SC) based on cell surface markers yields a highly purified stem cell population that can extensively expand in vitro and exhibit multilineage differentiation potential both in vitro and in vivo. The CNS-SC were isolated from fetal brain tissue using the cell surface markers CD133(+), CD34(-), CD45(-), and CD24(-/lo) (CD133(+) cells). Fluorescence-activated cell sorted (FACS) CD133(+) cells continue to expand exponentially as neurospheres while retaining multipotential differentiation capacity for >10 passages. CD133(-), CD34(-), and CD45(-) sorted cells (approximately 95% of total fetal brain tissue) fail to initiate neurospheres. Neurosphere cells transplanted into neonatal immunodeficient NOD-SCID mice proliferated, migrated, and differentiated in a site-specific manner. However, it has been difficult to evaluate human cell engraftment, because many of the available monoclonal antibodies against neural cells (beta-tubulin III and glial fibrillary acidic protein) are not species specific. To trace the progeny of human cells after transplantation, CD133(+)-derived neurosphere cells were transduced with lentiviral vectors containing enhanced green fluorescent protein (eGFP) expressed downstream of the phosphoglycerate kinase promoter. After transduction, GFP(+) cells were enriched by FACS, expanded, and transplanted into the lateral ventricular space of neonatal immunodeficient NOD-SCID brain. The progeny of transplanted cells were detected by either GFP fluorescence or antibody against GFP. GFP(+) cells were present in the subventricular zone-rostral migrating stream, olfactory bulb, and hippocampus as well as nonneurogenic sites, such as cerebellum, cerebral cortex, and striatum. Antibody against GFP revealed that some of the cells displayed differentiating dendrites and processes with neurons or glia cells. Thus, marking human CNS-SC with reporter genes introduced by lentiviral vectors is a useful tool with which to characterize migration and differentiation of human cells in this mouse transplantation model.

Lie, D.C., Dziewczapolski, G., Willhoite, A.R., Kaspar, B.K., Shults, C.W., Gage, F.H. The adult substantia nigra contains progenitor cells with neurogenic potential. (2002) Journal of Neuroscience. 22(15):6639-49. DOI: 20026700

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Kempermann, G., Gast, D., Gage, F.H. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. (2002) Ann. Neurol. 52(2):135-43. DOI: 10.1002/ana.10262

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Kempermann, G., Gage, F.H. Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task. (2002) European Journal of Neuroscience. 16(1):129-36.

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Horner, P.J., Thallmair, M., Gage, F.H. Defining the NG2-expressing cell of the adult CNS. (2002) Journal of Neurocytology. 31(6-7):469-80.

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Song, H., Stevens, C.F., Gage, F.H. Astroglia induce neurogenesis from adult neural stem cells. (2002) Naturaleza. 417(6884):39-44. DOI: 10.1038/417039a

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Song, H.J., Stevens, C.F., Gage, F.H. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. (2002) Nature Neuroscience. 5(5):438-45. DOI: 10.1038/nn844

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Wurmser, A.E., Gage, F.H. Stem cells: cell fusion causes confusion. (2002) Naturaleza. 416(6880):485-7. DOI: 10.1038/416485a

Kempermann, G., Gage, F.H. Genetic influence on phenotypic differentiation in adult hippocampal neurogenesis. (2002) Brain Res. Dev. Brain Res. 134(1-2):1-12.

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van Praag, H., Gage, F.H. Genetics of childhood disorders: XXXVI. Stem cell research, part 1: New neurons in the adult brain. (2002) J Am Acad Child Adolesc Psychiatry. 41(3):354-6.

D'Amour, K.A., Gage, F.H. Are somatic stem cells pluripotent or lineage-restricted? (2002) Nature Medicine. 8(3):213-4. DOI: 10.1038/nm0302-213

van Praag, H., Schinder, A.F., Christie, B.R., Toni, N., Palmer, T.D., Gage, F.H. Functional neurogenesis in the adult hippocampus. (2002) Naturaleza. 415(6875):1030-4. DOI: 10.1038/4151030a

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Kaspar, B.K., Vissel, B., Bengoechea, T., Crone, S., Randolph-Moore, L., Muller, R., Brandon, E.P., Schaffer, D., Verma, I.M., Lee, K.F., Heinemann, S.F., Gage, F.H. Adeno-associated virus effectively mediates conditional gene modification in the brain. (2002) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 99(4):2320-5. DOI: 10.1073/pnas.042678699

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Gage, F.H. Neurogenesis in the adult brain. (2002) Journal of Neuroscience. 22(3):612-3.

Kaspar, B.K., Erickson, D., Schaffer, D., Hinh, L., Gage, F.H., Peterson, D.A. Targeted retrograde gene delivery for neuronal protection. (2002) Mol. Ther. 5(1):50-6. DOI: 10.1006/mthe.2001.0520

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Vallières, L., Campbell, I.L., Gage, F.H., Sawchenko, P.E. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. (2002) Journal of Neuroscience. 22(2):486-92.

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Zhao, X., Lein, E.S., He, A., Smith, S.C., Aston, C., Gage, F.H. Transcriptional profiling reveals strict boundaries between hippocampal subregions. (2001) Journal of Comparative Neurology. 441(3):187-96.

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Pfeifer, A., Brandon, E.P., Kootstra, N., Gage, F.H., Verma, I.M. Delivery of the Cre recombinase by a self-deleting lentiviral vector: efficient gene targeting in vivo. (2001) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 98(20):11450-5. DOI: 10.1073/pnas.201415498

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Chu, V.T., Gage, F.H. Chipping away at stem cells. (2001) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 98(14):7652-3. DOI: 10.1073/pnas.141244198

van Praag, H., Barlow, C., Gage, F.H. Are drug targets missed owing to lack of physical activity? - Reply. (2001) Drug Discov. Today. 6(12):615-617.

Ray, J., Gage, F.H. Construction of cells expressing neurotrophins. (2001) Métodos en Biología Molecular. 169:115-33.

Matsuura, N., Lie, D.C., Hoshimaru, M., Asahi, M., Hojo, M., Ishizaki, R., Hashimoto, N., Noji, S., Ohuchi, H., Yoshioka, H., Gage, F.H. Sonic hedgehog facilitates dopamine differentiation in the presence of a mesencephalic glial cell line. (2001) Journal of Neuroscience. 21(12):4326-35.

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Palmer, T.D., Schwartz, P.H., Taupin, P., Kaspar, B., Stein, S.A., Gage, F.H. Cell culture. Progenitor cells from human brain after death. (2001) Naturaleza. 411(6833):42-3. DOI: 10.1038/35075141

Suhr, S.T., Senut, M.C., Whitelegge, J.P., Faull, K.F., Cuizon, D.B., Gage, F.H. Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. (2001) Journal of Cell Biology. 153(2):283-94.

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Anderson, D.J., Gage, F.H., Weissman, I.L. Can stem cells cross lineage boundaries? (2001) Nature Medicine. 7(4):393-5. DOI: 10.1038/86439

Allen, D.M., van Praag, H., Ray, J., Weaver, Z., Winrow, C.J., Carter, T.A., Braquet, R., Harrington, E., Ried, T., Brown, K.D., Gage, F.H., Barlow, C. Ataxia telangiectasia mutated is essential during adult neurogenesis. (2001) Genes & Development. 15(5):554-66. DOI: 10.1101/gad.869001

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Weissman, I.L., Anderson, D.J., Gage, F.H. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. (2001) Annual Review of Cell and Developmental Biology. 17:387-403. DOI: 10.1146/annurev.cellbio.17.1.387

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van Praag, H., Kempermann, G., Gage, F.H. Neural consequences of environmental enrichment. (2000) Nature Reviews Neuroscience. 1(3):191-8. DOI: 10.1038/35044558

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Kempermann, G., van Praag, H., Gage, F.H. Activity-dependent regulation of neuronal plasticity and self repair. (2000) Progress in Brain Research. 127:35-48.

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Uchida, N., Buck, D.W., He, D., Reitsma, M.J., Masek, M., Phan, T.V., Tsukamoto, A.S., Gage, F.H., Weissman, I.L. Direct isolation of human central nervous system stem cells. (2000) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 97(26):14720-5. DOI: 10.1073/pnas.97.26.14720

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Shihabuddin, L.S., Horner, P.J., Ray, J., Gage, F.H. Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. (2000) Journal of Neuroscience. 20(23):8727-35.

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Taupin, P., Ray, J., Fischer, W.H., Suhr, S.T., Hakansson, K., Grubb, A., Gage, F.H. FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine cofactor. (2000) Neuron. 28(2):385-97.

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Shults, C.W., Ray, J., Tsuboi, K., Gage, F.H. Fibroblast growth factor-2-producing fibroblasts protect the nigrostriatal dopaminergic system from 6-hydroxydopamine. (2000) Brain Research. 883(2):192-204.

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We tested the hypothesis that fibroblasts, which had been genetically engineered to produce fibroblast growth factor-2 (FGF-2), can protect nigrostriatal dopaminergic neurons. Three groups of rats received either a burr hole only (n=5) or implantation of fibroblasts, which had been genetically engineered to produce beta-galactosidase (beta-gal) (n=8) or FGF-2 (n=8), at two sites in the right striatum. Two weeks later, the animals received an injection of 25 microg of 6-hydroxydopamine hydrobromide (6-OHDA) midway between the two implant sites. The group that received FGF-2-fibroblasts had significantly fewer apomorphine-induced rotations than the groups that received a burr hole only or beta-gal-fibroblasts at weeks 2 and 3 following lesioning with 6-OHDA. Testing for amphetamine-induced rotation revealed a mild reduction in rotation in the beta-gal-fibroblast group compared to the burr hole only group, but a striking attenuation of amphetamine-induced rotation in the FGF-2-fibroblast group. There was also preservation of TH-IR neurons on the lesioned side relative to both control groups. The size of the grafts and the gliosis surrounding the injection sites did not differ between the FGF-2-fibroblast and beta-gal-fibroblast groups. To further characterize the production of FGF-2 by the FGF-2-fibroblasts, we implanted FGF-2-fibroblasts and beta-gal-fibroblast into the striatum of rats but did not lesion the animals with 6-OHDA. The animals were then sacrificed at 1, 2 and 5 weeks following implantation. Prior to implantation the FGF-2 fibroblasts contained 148 ng/mg of FGF-2-immunoreactive (FGF-2-IR) material per mg of protein of cell lysate. After implantation FGF-2-IR material was noted in the grafts of FGF-2-fibroblasts, most conspicuously at 1 and 2 weeks following implantation. We also noted FGF-2-IR material in the nuclei of reactive astrocytes adjacent to the implants, and OX-42-immunoreactive (OX-42-IR) cells adjacent and occasionally within the implants. Our work indicates that fibroblasts genetically engineered to produce FGF-2 and implanted in the striatum can protect the nigrostriatal dopaminergic system and may be useful in the treatment of Parkinson's disease.

Horner, P.J., Gage, F.H. Regenerating the damaged central nervous system. (2000) Naturaleza. 407(6807):963-70. DOI: 10.1038/35039559

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Zoghbi, H.Y., Gage, F.H., Choi, D.W. Neurobiology of disease. (2000) Current Opinion in Neurobiology. 10(5):655-60.

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Gage, F.H. Structural plasticity: cause, result, or correlate of depression. (2000) Biological Psychiatry. 48(8):713-4.

Palmer, T.D., Willhoite, A.R., Gage, F.H. Vascular niche for adult hippocampal neurogenesis. (2000) Journal of Comparative Neurology. 425(4):479-94.

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Young, M.J., Ray, J., Whiteley, S.J., Klassen, H., Gage, F.H. Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats. (2000) Molecular and Cellular Neurosciences. 16(3):197-205. DOI: 10.1006/mcne.2000.0869

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Verma, I.M., Gage, F.H. Genome and gene therapy. (2000) Molecular Therapy. 2(2):95. DOI: 10.1006/mthe.2000.0109

Kempermann, G., Gage, F.H. Neurogenesis in the adult hippocampus. (2000) Novartis Found. Symp. 231:220-35; discussion 235-41, 302.

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Kafri, T., van Praag, H., Gage, F.H., Verma, I.M. Lentiviral vectors: regulated gene expression. (2000) Molecular Therapy. 1(6):516-21. DOI: 10.1006/mthe.2000.0083

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Jacobs, B.L., van Praag, H., Gage, F.H. Adult brain neurogenesis and psychiatry: a novel theory of depression. (2000) Molecular Psychiatry. 5(3):262-9.

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D'Amour, K., Gage, F.H. New tools for human developmental biology. (2000) Nature Biotechnology. 18(4):381-2. DOI: 10.1038/74429

Horner, P.J., Power, A.E., Kempermann, G., Kuhn, H.G., Palmer, T.D., Winkler, J., Thal, L.J., Gage, F.H. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. (2000) Journal of Neuroscience. 20(6):2218-28.

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Gage, F.H. Mammalian neural stem cells. (2000) Ciencia. 287(5457):1433-8.

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Senut, M.C., Suhr, S.T., Kaspar, B., Gage, F.H. Intraneuronal aggregate formation and cell death after viral expression of expanded polyglutamine tracts in the adult rat brain. (2000) Journal of Neuroscience. 20(1):219-29.

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Spain, B.H., Larson, C.J., Shihabuddin, L.S., Gage, F.H., Verma, I.M. Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations. (1999) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 96(24):13920-5.

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van Praag, H., Christie, B.R., Sejnowski, T.J., Gage, F.H. Running enhances neurogenesis, learning, and long-term potentiation in mice. (1999) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 96(23):13427-31.

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Shihabuddin, L.S., Palmer, T.D., Gage, F.H. The search for neural progenitor cells: prospects for the therapy of neurodegenerative disease. (1999) Mol Med Today. 5(11):474-80.

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Sailer, A., Swanson, G.T., Pérez-Otaño, I., O'Leary, L., Malkmus, S.A., Dyck, R.H., Dickinson-Anson, H., Schiffer, H.H., Maron, C., Yaksh, T.L., Gage, F.H., O'Gorman, S., Heinemann, S.F. Generation and analysis of GluR5(Q636R) kainate receptor mutant mice. (1999) Journal of Neuroscience. 19(20):8757-64.

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Palmer, T.D., Markakis, E.A., Willhoite, A.R., Safar, F., Gage, F.H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. (1999) Journal of Neuroscience. 19(19):8487-97.

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Sakurada, K., Ohshima-Sakurada, M., Palmer, T.D., Gage, F.H. Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. (1999) Development. 126(18):4017-26.

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Takahashi, M., Miyoshi, H., Verma, I.M., Gage, F.H. Rescue from photoreceptor degeneration in the rd mouse by human immunodeficiency virus vector-mediated gene transfer. (1999) Journal of Virology. 73(9):7812-6.

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Smith, D.E., Roberts, J., Gage, F.H., Tuszynski, M.H. Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. (1999) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 96(19):10893-8.

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Kempermann, G., Gage, F.H. Experience-dependent regulation of adult hippocampal neurogenesis: effects of long-term stimulation and stimulus withdrawal. (1999) Hippocampus. 9(3):321-32. DOI: 10.1002/(SICI)1098-1063(1999)9:3<321::aid-hipo11>3

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Kempermann, G., Gage, F.H. New nerve cells for the adult brain. (1999) Sci. Am. 280(5):48-53.

Steward, O., Schauwecker, P.E., Guth, L., Zhang, Z., Fujiki, M., Inman, D., Wrathall, J., Kempermann, G., Gage, F.H., Saatman, K.E., Raghupathi, R., McIntosh, T. Genetic approaches to neurotrauma research: opportunities and potential pitfalls of murine models. (1999) Experimental Neurology. 157(1):19-42. DOI: 10.1006/exnr.1999.7040

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Senut, M.C., Gage, F.H. Prenatal gene therapy: can the technical hurdles be overcome? (1999) Mol Med Today. 5(4):152-6.

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Markakis, E.A., Gage, F.H. Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. (1999) Journal of Comparative Neurology. 406(4):449-60.

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Ueba, T., Kaspar, B., Zhao, X., Gage, F.H. Repression of human fibroblast growth factor 2 by a novel transcription factor. (1999) Revista de Química Biológica. 274(15):10382-7.

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van Praag, H., Kempermann, G., Gage, F.H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. (1999) Nature Neuroscience. 2(3):266-70. DOI: 10.1038/6368

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Suhr, S.T., Gage, F.H. Gene therapy in the central nervous system: the use of recombinant retroviruses. (1999) Archives of Neurology. 56(3):287-92.

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Peterson, D.A., Dickinson-Anson, H.A., Leppert, J.T., Lee, K.F., Gage, F.H. Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. (1999) Journal of Comparative Neurology. 404(1):1-20.

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Takahashi, J., Palmer, T.D., Gage, F.H. Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adult-derived neural stem cell cultures. (1999) Journal of Neurobiology. 38(1):65-81.

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Shihabuddin, L.S., Ray, J., Gage, F.H. Stem cell technology for basic science and clinical applications. (1999) Archives of Neurology. 56(1):29-32.

Kafri, T., van Praag, H., Ouyang, L., Gage, F.H., Verma, I.M. A packaging cell line for lentivirus vectors. (1999) Journal of Virology. 73(1):576-84.

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Mandel, R.J., Gage, F.H., Clevenger, D.G., Spratt, S.K., Snyder, R.O., Leff, S.E. Nerve growth factor expressed in the medial septum following in vivo gene delivery using a recombinant adeno-associated viral vector protects cholinergic neurons from fimbria-fornix lesion-induced deg (1999) Experimental Neurology. 155(1):59-64. DOI: 10.1006/exnr.1998.6961

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Chiang, M.Y., Misner, D., Kempermann, G., Schikorski, T., Giguère, V., Sucov, H.M., Gage, F.H., Stevens, C.F., Evans, R.M. An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression. (1998) Neuron. 21(6):1353-61.

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Takahashi, M., Palmer, T.D., Takahashi, J., Gage, F.H. Widespread integration and survival of adult-derived neural progenitor cells in the developing optic retina. (1998) Molecular and Cellular Neurosciences. 12(6):340-8. DOI: 10.1006/mcne.1998.0721

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Eriksson, P.S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., Gage, F.H. Neurogenesis in the adult human hippocampus. (1998) Nature Medicine. 4(11):1313-7. DOI: 10.1038/3305

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Kempermann, G., Kuhn, H.G., Winkler, J., Gage, F.H. [New nerve cells for the adult brain. Adult neurogenesis and stem cell concepts in neurologic research]. (1998) Nervenarzt. 69(10):851-7.

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Gage, F.H. Stem cells of the central nervous system. (1998) Current Opinion in Neurobiology. 8(5):671-6.

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Miyoshi, H., Blömer, U., Takahashi, M., Gage, F.H., Verma, I.M. Development of a self-inactivating lentivirus vector. (1998) Journal of Virology. 72(10):8150-7.

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Varki, A., Wills, C., Perlmutter, D., Woodruff, D., Gage, F.H., Moore, J., Semendeferi, K., Bernirschke, K., Katzman, R., Doolittle, R., Bullock, T. Great Ape Phenome Project? (1998) Ciencia. 282(5387):239-40.

Aubert, I., Ridet, J.L., Schachner, M., Rougon, G., Gage, F.H. Expression of L1 and PSA during sprouting and regeneration in the adult hippocampal formation. (1998) Journal of Comparative Neurology. 399(1):1-19.

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Berger, F., Gage, F.H., Vijayaraghavan, S. Nicotinic receptor-induced apoptotic cell death of hippocampal progenitor cells. (1998) Journal of Neuroscience. 18(17):6871-81.

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Gage, F.H., Kempermann, G., Palmer, T.D., Peterson, D.A., Ray, J. Multipotent progenitor cells in the adult dentate gyrus. (1998) Journal of Neurobiology. 36(2):249-66.

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Suhr, S.T., Gil, E.B., Senut, M.C., Gage, F.H. High level transactivation by a modified Bombyx ecdysone receptor in mammalian cells without exogenous retinoid X receptor. (1998) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 95(14):7999-8004.

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Winkler, J., Thal, L.J., Gage, F.H., Fisher, L.J. Cholinergic strategies for Alzheimer's disease. (1998) Journal of Molecular Medicine. 76(8):555-67.

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Alzheimer's disease is a devastating degenerative disorder of the central nervous system that results in gradual deterioration of cognitive function and severe alteration of personality. Degeneration of neurons in the nucleus basalis Meynert, the origin of the major cholinergic projections to the neocortex, occurs early in the course of the disease, and is correlated with the cognitive decline. This link between cholinergic dysfunction in the basal-cortical system and cognitive deficits has focused scientific efforts on developing tools to elucidate the neurobiological role of the cholinergic system in cognition and to develop therapeutic interventions in the disorder. An important step in understanding the mechanisms underlying cognitive dysfunction has been the development of in vivo rodent models that mimic some of the features of Alzheimer's disease. Acute excitotoxic or immunotoxic lesions of the nucleus basalis in rodents have revealed a role of the basal-cortical system in attention, learning and memory. More recent advances in developing mouse gene technology offer newer models to systematically examine the underlying neuropathological cascade leading to dysfunctions in mnemonic processing. Using in vivo rodent models, several cholinergic enhancement strategies have been tested and proven to be effective in alleviating lesion-induced cognitive deficits, including neuropharmacological approaches (acetylcholinesterase inhibitors), neurotrophic factor administration (nerve growth factor), and transplantation of cholinergic-enriched fetal grafts. Successful results have also been obtained using ex vivo gene transfer to deliver nerve growth factor or acetylcholine to compromised regions of the basal-cortical system. Gene therapy may be of particular interest for clinical applications, because this approach provides a method for topographically restricted and selective delivery of therapeutic genes and their products to afflicted areas of the brain. Advanced techniques in molecular biology (e.g., exogenous regulatable gene transfer) and newly developed tools of modern neuroscience (e.g., neural precursor cells) will be important contributions for deciphering the biological bases of neuronal degeneration and for refining therapeutic strategies for Alzheimer's disease.

McTigue, D.M., Horner, P.J., Stokes, B.T., Gage, F.H. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. (1998) Journal of Neuroscience. 18(14):5354-65.

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Kempermann, G., Brandon, E.P., Gage, F.H. Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. (1998) Current Biology. 8(16):939-42.

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Dickinson-Anson, H., Aubert, I., Gage, F.H., Fisher, L.J. Hippocampal grafts of acetylcholine-producing cells are sufficient to improve behavioural performance following a unilateral fimbria-fornix lesion. (1998) Neuroscience. 84(3):771-81.

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Kempermann, G., Kuhn, H.G., Gage, F.H. Experience-induced neurogenesis in the senescent dentate gyrus. (1998) Journal of Neuroscience. 18(9):3206-12.

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Kempermann, G., Gage, F.H. Closer to neurogenesis in adult humans. (1998) Nature Medicine. 4(5):555-7.

Senut, M.C., Suhr, S.T., Gage, F.H. Gene transfer to the rodent placenta in situ. A new strategy for delivering gene products to the fetus. (1998) Journal of Clinical Investigation. 101(8):1565-71. DOI: 10.1172/JCI1959

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Mulle, C., Sailer, A., Pérez-Otaño, I., Dickinson-Anson, H., Castillo, P.E., Bureau, I., Maron, C., Gage, F.H., Mann, J.R., Bettler, B., Heinemann, S.F. Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. (1998) Naturaleza. 392(6676):601-5. DOI: 10.1038/33408

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Gage, F.H. Cell therapy. (1998) Naturaleza. 392(6679 Suppl):18-24.

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Blömer, U., Kafri, T., Randolph-Moore, L., Verma, I.M., Gage, F.H. Bcl-xL protects adult septal cholinergic neurons from axotomized cell death. (1998) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 95(5):2603-8.

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Shihabuddin, L.S., Ray, J., Gage, F.H. FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord. (1997) Exp. Neurol. 148(2):577-86. DOI: 10.1006/exnr.1997.6697

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Ridet, J.L., Malhotra, S.K., Privat, A., Gage, F.H. Reactive astrocytes: cellular and molecular cues to biological function. (1997) Trends in Neurosciences. 20(12):570-7.

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Kafri, T., Blömer, U., Peterson, D.A., Gage, F.H., Verma, I.M. Sustained expression of genes delivered directly into liver and muscle by lentiviral vectors. (1997) Nature Genetics. 17(3):314-7. DOI: 10.1038/ng1197-314

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Kempermann, G., Kuhn, H.G., Gage, F.H. Genetic influence on neurogenesis in the dentate gyrus of adult mice. (1997) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 94(19):10409-14.

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Miyoshi, H., Takahashi, M., Gage, F.H., Verma, I.M. Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector. (1997) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 94(19):10319-23.

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Blömer, U., Naldini, L., Kafri, T., Trono, D., Verma, I.M., Gage, F.H. Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector. (1997) Journal of Virology. 71(9):6641-9.

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Kuhn, H.G., Winkler, J., Kempermann, G., Thal, L.J., Gage, F.H. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. (1997) Journal of Neuroscience. 17(15):5820-9.

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Peterson, D.A., Leppert, J.T., Lee, K.F., Gage, F.H. Basal forebrain neuronal loss in mice lacking neurotrophin receptor p75. (1997) Ciencia. 277(5327):837-9.

Grill, R., Murai, K., Blesch, A., Gage, F.H., Tuszynski, M.H. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. (1997) Journal of Neuroscience. 17(14):5560-72.

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Schinstine, M., Ray, J., Gage, F.H. Potential effect of cytokines on transgene expression in primary fibroblasts implanted into the rat brain. (1997) Brain Res. Mol. Brain Res. 47(1-2):195-201.

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Ray, J., Baird, A., Gage, F.H. A 10-amino acid sequence of fibroblast growth factor 2 is sufficient for its mitogenic activity on neural progenitor cells. (1997) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 94(13):7047-52.

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Palmer, T.D., Takahashi, J., Gage, F.H. The adult rat hippocampus contains primordial neural stem cells. (1997) Molecular and Cellular Neurosciences. 8(6):389-404. DOI: 10.1006/mcne.1996.0595

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Sah, D.W., Ray, J., Gage, F.H. Bipotent progenitor cell lines from the human CNS. (1997) Nature Biotechnology. 15(6):574-80. DOI: 10.1038/nbt0697-574

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Kempermann, G., Kuhn, H.G., Gage, F.H. More hippocampal neurons in adult mice living in an enriched environment. (1997) Naturaleza. 386(6624):493-5. DOI: 10.1038/386493a0

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Fagan, A.M., Suhr, S.T., Lucidi-Phillipi, C.A., Peterson, D.A., Holtzman, D.M., Gage, F.H. Endogenous FGF-2 is important for cholinergic sprouting in the denervated hippocampus. (1997) Journal of Neuroscience. 17(7):2499-511.

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Raymon, H.K., Thode, S., Gage, F.H. Application of ex vivo gene therapy in the treatment of Parkinson's disease. (1997) Exp. Neurol. 144(1):82-91. DOI: 10.1006/exnr.1996.6392

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Winkler, J., Ramirez, G.A., Kuhn, H.G., Peterson, D.A., Day-Lollini, P.A., Stewart, G.R., Tuszynski, M.H., Gage, F.H., Thal, L.J. Reversible Schwann cell hyperplasia and sprouting of sensory and sympathetic neurites after intraventricular administration of nerve growth factor. (1997) Annals of Neurology. 41(1):82-93. DOI: 10.1002/ana.410410114

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Sah, D.W., Ray, J., Gage, F.H. Regulation of voltage- and ligand-gated currents in rat hippocampal progenitor cells in vitro. (1997) Journal of Neurobiology. 32(1):95-110.

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Senut, M.C., Suhr, S.T., Gage, F.H. Intracerebral xenografts: Sertoli cells to the rescue? (1996) Nature Biotechnology. 14(13):1650-1. DOI: 10.1038/nbt1296-1650

Suhonen, J.O., Peterson, D.A., Ray, J., Gage, F.H. Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. (1996) Naturaleza. 383(6601):624-7. DOI: 10.1038/383624a0

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Naldini, L., Blömer, U., Gage, F.H., Trono, D., Verma, I.M. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. (1996) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 93(21):11382-8.

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Lipkin, S.M., Grider, T.L., Heyman, R.A., Glass, C.K., Gage, F.H. Constitutive retinoid receptors expressed from adenovirus vectors that specifically activate chromosomal target genes required for differentiation of promyelocytic leukemia and teratocarcinoma cells. (1996) Journal of Virology. 70(10):7182-9.

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Sufficient knowledge of transcription factor structure and function has accumulated to allow attempts at the rational design of novel transcription factors for the study of gene regulation and potential application in gene therapy. In the present studies, we have systematically evaluated the function of chimeric retinoid receptors generated by fusion with the transactivation domain of VP16 and expression in adenovirus vectors. By varying the location of fusion of the VP16 transactivation domain with the retinoic acid receptor (RAR) or retinoid X receptor (RXR), marked differences in the specificity of gene activation were obtained. Although several chimeric proteins activated both RAR and RXR target genes, fusion of the NT16 transactivation domain to the N terminus of RAR permitted specific activation of reporter genes containing retinoic acid response elements. In contrast, fusion of the VP16 transactivation domain to the C terminus of RXR permitted specific activation of reporter genes containing RXR response elements. When tested for their ability to activate chromosomal targets, the chimera consisting of VP16 linked to the N terminus of PAR was much more active in promoting the differentiation of HL-60 cells and NTera-2 cells than the chimera consisting of VP16 linked to the C terminus of RXR. These observations support the existence of two distinct retinoid signalling pathways predicted on the basis of biochemical and pharmacologic studies and provide direct evidence that the programs of differentiation elicited by retinoic acid in these cells are mediated by a specific subset of binding sites for RAR-RXR heterodimers. VP16-RAR and VP16-RXR fusion proteins should be of further use in dissecting the relative contributions of RARs and RXRs to specific programs of gene expression. Constitutive retinoid receptors may also be considered for use as novel tumor suppressor genes for genetically based treatment of retinoid-responsive cancers.

Choi, D.W., Gage, F.H. Disease, transplantation and regeneration. (1996) Current Opinion in Neurobiology. 6(5):635-7.

Minger, S.L., Fisher, L.J., Ray, J., Gage, F.H. Long-term survival of transplanted basal forebrain cells following in vitro propagation with fibroblast growth factor-2. (1996) Exp. Neurol. 141(1):12-24. DOI: 10.1006/exnr.1996.0134

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The intracerebral transplantation of freshly dissected fetal tissue containing cholinergic neurons of the developing basal forebrain has been reported to reverse lesion-induced or age-related cognitive deficits in animal models of cholinergic neuronal degeneration. Grafts of cultured fetal neurons, however, have generally shown poor cellular survival and limited therapeutic benefit. We tested the hypothesis that recent advances in the identification of growth factors that promote the survival and propagation of fetal precursor cells in vitro would improve the long-term survival of cultured neurons following intracerebral implantation. Dissociated cells from gestational Day 14 rodent basal forebrain were grown in chemically defined media supplemented with 20 ng/ml basic fibroblast growth factor. Two weeks postplating, numerous cells were present in the cultures and showed immunoreactive labeling for a variety of markers, including glutamic acid decarboxylase, neuron-specific enolase, neurofilament proteins, glial fibrillary acidic protein and, occasionally, choline acetyltransferase. To determine if cultured basal forebrain cells would survive intracerebral implantation, the cells were implanted homotypically into the nucleus basalis magnocellularis. To enhance the potential for graft survival in vivo, cells were also implanted into the nucleus basalis magnocellularis following an ibotenic acid lesion and into the denervated frontal cortex. Animals sacrificed between 2 weeks and 7 months following transplantation showed good and comparable graft survival in all sites. Immunocytochemical analysis revealed that representative populations of cells observed in vitro survived for prolonged periods in vivo, even in sites distal from their normal cellular targets. Thus, neuronal populations expanded in vitro can successfully survive and maintain cellular phenotypes post-transplantation. These results suggest a potential for isolating and growing specific neuronal populations in vitro for intracerebral transplantation.

Nakajima, T., Fukamizu, A., Takahashi, J., Gage, F.H., Fisher, T., Blenis, J., Montminy, M.R. The signal-dependent coactivator CBP is a nuclear target for pp90RSK. (1996) Móvil. 86(3):465-74.

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Chalmers, G.R., Peterson, D.A., Gage, F.H. Sprouting adult CNS cholinergic axons express NILE and associate with astrocytic surfaces expressing neural cell adhesion molecule. (1996) Journal of Comparative Neurology. 371(2):287-99. DOI: 10.1002/(SICI)1096-9861(19960722)371:2<287::AID

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Nakahara, Y., Gage, F.H., Tuszynski, M.H. Grafts of fibroblasts genetically modified to secrete NGF, BDNF, NT-3, or basic FGF elicit differential responses in the adult spinal cord. (1996) Cell Transplantation. 5(2):191-204.

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Naldini, L., Blömer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F.H., Verma, I.M., Trono, D. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. (1996) Ciencia. 272(5259):263-7.

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Tuszynski, M.H., Roberts, J., Senut, M.C., U, H.S., Gage, F.H. Gene therapy in the adult primate brain: intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. (1996) Gene Therapy. 3(4):305-14.

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Kuhn, H.G., Dickinson-Anson, H., Gage, F.H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. (1996) Journal of Neuroscience. 16(6):2027-33.

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Lucidi-Phillipi, C.A., Clary, D.O., Reichardt, L.F., Gage, F.H. TrkA activation is sufficient to rescue axotomized cholinergic neurons. (1996) Neuron. 16(3):653-63.

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Tuszynski, M.H., Gage, F.H. Somatic gene therapy for nervous system disease. (1996) Ciba Foundation Symposium. 196:85-94; discussion 94-7.

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Hoshimaru, M., Ray, J., Sah, D.W., Gage, F.H. Differentiation of the immortalized adult neuronal progenitor cell line HC2S2 into neurons by regulatable suppression of the v-myc oncogene. (1996) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 93(4):1518-23.

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Peterson, D.A., Lucidi-Phillipi, C.A., Murphy, D.P., Ray, J., Gage, F.H. Fibroblast growth factor-2 protects entorhinal layer II glutamatergic neurons from axotomy-induced death. (1996) Journal of Neuroscience. 16(3):886-98.

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Blömer, U., Naldini, L., Verma, I.M., Trono, D., Gage, F.H. Applications of gene therapy to the CNS. (1996) Human Molecular Genetics. 5 Spec No:1397-404.

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Tuszynski, M.H., Gabriel, K., Gage, F.H., Suhr, S., Meyer, S., Rosetti, A. Nerve growth factor delivery by gene transfer induces differential outgrowth of sensory, motor, and noradrenergic neurites after adult spinal cord injury. (1996) Experimental Neurology. 137(1):157-73. DOI: 10.1006/exnr.1996.0016

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Eagle, K.S., Chalmers, G.R., Clary, D.O., Gage, F.H. Axonal regeneration and limited functional recovery following hippocampal deafferentation. (1995) Journal of Comparative Neurology. 363(3):377-88. DOI: 10.1002/cne.903630304

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Gage, F.H., Coates, P.W., Palmer, T.D., Kuhn, H.G., Fisher, L.J., Suhonen, J.O., Peterson, D.A., Suhr, S.T., Ray, J. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. (1995) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 92(25):11879-83.

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Ray, J., Raymon, H.K., Gage, F.H. Generation and culturing of precursor cells and neuroblasts from embryonic and adult central nervous system. (1995) Methods in Enzymology. 254:20-37.

Palmer, T.D., Ray, J., Gage, F.H. FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. (1995) Molecular and Cellular Neurosciences. 6(5):474-86. DOI: 10.1006/mcne.1995.1035

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Aubert, I., Ridet, J.L., Gage, F.H. Regeneration in the adult mammalian CNS: guided by development. (1995) Current Opinion in Neurobiology. 5(5):625-35.

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Senut, M.C., Tuszynski, M.H., Raymon, H.K., Suhr, S.T., Liou, N.H., Jones, K.R., Reichardt, L.F., Gage, F.H. Regional differences in responsiveness of adult CNS axons to grafts of cells expressing human neurotrophin 3. (1995) Experimental Neurology. 135(1):36-55. DOI: 10.1006/exnr.1995.1064

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Chen, K.S., Masliah, E., Mallory, M., Gage, F.H. Synaptic loss in cognitively impaired aged rats is ameliorated by chronic human nerve growth factor infusion. (1995) Neuroscience. 68(1):19-27.

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Fisher, L.J., Gage, F.H. Novel therapeutic directions for Parkinson's disease. (1995) Mol Med Today. 1(4):181-7.

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Winkler, J., Suhr, S.T., Gage, F.H., Thal, L.J., Fisher, L.J. Essential role of neocortical acetylcholine in spatial memory. (1995) Naturaleza. 375(6531):484-7. DOI: 10.1038/375484a0

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Tuszynski, M.H., Gage, F.H. Maintaining the neuronal phenotype after injury in the adult CNS. Neurotrophic factors, axonal growth substrates, and gene therapy. (1995) Molecular Neurobiology. 10(2-3):151-67. DOI: 10.1007/BF02740673

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Gage, F.H., Ray, J., Fisher, L.J. Isolation, characterization, and use of stem cells from the CNS. (1995) Annual Review of Neuroscience. 18:159-92. DOI: 10.1146/annurev.ne.18.030195.001111

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The nervous system of adult mammals, unlike the rest of the organs in the body, has been considered unique in its apparent inability to replace neurons following injury. However, in certain regions of the brain, neurogenesis occurs postnatally and continues through adulthood. The nature, fate, and longevity of cells undergoing proliferation within the CNS are unknown. These cells are increasingly becoming the focus of intense scrutiny; this is a recent development that has led to considerable controversy over the appropriate terminology to describe neural cells as they pass through different stages of proliferation, migration, and differentiation. Continuing studies detailing the properties of mitotic populations in the adult CNS will provide a better understanding of the nature of these cells during their development and should lead to a more consistent nomenclature. Studies of neural precursors isolated from the embryonic brain have indicated that many subgroups of cells undergo mitosis and subsequent differentiation into neurons and glia in vitro. A number of substances, such as growth factors and substrate molecules, are essential for these processes and also for lineage restriction and fate determination of these cells. Recent studies have shown that cells with proliferative capabilities can also be isolated from the adult brain. The nature of these cells is unknown, but there is evidence that both multipotent cells (stem cells) and lineage-restricted cells (neuroblasts or glioblasts) are resident within the mature CNS and that they can be maintained and induced to divide and differentiate in response to many of the same factors that influence their embryonic counterparts. Presently, it is unclear how many potentially quiescent precursor cells exist in the adult brain or what combination of growth factors and substrate molecules is involved in the proliferation and differentiation of these cells. Some of these questions are currently being addressed by using immortalized neural precursors or growth factor-expanded populations of primary precursors to model precursor responsiveness to environmental manipulations. Because in vitro culture conditions are unlikely to provide all of the factors necessary for inducing the proliferation and differentiation of neural precursors, recent studies have explored the properties of well-characterized precursor populations after implantation back into specific regions of the developing or adult CNS. These studies have highlighted the importance of the microenvironment in precursor differentiation and further suggested that precursor plasticity is a characteristic that is probably common to neural precursors throughout the CNS.(ABSTRACT TRUNCATED AT 400 WORDS)

Tuszynski, M.H., Gage, F.H. Bridging grafts and transient nerve growth factor infusions promote long-term central nervous system neuronal rescue and partial functional recovery. (1995) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 92(10):4621-5.

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Chalmers, G.R., Fisher, L.J., Niijima, K., Patterson, P.H., Gage, F.H. Adrenal chromaffin cells transdifferentiate in response to basic fibroblast growth factor and show directed outgrowth to a nerve growth factor source in vivo. (1995) Exp. Neurol. 133(1):32-42. DOI: 10.1006/exnr.1995.1005

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Chromaffin cells exposed to basic fibroblast growth factor (bFGF) in vitro express characteristics of sympathetic neurons, extend neurites, and become dependent on nerve growth factor (NGF) for survival. We explored whether the growth factor responsiveness of chromaffin cells could be exploited to enhance the transdifferentiation, neurite outgrowth and functional efficacy of chromaffin cells implanted into rats with unilateral 6-hydroxydopamine lesions. Cografts of neonatal chromaffin cells and fibroblasts genetically modified to produce bFGF were placed into the dopamine-depleted striatum of adult rats. Either control-transfected or NGF-producing fibroblasts were then transplanted 1 mm distal to the cograft. Chromaffin cells transdifferentiated under the influence of bFGF, as indicated by the growth of neurites and the expression of neuron-specific proteins. Distal grafts of NGF-producing fibroblasts successfully induced chromaffin neurites to traverse through the host parenchyma to the NGF source. In the absence of NGF fibroblast grafts, neither neurite extension nor good, long-term survival of the chromaffin-derived neurons was observed. Assessments of apomorphine-induced rotational behavior 2- and 4-weeks postgrafting revealed no behavior improvements in any of the groups. These results indicate that localized sources of growth factors are effective in inducing the transdifferentiation of grafted chromaffin cells as well as the extension of chromaffin-derived neurites into the host parenchyma. Such chromaffin cell-derived neurons are, however, functionally ineffective in this rat model of Parkinson's disease. Whether the lack of behavioral improvement reflected the tropic growth of neurites to an inappropriate striatal region or the noradrenergic nature of the chromaffin cell-derived neurons remains to be clarified. Nonetheless, these results caution that promoting transdifferentiation and neurite extension from engrafted chromaffin cells may not be sufficient to achieve desired functional effects of such grafts.

Lucidi-Phillipi, C.A., Gage, F.H., Shults, C.W., Jones, K.R., Reichardt, L.F., Kang, U.J. Brain-derived neurotrophic factor-transduced fibroblasts: production of BDNF and effects of grafting to the adult rat brain. (1995) Journal of Comparative Neurology. 354(3):361-76. DOI: 10.1002/cne.903540306

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Chen, K.S., Gage, F.H. Somatic gene transfer of NGF to the aged brain: behavioral and morphological amelioration. (1995) Journal of Neuroscience. 15(4):2819-25.

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Fisher, L.J., Gage, F.H. Radical directions in Parkinson's disease. (1995) Nature Medicine. 1(3):201-3.

Niijima, K., Chalmers, G.R., Peterson, D.A., Fisher, L.J., Patterson, P.H., Gage, F.H. Enhanced survival and neuronal differentiation of adrenal chromaffin cells cografted into the striatum with NGF-producing fibroblasts. (1995) Journal of Neuroscience. 15(2):1180-94.

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Ray, J., Hogg, J., Beutler, A.S., Takayama, H., Baird, A., Gage, F.H. Expression of biologically active basic fibroblast growth factor by genetically modified rat primary skin fibroblasts. (1995) Journal of Neurochemistry. 64(2):503-13.

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Beutler, A.S., Banck, M.S., Bach, F.W., Gage, F.H., Porreca, F., Bilsky, E.J., Yaksh, T.L. Retrovirus-mediated expression of an artificial beta-endorphin precursor in primary fibroblasts. (1995) J. Neurochem. 64(2):475-81.

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Takayama, H., Ray, J., Raymon, H.K., Baird, A., Hogg, J., Fisher, L.J., Gage, F.H. Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson's disease. (1995) Nature Medicine. 1(1):53-8.

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Gonzalez, A.M., Carman, L.S., Ong, M., Ray, J., Gage, F.H., Shults, C.W., Baird, A. Storage, metabolism, and processing of 125I-fibroblast growth factor-2 after intracerebral injection. (1994) Brain Research. 665(2):285-92.

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Peterson, D.A., Lucidi-Phillipi, C.A., Eagle, K.L., Gage, F.H. Perforant path damage results in progressive neuronal death and somal atrophy in layer II of entorhinal cortex and functional impairment with increasing postdamage age. (1994) Journal of Neuroscience. 14(11 Pt 2):6872-85.

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Choi, D., Gage, F.H. Disease, transplantation and regeneration. (1994) Current Opinion in Neurobiology. 4(5):693-5.

Tuszynski, M.H., Gage, F.H. Neurotrophic factors and diseases of the nervous system. (1994) Annals of Neurology. 35 Suppl:S9-12.

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Ray, J., Gage, F.H. Spinal cord neuroblasts proliferate in response to basic fibroblast growth factor. (1994) Journal of Neuroscience. 14(6):3548-64.

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Trophic factors may function as one of the epigenic signals responsible for the proliferation, growth, migration, and differentiation of neurons and glia during embryogenesis. The present study reports that basic fibroblast growth factor (bFGF) at high concentrations (10-100 ng/ml) is a mitogen for embryonic spinal cord cells that have already committed to a neuronal pathway and are expressing neuronal phenotypes (neuroblasts). Neuroblasts proliferate with a doubling time of 2.5 d. To characterize the nature of cells proliferating in response to bFGF, we have established long-term cultures of neuroblasts that can be passaged, freeze thawed, and recultured. In cultures the proportion of astrocytes remained the same, indicating limited survival and proliferation of these cells in response to bFGF. These results indicate that bFGF has mitogenic effects preferably on neuroblasts. The morphological and biochemical characterizations of the neuronal populations present in the long-term neuroblast cultures are presented here. The presence of cholinergic and GABAergic neurons in the cultures was established by immunocytochemical analysis. The cultures contain a small number of motoneurons as judged by their immunostaining with ChAT, low-affinity NGF receptor (LNGFR), and large size. Among all other growth factors tested for their mitogenic effects on embryonic spinal cord cells in culture, only epidermal growth factor (EGF) showed such effects, but to a lesser degree. The proliferative nature of neuroblasts has made it possible to transduce the Escherichia coli beta-galactosidase (LacZ) gene stably into these cells in vitro using a retroviral vector. The transfected cells expressing the foreign gene can be passaged, freeze thawed, and recultured without the loss of transgenes. The ability to transduce foreign genes stably into these cells permits implantation of these cells in the spinal cord to study cellular and biochemical behaviors and gene expression in defined neuronal populations in in vivo environments.

Gage, F.H. Neuronal stem cells: their characterization and utilization. (1994) Neurobiology of Aging. 15 Suppl 2:S191.

Barba, D., Hardin, J., Sadelain, M., Gage, F.H. Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors. (1994) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 91(10):4348-52.

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Fisher, L.J., Gage, F.H. Intracerebral transplantation: basic and clinical applications to the neostriatum. (1994) Revista FASEB. 8(8):489-96.

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Dekker, A.J., Winkler, J., Ray, J., Thal, L.J., Gage, F.H. Grafting of nerve growth factor-producing fibroblasts reduces behavioral deficits in rats with lesions of the nucleus basalis magnocellularis. (1994) Neuroscience. 60(2):299-309.

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Rats received bilateral lesions of the nucleus basalis magnocellularis by infusion of biotenic acid. Two weeks after the lesion, a suspension of genetically modified primary rat fibroblasts was grafted dorsal to the nucleus basalis magnocellularis (2 x 10(5) cells per side). The fibroblasts were either infected with the gene for human beta-nerve growth factor or Escherichia coli beta-galactosidase. The nerve growth factor-producing fibroblasts released 67 ng nerve growth factor/10(5) cells per day in vitro. Two weeks after implantation of the fibroblasts, spatial learning was tested in the Morris water-maze. Nerve growth factor-producing fibroblasts, but not beta-galactosidase-producing fibroblasts ameliorated the deficit in acquisition of the water-maze task. In addition, spatial acuity was improved to near-normal levels by the nerve growth factor-producing grafts. Choline acetyltransferase activity in cortical areas and hippocampus was not affected by the nerve growth factor-producing grafts. Both grafted groups showed a similar reduction in the level of dopamine, but not homovanillic acid or 3-methoxytyramine, in the frontal cortex. Levels of norepinephrine, epinephrine and serotonin and their metabolites in the neocortex and hippocampus were not affected by the lesion or the grafts. Nerve growth factor-producing grafts increased the size of remaining nerve growth factor-receptor (p75) immunoreactive neurons in the nucleus basalis magnocellularis by 25%. Nucleus basalis magnocellularis lesions reduced the integrated optic density of choline acetyltransferase-positive fiber staining in the ventral neocortex by 46%, but nerve growth factor-producing grafts restored this area to 86% of control. These data suggest that nerve growth factor-producing grafts can cause a marked behavioral improvement, probably through the partial restoration of the lesioned projection from nucleus basalis magnocellularis to neocortex.

Beeson, J.G., Shelton, E.R., Chan, H.W., Gage, F.H. Differential distribution of amyloid protein precursor immunoreactivity in the rat brain studied by using five different antibodies. (1994) Journal of Comparative Neurology. 342(1):78-96. DOI: 10.1002/cne.903420109

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Beeson, J.G., Shelton, E.R., Chan, H.W., Gage, F.H. Age and damage induced changes in amyloid protein precursor immunohistochemistry in the rat brain. (1994) Journal of Comparative Neurology. 342(1):69-77. DOI: 10.1002/cne.903420108

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Dekker, A.J., Fagan, A.M., Gage, F.H., Thal, L.J. Effects of brain-derived neurotrophic factor and nerve growth factor on remaining neurons in the lesioned nucleus basalis magnocellularis. (1994) Brain Research. 639(1):149-55.

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Tuszynski, M.H., Peterson, D.A., Ray, J., Baird, A., Nakahara, Y., Gage, F.H. Fibroblasts genetically modified to produce nerve growth factor induce robust neuritic ingrowth after grafting to the spinal cord. (1994) Experimental Neurology. 126(1):1-14.

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Fagan, A.M., Gage, F.H. Mechanisms of sprouting in the adult central nervous system: cellular responses in areas of terminal degeneration and reinnervation in the rat hippocampus. (1994) Neuroscience. 58(4):705-25.

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Neurons of the adult mammalian central nervous system are limited in their ability to regenerate in response to injury. In certain circumstances, however, such neurons can exhibit morphological plasticity (e.g. sprouting). Unilateral transection of the perforant path in the adult rat induces terminal degeneration of entorhinal axons within the molecular layer of the ipsilateral hippocampal dentate gyrus. Cholinergic (and other) afferents subsequently sprout within the denervated zone. We show that despite the breach in the blood-brain barrier at the site of the aspirative lesion, the barrier remains intact in the areas of terminal degeneration (and reinnervation), and peripheral monocytic macrophages do not infiltrate this area to participate in the degenerative and/or regenerative events. Perforant path transection does not induce expression of major histocompatibility antigens on reactive cells within the denervated zone, nor are T lymphocytes recruited to this area. T lymphocyte-deficient Nude rats exhibit normal cholinergic sprouting. Perforant path transection does induce rapid and robust proliferation of microglia, and astrocytes to a lesser extent, in areas undergoing terminal degeneration. Histological evaluation after antimitotic administration shows that this glial proliferation is not required for the subsequent neuronal sprouting events. These results show that the reparative process in this model system involves interactions between cells endogenous to the brain in a non-immune context. Knowledge of these cellular responses provides a framework from which to further investigate putative molecular signals involved in initiating the neuronal sprouting events. Discovering the cellular and molecular interactions taking place under sprouting conditions is likely to be critical for understanding the mechanisms of reactive neuronal growth and, furthermore, may provide insights as to why regeneration is so limited in the central nervous system.

Holtzman, D.M., Li, Y., Chen, K., Gage, F.H., Epstein, C.J., Mobley, W.C. Nerve growth factor reverses neuronal atrophy in a Down syndrome model of age-related neurodegeneration. (1993) Neurology. 43(12):2668-73.

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Kang, U.J., Fisher, L.J., Joh, T.H., O'Malley, K.L., Gage, F.H. Regulation of dopamine production by genetically modified primary fibroblasts. (1993) Journal of Neuroscience. 13(12):5203-11.

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Barba, D., Hardin, J., Ray, J., Gage, F.H. Thymidine kinase-mediated killing of rat brain tumors. (1993) Journal of Neurosurgery. 79(5):729-35. DOI: 10.3171/jns.1993.79.5.0729

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Gene therapy has many potential applications in central nervous system (CNS) disorders, including the selective killing of tumor cells in the brain. A rat brain tumor model was used to test the herpes simplex virus (HSV)-thymidine kinase (TK) gene for its ability to selectively kill C6 and 9L tumor cells in the brain following systemic administration of the nucleoside analog ganciclovir. The HSV-TK gene was introduced in vitro into tumor cells (C6-TK and 9L-TK), then these modified tumor cells were evaluated for their sensitivity to cell killing by ganciclovir. In a dose-response assay, both C6-TK and 9L-TK cells were 100 times more sensitive to killing by ganciclovir (median lethal dose: C6-TK, 0.1 microgram ganciclovir/ml; C6, 5.0 micrograms ganciclovir/ml) than unmodified wild-type tumor cells or cultured fibroblasts. In vivo studies confirmed the ability of intraperitoneal ganciclovir administration to kill established brain tumors in rats as quantified by both stereological assessment of brain tumor volumes and studies of animal survival over 90 days. Rats with brain tumors established by intracerebral injection of wild-type or HSV-TK modified tumor cells or by a combination of wild-type and HSV-TK-modified cells were studied with and without ganciclovir treatments. Stereological methods determined that ganciclovir treatment eliminated tumors composed of HSV-TK-modified cells while control tumors grew as expected (p < 0.001). In survival studies, all 10 rats with 9L-TK tumors treated with ganciclovir survived 90 days while all untreated rats died within 25 days. Curiously, tumors composed of combinations of 9L and 9L-TK cells could be eliminated by ganciclovir treatments even when only one-half of the tumor cells carried the HSV-TK gene. While not completely understood, this additional tumor cell killing appears to be both tumor selective and local in nature. It is concluded that HSV-TK gene therapy with ganciclovir treatment does selectively kill tumor cells in the brain and has many potential applications in CNS disorders, including the treatment of cancer.

Suhr, S.T., Gage, F.H. Gene therapy for neurologic disease. (1993) Archives of Neurology. 50(11):1252-68.

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Fisher, L.J., Schinstine, M., Salvaterra, P., Dekker, A.J., Thal, L., Gage, F.H. In vivo production and release of acetylcholine from primary fibroblasts genetically modified to express choline acetyltransferase. (1993) Journal of Neurochemistry. 61(4):1323-32.

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Fisher, L.J., Raymon, H.K., Gage, F.H. Cells engineered to produce acetylcholine: therapeutic potential for Alzheimer's disease. (1993) Annals of the New York Academy of Sciences. 695:278-84.

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Alzheimer's disease (AD) is a debilitating disorder of the central nervous system which may affect up to 50% of the population over the age of 85 years. The etiology of AD is unknown and there is currently no cure for the disease. Well-documented losses in cholinergic and other neurotransmitter systems have provided a focal point for attempting pharmacological interventions in AD to ameliorate some of the cognitive deficits that occur. However, current systemic strategies have met with limited success. An alternative strategy, that has been pursued in animal models of neurodegenerative disease, is to augment neurotransmitter function within the brain through tissue transplantation. Such implants have an advantage over conventional drug therapies in that the cells can be precisely placed within compromised areas of the brain. We have pursued a strategy of designing cells, through the use of molecular biology techniques, to produce neurotrophic factors and neurotransmitters. Recently, we developed a primary fibroblast cell line that was genetically modified to express choline acetyltransferase (ChAT). In vitro, these cells produced and released acetylcholine at levels that varied with the amount of choline in the culture media. When implanted into the hippocampus of rats, the in vivo microdialysis technique revealed that the ChAT-expressing fibroblasts continued to produce and release acetylcholine after grafting. Most importantly, the levels of acetylcholine synthesized by the cells could be regulated by the localized infusion of choline in the vicinity of the grafts. These results confirmed previous work which indicated that engineered fibroblasts provide an effective delivery vehicle of different substances to the brain. While the intracerebral implantation of genetically modified cells will not cure AD, the continuing development of this strategy may ultimately provide a powerful approach for ameliorating the devastating cognitive impairments which are a hallmark of this disease.

Hammond, R.R., Gage, F.H., Terry, R.D. Alzheimer's disease and spirochetes; a questionable relationship. (1993) Neuroreport. 4(7):840.

Fisher, L.J., Gage, F.H. Grafting in the mammalian central nervous system. (1993) Physiological Reviews. 73(3):583-616.

Nilsson, O.G., Gage, F.H. Anticholinergic sensitivity in the aging rat septohippocampal system as assessed in a spatial memory task. (1993) Neurobiology of Aging. 14(5):487-97.

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Shimohama, S., Fisher, L.J., Gage, F.H. Intracerebral grafting of genetically modified cells. Applications to a rat model of Parkinson's disease. (1993) Advances in Neurology. 60:744-8.

Schinstine, M., Gage, F.H. Factors affecting proviral expression in primary cells grafted into the CNS. (1993) Res Publ Assoc Res Nerv Ment Dis. 71:311-23.

Ray, J., Peterson, D.A., Schinstine, M., Gage, F.H. Proliferation, differentiation, and long-term culture of primary hippocampal neurons. (1993) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 90(8):3602-6.

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Gage, F.H. Parkinson's disease. Fetal implants put to the test. (1993) Naturaleza. 361(6411):405-6. DOI: 10.1038/361405a0

Shimohama, S., Saitoh, T., Gage, F.H. Changes in protein kinase C isozymes in the rat hippocampal formation following hippocampal lesion. (1993) Hippocampus. 3(1):43-55. DOI: 10.1002/hipo.450030105

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The cellular and regional distribution of the four protein kinase C (PKC) isoforms in the rat hippocampal formation and the response of PKC to lesions were determined by employing immunohistochemical and immunochemical techniques with antibodies specific to PKC(alpha), -(beta I), -(beta II), and -(gamma). PKC(alpha) intensely stained the periphery of the pyramidal cell in the stratum pyramidale. The granule cells, glial cells, and mossy fibers were anti-PKC(alpha) negative. The cytoplasm, axons, and dendrites of basket cells and interneurons in the hilus were labeled with anti-PKC(alpha). Anti-PKC(beta I) immunoreactivity was localized on the periphery of pyramidal cells and interneurons of the hilus, as well as the oriens, radiatum, and molecular layers of the CA regions. Anti-PKC(beta II) immunoreactivity was mainly cytoplasmic, extending into the dendrites in the hippocampal pyramidal cells and the dentate granule cells, and also in some glial cells. In the stratum radiatum of the CA1, anti-PKC(gamma) immunoreactivity localized to the pyramidal cell cytoplasm, extending into the dendrites. Following fimbria-fornix (FF) lesions, the anti-PKC(alpha) and -(beta I) staining of the pyramidal cell periphery was markedly reduced. The anti-PKC(gamma) staining of the pyramidal and granular cells of the dentate gyrus was reduced whereas the interneuron staining in the hilus was increased. In the FF-lesioned hippocampus, anti-PKC(alpha) and anti-PKC(beta II) labeled reactive glial cells, whereas anti-PKC(beta I) and -(gamma) did not. Quantitative Western blot analysis revealed a dramatic increase in the particulate/total PKC for all isozyme forms, although the total levels of PKC, except PKC(gamma), did not change following FF lesions. The PKC(gamma) concentration doubled after FF lesions. Perforant path lesions resulted in a marked alteration in the neuronal staining in dentate gyrus with anti-PKC(alpha) and -(beta I) and in increased numbers of anti-PKC(alpha)- and anti-PKC(beta II)-positive glial cells. Anti-PKC(gamma) staining did not change noticeably. The total PKC concentration did not change for isozymes alpha, beta I, and gamma, but PKC (beta II) concentration increased by 48% following perforant path lesions as detected by Western blot analysis. The particulate/total PKC decreased for all four isozymes although the reduction in PKC(beta I) concentration was not statistically significant. This change in PKC compartmentalization is in marked contrast to an increased level of particulate PKC following FF lesions. Thus, the effects of deafferentation and deafferentation for each PKC isoform were different.

Ray, J., Gage, F.H. Gene transfer into established and primary fibroblast cell lines: comparison of transfection methods and promoters. (1992) BioTechniques. 13(4):598-603.

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Fischer, W., Chen, K.S., Gage, F.H., Björklund, A. Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging. (1992) Neurobiology of Aging. 13(1):9-23.

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Rats distributed over five different age groups, 3, 12, 18, 24 and 30 months of age, were screened for their spatial learning and memory ability in the Morris water maze, and the degree of place navigational impairments was correlated with morphological changes in the four major forebrain cholinergic cell groups (medial septum, MS; vertical limb of the diagonal band of Broca, VDB; nucleus basalis magnocellularis, NBM; and striatum) using choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr) histochemistry. Impaired place navigation developed progressively with age, such that 8% of the 12-month-old rats, 45% of the 18-month-old, 53% of the 24-month-old, and over 90% of the 30-month-old rats were behaviorally impaired. Significant reductions in the number of ChAT/NGFr-positive cell bodies, amounting to between 19 and 45%, were observed in all four cell groups, and the remaining cells were reduced in size (6-24% reduction in cross-sectional area in the oldest age groups). Although the morphological changes were less severe and tended to develop later than the behavioral impairments, there was overall a significant correlation between water maze performance and ChAT/NGFr-positive cell counts, and to a lesser degree also cell size in all four cell groups. These changes were also highly correlated with age. The highest correlations were seen in MS, VDB and NBM, which are known to play a role in spatial memory performance in young rats. The results indicate that degenerative and/or atrophic changes in the forebrain cholinergic system and decline in spatial learning ability are parallel processes during aging. Although the magnitude of the morphological changes does not appear to be substantial enough, by itself, to explain the severe spatial learning impairments that develop in the oldest animals, the present data are consistent with the view that impaired function in the forebrain cholinergic system can contribute to age-dependent cognitive decline in rodents.

Yoshida, K., Kakihana, M., Chen, L.S., Ong, M., Baird, A., Gage, F.H. Cytokine regulation of nerve growth factor-mediated cholinergic neurotrophic activity synthesized by astrocytes and fibroblasts. (1992) Journal of Neurochemistry. 59(3):919-31.

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The neurotrophic activity of astrocytes and fibroblasts and its regulation by various cytokines were investigated. Astrocyte conditioned medium (ACM) enhanced the survival of neurons and the proliferation of astrocytes in embryonic cortical cultures grown in serum-free defined medium. However, these results were not affected by acidic fibroblast growth factor, interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF alpha), and transforming growth factor-beta 1. In contrast, ACM induced choline acetyltransferase expression in septal cholinergic neurons via nerve growth factor (NGF)-dependent and -independent mechanisms. However, neither acidic nor basic fibroblast growth factor is involved in this biological activity in ACM. The cytokines listed above mainly stimulate NGF-mediated cholinergic neurotrophic activity in ACM. A combination of IL-1 beta and TNF alpha significantly enhanced choline acetyltransferase activity in septal neurons co-cultured with astrocytes, and this effect was found to be mediated by NGF produced by activated astrocytes. Effects of astrocytes on GABAergic neurons were also examined. ACM was found to increase glutamate decarboxylase activity in neuronal cultures from septum in the presence of Ara-C. However, the cytokines did not enhance this activity in ACM. Moreover, a combination of IL-1 beta and TNF alpha had no effect on glutamate decarboxylase activity in septal neurons co-cultured with astrocytes. In a final set of experiments, cholinergic neurotrophic activity in skin-derived fibroblast conditioned medium (FCM) was examined. FCM was found to possess biological activity similar to that of ACM on septal neurons grown in serum-free defined medium with Ara-C. The cytokines also enhanced NGF-mediated cholinergic neurotrophic activity in FCM. Astrocytes and fibroblasts were found to possess NGF-type and non-NGF-type cholinergic neurotrophic activity, and various cytokines were found to regulate the NGF-type cholinergic neurotrophic activity in both types of cells. NGF produced by astrocytes and fibroblasts that are activated by cytokines is likely to be important for development and regeneration of NGF-sensitive neurons in the central and peripheral nervous systems.

Thal, L.J., Gilbertson, E., Armstrong, D.M., Gage, F.H. Development of the basal forebrain cholinergic system: phenotype expression prior to target innervation. (1992) Neurobiology of Aging. 13(1):67-72.

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Holtzman, D.M., Li, Y., Gage, F.H., Epstein, C.J., Mobley, W.C. Neurodegeneration and gene dysregulation: studies utilizing the mouse trisomy 16 model of Down syndrome. (1992) Progress in Clinical and Biological Research. 379:227-44.

Kawaja, M.D., Rosenberg, M.B., Yoshida, K., Gage, F.H. Somatic gene transfer of nerve growth factor promotes the survival of axotomized septal neurons and the regeneration of their axons in adult rats. (1992) Journal of Neuroscience. 12(7):2849-64.

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Schinstine, M., Rosenberg, M.B., Routledge-Ward, C., Friedmann, T., Gage, F.H. Effects of choline and quiescence on Drosophila choline acetyltransferase expression and acetylcholine production by transduced rat fibroblasts. (1992) Journal of Neurochemistry. 58(6):2019-29.

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Gage, F.H. Repopulating the mortal brain with immortal cells. (1992) Current Biology. 2(5):232-4.

Lyden, P.D., Zivin, J.A., Chabolla, D.R., Jacobs, M.A., Gage, F.H. Quantitative effects of cerebral infarction on spatial learning in rats. (1992) Experimental Neurology. 116(2):122-32.

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Kawaja, M.D., Gage, F.H. Morphological and neurochemical features of cultured primary skin fibroblasts of Fischer 344 rats following striatal implantation. (1992) Journal of Comparative Neurology. 317(1):102-16. DOI: 10.1002/cne.903170108

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In order to assess the feasibility of using primary skin fibroblasts as a donor population for genetic modification and subsequent intracerebral grafting, the present study examines the structural and neurochemical characteristics of intrastriatal grafts of isogeneic primary fibroblasts over a period of 6 months. In culture, primary skin fibroblasts obtained from a female Fischer 344 rat display robust growth, but once confluent these cells exhibit contact inhibition. Following the implantation of cultured primary cells within the striatum of other adult rats from the same inbred strain, isologous grafts stain immunohistochemically for fibronectin at 1 week, and this immunostaining persists up to 6 months. Immunoreactivity for laminin is intense within the grafts from 1 to 8 weeks, but decreases by 6 months. Astrocytes within the striatum respond dramatically to the implantation of primary fibroblasts, such that immunohistochemical staining for glial fibrillary acidic protein increases markedly from 1 to 8 weeks after implantation. Although the intensity of immunostaining for glial fibrillary acidic protein diminishes among striatal astrocytes between 8 weeks and 6 months, the astrocytic border between the grafts and striatal neuropil remains intensely immunoreactive. Capillaries within the grafts stain immunohistochemically for glucose transporter (a facilitated glucose uptake carrier) as early as 3 weeks after implantation. Following intravenous infusions of peroxidase, capillaries within fibroblast grafts do not permit the extravasation of this macromolecule at 8 weeks and 6 months. Thus, capillaries formed within intracerebral grafts of primary skin fibroblasts exhibit a functional impermeable barrier to macromolecules similar to those capillaries of the host striatum. At the ultrastructural level, grafts possess numerous fibroblasts and have an extracellular matrix filled with collagen. Reactive astrocytic processes filled with intermediate filaments are found throughout the grafts. Hypertrophied astrocytes and their processes also appear to form a continuous border between the grafts and striatal neuropil. Grafts of primary fibroblasts also possess an extensive vasculature that is composed of capillaries with nonfenestrated endothelial cells; the occurrence of reactive astrocytic processes closely associated with or enveloping capillaries is variable. These results provide direct morphological and neurochemical evidence for the long-term survival of isologous fibroblasts after implantation within the rat striatum. From these data, we propose that isologous skin fibroblasts can be considered as donor candidates for successful intracerebral grafting following gene transfer.

Buzsáki, G., Gage, F.H. Fetal brain tissue grafts modulate neuronal excitability in a chronic model of epilepsy. (1992) Epilepsy Res. Suppl. 8:271-81.

Holtzman, D.M., Li, Y.W., DeArmond, S.J., McKinley, M.P., Gage, F.H., Epstein, C.J., Mobley, W.C. Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants. (1992) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 89(4):1383-7.

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Jinnah, H.A., Hess, E.J., Wilson, M.C., Gage, F.H., Friedmann, T. Localization of hypoxanthine-guanine phosphoribosyltransferase mRNA in the mouse brain by in situ hybridization. (1992) Molecular and Cellular Neurosciences. 3(1):64-78.

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Gage, F.H., Chen, K.S. Neural transplants: prospects for Alzheimer's disease. (1992) Current Opinion in Neurology and Neurosurgery. 5(1):94-9.

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Dekker, A.J., Gage, F.H., Thal, L.J. Delayed treatment with nerve growth factor improves acquisition of a spatial task in rats with lesions of the nucleus basalis magnocellularis: evaluation of the involvement of different neurotransmitt (1992) Neuroscience. 48(1):111-9.

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Yoshida, K., Gage, F.H. Cooperative regulation of nerve growth factor synthesis and secretion in fibroblasts and astrocytes by fibroblast growth factor and other cytokines. (1992) Brain Research. 569(1):14-25.

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Acidic fibroblast growth factor (aFGF) enhances nerve growth factor (NGF) synthesis by astrocytes obtained from various brain regions. NGF secretion by fibrous-shaped astrocytes transformed by dibutyryl-cAMP (db-cAMP) pretreatment was less than that by untreated astrocytes. However, aFGF also enhanced NGF secretion by fibrous-shaped astrocytes. The effects of various kinds of intracellular signaling modulators on NGF synthesis were examined. None of the following second messenger effectors had an effect on NGF synthesis: protein kinase C (PKC) agonist (phorbol myristate acetate (PMA)) or antagonist (sphingosine (SP)). LiCl, and ionomycin (Iono). Further, increases of intracellular cAMP by forskolin (FK) or db-cAMP have no significant effect on NGF synthesis in astrocytes under a standard culture condition. However, NGF synthesis by astrocytes in the presence of aFGF was significantly enhanced by db-cAMP, but not by FK or sodium butyrate. These results indicate that an excessive amount of cAMP enhances the effect of aFGF on NGF synthesis in astrocytes. NGF synthesis in astrocytes was not affected by treatment with anti-aFGF or anti-bFGF neutralizing antibodies, indicating that FGFs are not involved in the autocrine regulation of NGF synthesis in astrocytes. Transforming growth factor-beta 1 (TGF-beta 1), which inhibits some effects of FGFs, increased NGF synthesis in concert with aFGF. Furthermore, the highest NGF synthesis was observed when astrocytes were stimulated by all of the following cytokines: aFGF, interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and TGF-beta 1. The mechanism regulating NGF synthesis in fibroblasts obtained from prenatal rat skin was also investigated. Acidic FGF, basic FGF (bFGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-alpha (TGF-alpha), TGF-beta 1, IL-1 beta, and TNF-alpha were found to be regulators of NGF synthesis in skin fibroblasts. Among these cytokines, aFGF is the most potent regulator of NGF synthesis in fibroblasts. NGF synthesis by skin fibroblasts, either in the presence or absence of aFGF, was not modified by any of the following: FK, PMA, SP, LiCl, and Iono. However, db-cAMP significantly enhanced NGF synthesis in both conditions. Sodium butyrate enhanced NGF synthesis in the presence of aFGF, but not in the absence of aFGF. These results suggest that an excessive amount of cAMP and butyrate moiety regulate NGF synthesis in skin fibroblasts in different ways.(ABSTRACT TRUNCATED AT 400 WORDS)

Buzsáki, G., Hsu, M., Horváth, Z., Gage, F.H. Physiological and behavioral consequences of delayed septal grafts in the subcortically denervated hippocampus. (1992) Restor. Neurol. Neurosci. 4(6):369-80. DOI: 10.3233/RNN-1992-4602

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Johnson, P.A., Yoshida, K., Gage, F.H., Friedmann, T. Effects of gene transfer into cultured CNS neurons with a replication-defective herpes simplex virus type 1 vector. (1992) Brain Research. Molecular Brain Research. 12(1-3):95-102.

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Jinnah, H.A., Gage, F.H., Friedmann, T. Amphetamine-induced behavioral phenotype in a hypoxanthine-guanine phosphoribosyltransferase-deficient mouse model of Lesch-Nyhan syndrome. (1991) Behavioral Neuroscience. 105(6):1004-12.

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Kawaja, M.D., Gage, F.H. Reactive astrocytes are substrates for the growth of adult CNS axons in the presence of elevated levels of nerve growth factor. (1991) Neuron. 7(6):1019-30.

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Tuszynski, M.H., Sang, H., Yoshida, K., Gage, F.H. Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brain. (1991) Annals of Neurology. 30(5):625-36. DOI: 10.1002/ana.410300502

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Kawaja, M.D., Ray, J., Gage, F.H. Employment of fibroblasts for gene transfer: applications for grafting into the central nervous system. (1991) Genetic Engineering. 13:205-20.

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Gage, F.H., Kang, U.J., Fisher, L.J. Intracerebral grafting in the dopaminergic system: issues and controversy. (1991) Current Opinion in Neurobiology. 1(3):414-9.

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Dekker, A.J., Langdon, D.J., Gage, F.H., Thal, L.J. NGF increases cortical acetylcholine release in rats with lesions of the nucleus basalis. (1991) Neuroreport. 2(10):577-80.

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Schinstine, M., Kawaja, M.D., Gage, F.H. Intracerebral delivery of growth factors: potential application of genetically modified fibroblasts. (1991) Progress in Growth Factor Research. 3(1):57-66.

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Masliah, E., Fagan, A.M., Terry, R.D., DeTeresa, R., Mallory, M., Gage, F.H. Reactive synaptogenesis assessed by synaptophysin immunoreactivity is associated with GAP-43 in the dentate gyrus of the adult rat. (1991) Experimental Neurology. 113(2):131-42.

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Reactive synaptogenesis and terminal proliferation are known to occur in the dentate gyrus of the rat hippocampus following removal of specific afferents. In the present study we have examined the relation of synaptophysin immunoreactivity to the immunohistochemical staining pattern of GAP-43, a putative marker of neuritic growth. Within the molecular layer of the normal dentate gyrus, synaptophysin immunolabeling shows a trilaminar pattern, with the inner and outer layers having the greatest density of staining. Within the first week following denervation, there was a significant decrease in the staining density in the outer two-thirds of the molecular layer, followed by a moderate recovery at 14 days and 80% recovery by 30 days. This pattern is consistent with the time course of denervation and reinnervation in this system as determined previously by electron microscopy. By comparison, the staining pattern for GAP-43 in the intact dentate gyrus showed the middle and outer thirds of the molecular layer to be less densely stained than the inner third. Within a week following deafferentation, the outer two-thirds of the molecular layer displayed decreased levels of GAP-43 immunoreactivity, followed by recovery to normal levels by 30 days. By 84 days postlesion, patterns of both synaptophysin and GAP-43 immunostaining reflected an increased width of the inner molecular layer. Laser confocal imaging of double-immunolabeled sections at 14 days postlesion showed a 370% increase in the number of GAP-43-positive terminals in the molecular layer as compared to unoperated controls. Many of these GAP 43-positive terminals were synaptophysin negative. We conclude that GAP-43 may play a role in the synaptic remodeling that occurs in the denervated rat hippocampus and that quantitative morphometry of synaptophysin immunolabeling accurately reflects the fate of presynaptic terminals in this model of degeneration and reinnervation.

Gage, F.H., Kawaja, M.D., Fisher, L.J. Genetically modified cells: applications for intracerebral grafting. (1991) Trends in Neurosciences. 14(8):328-33.

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Buzsáki, G., Masliah, E., Chen, L.S., Horváth, Z., Terry, R., Gage, F.H. Hippocampal grafts into the intact brain induce epileptic patterns. (1991) Brain Research. 554(1-2):30-7.

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Carman, L.S., Gage, F.H., Shults, C.W. Partial lesion of the substantia nigra: relation between extent of lesion and rotational behavior. (1991) Brain Research. 553(2):275-83.

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Fischer, W., Björklund, A., Chen, K., Gage, F.H. NGF improves spatial memory in aged rodents as a function of age. (1991) Journal of Neuroscience. 11(7):1889-906.

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Gage, F.H., Tuszynski, M.H., Chen, K.S., Fagan, A.M., Higgins, G.A. Nerve growth factor function in the central nervous system. (1991) Current Topics in Microbiology and Immunology. 165:71-93.

Holtzman, D.M., Li, Y.W., Gage, F.H., DeArmond, S.J., Epstein, C.J., McKinley, M.P., Mobley, W.C. Modeling cholinergic abnormalities in Down syndrome and Alzheimer's disease. (1991) Progress in Clinical and Biological Research. 373:189-202.

Gonzalez, A.M., Lappi, D.A., Buscaglia, M.L., Carman, L.S., Gage, F.H., Baird, A. Basic FGF-SAP mitotoxin in the hippocampus. Specific lethal effect on cells expressing the basic FGF receptor. (1991) Annals of the New York Academy of Sciences. 638:442-4.

Kawaja, M.D., Fagan, A.M., Firestein, B.L., Gage, F.H. Intracerebral grafting of cultured autologous skin fibroblasts into the rat striatum: an assessment of graft size and ultrastructure. (1991) Journal of Comparative Neurology. 307(4):695-706. DOI: 10.1002/cne.903070414

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Masliah, E., Yoshida, K., Shimohama, S., Gage, F.H., Saitoh, T. Differential expression of protein kinase C isozymes in rat glial cell cultures. (1991) Brain Research. 549(1):106-11.

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Kawaja, M.D., Gage, F.H. Nerve growth factor receptor immunoreactivity in the rat septohippocampal pathway: a light and electron microscope investigation. (1991) J. Comp. Neurol. 307(3):517-29. DOI: 10.1002/cne.903070313

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Nerve growth factor receptor immunoreactivity in the septohippocampal pathway of adult Fischer 344 rats was assessed at the light and electron microscope level. The medial septum possesses immunoreactive somata, dendrites, axons, and terminals. Immunostained somata are either bipolar or multipolar in appearance. Dendritic processes of immunoreactive septal neurons are categorized into two groups: proximal dendrites with smooth plasma membranes and distal dendrites with numerous swellings. Immunoreactive axons within the septum are long and slender and do not possess varicosities. At the electron microscope level, immunoreactivity is confined predominantly to the plasma membrane of cell bodies and dendrites of septal neurons, as well as to the plasma membrane of axons and terminals. Both immunoreactive and nonimmunoreactive terminals that contain clear, spherical vesicles are observed contacting immunoreactive dendrites and somata. Although accumulations of vesicles are evident within these terminals at sites of contact, distinct synaptic specializations are difficult to distinguish due to the localization of reaction product on the apposing plasma membranes. Axons possessing immunoreactivity are also observed in the fimbria-fornix pathway, a major source of afferent inputs to the hippocampus. Immunoreactive axons and terminals are topographically organized in the hippocampal dentate gyrus. The density of immunostained axons and terminals is highest immediately adjacent to the granular layer. In comparison, a moderate density of immunoreactive axons is found in the outer molecular layer and a weak density in the inner molecular, granular, and polymorphic layers. Immunoreactivity is found on the plasma membrane of small unmyelinated axons and terminals aggregated into clusters throughout the dentate gyrus. Definitive examples of axosomatic and axodendritic synapses possessing immunoreactivity presynaptically are not observed. Immunoreactive profiles within the medial septum and hippocampus also circumfuse a small number of intracerebral vessels. Ultrastructural examination reveals that immunoreactivity is present within a narrowed extension of the subarachnoid space and appears to be closely associated with the plasma membrane of leptomeningeal cell processes. The present study provides direct evidence for the cellular distribution of nerve growth factor receptor immunoreactivity in the medial septum and dentate gyrus in the adult rat and offers new insight into the ultrastructural localization of nerve growth factor receptor among septal cholinergic neurons and their efferent projections to the hippocampus.

Tuszynski, M.H., Gage, F.H. In vivo assay of neuron-specific effects of nerve growth factor. (1991) Methods in Enzymology. 198:35-48.

Buzsáki, G., Hsu, M., Slamka, C., Gage, F.H., Horváth, Z. Emergence and propagation of interictal spikes in the subcortically denervated hippocampus. (1991) Hippocampus. 1(2):163-80. DOI: 10.1002/hipo.450010205

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Spontaneous and evoked field potentials and cellular discharges of the subcortically denervated dorsal hippocampus were studied by multisite recordings in the freely behaving rat. Characteristic short-duration (< 100 ms), large-amplitude (up to 10 mV) transients, termed interictal spikes (IIS), were seen after fimbria-fornix (FF) lesion. Both pyramidal cells and putative interneurons fired maximally during IIS, with some interneurons sustaining long bursts (up to 400 ms) of high-frequency discharges (400-600 Hz) after the IIS. The speed of propagation of IIS along the longitudinal axis of the hippocampus varied from 0.2 m/s to > 3 m/s. The majority of IIS (type 1) could be accounted for by an enhanced activity of the intrahippocampal associational systems; a second class of IIS (type 2) had positive polarities in the stratum radiatum of CA1 and CA3 and propagated very rapidly (> 1.5 m/s). The authors propose that type 2 IIS reflect somatic depolarization and discharge of pyramidal neurons due to nonsynaptic (probably ephaptic) effects. Ephaptic interactions may also explain the longitudinal propagation of IIS at speeds higher than the conduction velocities (0.5 m/s) of hippocampal fiber systems. IIS emerged during the first 3 weeks after fimbria-fornix lesion, their incidence reaching a plateau of 2/min thereafter. During the same time period, paired-pulse suppression increased in the dentate gyrus. The amplitude of test responses to angular bundle stimulation was potentiated by small-amplitude IIS but suppressed by large-amplitude IIS. The incidence of IIS was significantly suppressed during walking relative to standing still. Tetanic stimulation of the angular bundle or handling-induced stress resulted in a 10- to 20-fold increase in the incidence of IIS that lasted for about 30 minutes. There was a negative correlation between evoked field PSP slope and population spike amplitude in the dentate gyrus of FF-lesioned rats; this correlation was positive in intact rats. The authors attribute the above pathophysiological changes to sprouting of both excitatory and inhibitory GABAergic pathways as a result of denervation of the intrahippocampal circuitry. They hypothesize that the majority of the observed physiological alterations can be traced to a weakening of feedforward inhibition coupled with an enhancement of feedback inhibition and excitation.

Chen, L.S., Ray, J., Fisher, L.J., Kawaja, M.D., Schinstine, M., Kang, U.J., Gage, F.H. Cellular replacement therapy for neurologic disorders: potential of genetically engineered cells. (1991) Journal of Cellular Biochemistry. 45(3):252-7. DOI: 10.1002/jcb.240450305

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Shults, C.W., O'Connor, D.T., Baird, A., Hill, R., Goetz, C.G., Watts, R.L., Klawans, H.L., Carvey, P.M., Bakay, R.A., Gage, F.H. Clinical improvement in parkinsonian patients undergoing adrenal to caudate transplantation is not reflected by chromogranin A or basic fibroblast growth factor in ventricular fluid. (1991) Exp. Neurol. 111(3):276-81.

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Dawson, T.M., Dawson, V.L., Gage, F.H., Fisher, L.J., Hunt, M.A., Wamsley, J.K. Functional recovery of supersensitive dopamine receptors after intrastriatal grafts of fetal substantia nigra. (1991) Experimental Neurology. 111(3):282-92.

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Interruption of the ascending dopamine neurons of the nigrostriatal pathway, by 6-hydroxydopamine (6-OHDA) lesion in rats, produced a significant loss of the dopamine transport complexes labeled with the phencyclidine derivative [3H]BTCP. This loss of dopamine innervation in the striatum was present at least 12 to 14 months after lesioning and was functionally manifested by ipsilateral rotation of the animals in response to amphetamine. In these same animals, in comparison to controls, there was a significant increase in the number (Bmax) of [3H]SCH 23390-labeled D-1 receptors in the striatum (36.7%) and the substantia nigra (35.1%) and a 54.4% increase in the number (Bmax) of [3H]sulpiride-labeled striatal D-2 receptors without an apparent change in affinity (Kd). Ten to twelve months after the transplantation of homologous fetal substantia nigra into the denervated striatum, there was a significant decrease in amphetamine-induced turning behavior. In these animals, there was an ingrowth of dopamine nerve terminals in the striatum as demonstrated by a return of [3H]BTCP binding. Accompanying this reinnervation was the normalization of D-1 and D-2 receptors to control values in the striatum as well as the return of D-1 receptors to prelesion densities in the substantia nigra. In a subgroup of transplanted rats, amphetamine continued to induce ipsilateral turning. In these animals both D-1 and D-2 receptors remained supersensitive. These results support the hypothesis that the functional recovery of transplanted animals is due, in part, to reinnervation of the striatum. In addition, long-term alterations in receptor density may be related to the behavioral deficits that are associated with the 6-OHDA-lesioned rat. Furthermore, dopamine receptor plasticity may play a role in the functional recovery of substantia nigra transplanted animals and graft viability seems to be a prerequisite for behavioral recovery as well as receptor normalization.

Fisher, L.J., Jinnah, H.A., Kale, L.C., Higgins, G.A., Gage, F.H. Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce L-dopa. (1991) Neuron. 6(3):371-80.

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Fisher, L.J., Young, S.J., Tepper, J.M., Groves, P.M., Gage, F.H. Electrophysiological characteristics of cells within mesencephalon suspension grafts. (1991) Neuroscience. 40(1):109-22.

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Both spontaneous and evoked extracellular electrophysiological activity of neurons within fetal mesencephalon suspension grafts to the dopamine-depleted striatum of rats were examined. In some cases, extracellular recording was combined with intracellular labeling to identify recorded neurons. Grafted rats displaying a complete cessation of ipsilateral rotations following amphetamine administration were examined at post-implantation time intervals of two, four, five, eight and nine months. Four separate classes of neurons were distinguished within the transplanted striatum based on electrophysiological properties. The first of these groups, the type I cells, appeared to be non-grafted striatal neurons. When spontaneously active, these striatal-like cells fired bursts of action potentials separated by periods of decreased activity. Evoked responses in these cells were characteristic of striatal cells. Type I cells which were intracellularly labeled were found outside the grafts and displayed the characteristic morphology of the medium spiny neuron of the neostriatum. The other three cell classes displayed electrophysiological properties similar to neurons recorded in situ within the reticular formation, substantia nigra pars compacta and substantia nigra pars reticulata. Neurons from these three groups which were labeled with an intracellular marker were found to lie within the suspension grafts. The spontaneous activity of the pars compacta dopaminergic-like neurons was predominantly irregular, with some cells also firing in a regular or pacemaker-like pattern. Infrequently, irregular firing dopaminergic-like neurons displayed episodes of doublet bursting. Many of the grafted neurons responded to electrical stimulation of prefrontal cortex and striatum, indicating that the graft was receiving functional inputs from host neurons. Comparison of the firing rate and pattern of grafted neurons to in situ mesencephalic neurons as a function of time following grafting suggested that the grafted neurons and/or the neuronal circuitry is slowly developing within the host environment. A prolonged time-course for the maturation of the graft may be reflected in the time required to achieve improvements in some behavioral deficits following transplantation. However, the relatively rapid recovery of drug-induced rotational asymmetry following grafting suggests that this form of recovery may not require mature functioning of the grafted neurons.

Wamsley, J.K., Dawson, T.M., Dawson, V.L., Hunt, M.A., Fisher, L.J., Gage, F.H. Reversal of nigrostriatal-lesion-induced receptor alterations by grafting of fetal mesencephalic dopaminergic neurons. (1991) Advances in Experimental Medicine and Biology. 287:221-35.

Dawson, T.M., Dawson, V.L., Gage, F.H., Fisher, L.J., Hunt, M.A., Wamsley, J.K. Downregulation of muscarinic receptors in the rat caudate-putamen after lesioning of the ipsilateral nigrostriatal dopamine pathway with 6-hydroxydopamine (6-OHDA): normalization by fetal mesencephali (1991) Brain Research. 540(1-2):145-52.

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Yoshida, K., Gage, F.H. Fibroblast growth factors stimulate nerve growth factor synthesis and secretion by astrocytes. (1991) Brain Research. 538(1):118-26.

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Gage, F.H., Fisher, L.J. Intracerebral grafting: a tool for the neurobiologist. (1991) Neuron. 6(1):1-12.

Hellweg, R., Fischer, W., Hock, C., Gage, F.H., Björklund, A., Thoenen, H. Nerve growth factor levels and choline acetyltransferase activity in the brain of aged rats with spatial memory impairments. (1990) Brain Research. 537(1-2):123-30.

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Tuszynski, M.H., U, H.S., Amaral, D.G., Gage, F.H. Nerve growth factor infusion in the primate brain reduces lesion-induced cholinergic neuronal degeneration. (1990) Journal of Neuroscience. 10(11):3604-14.

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Gage, F.H. Intracerebral grafting of genetically modified cells acting as biological pumps. (1990) Tendencias en Ciencias Farmacológicas. 11(11):437-9.

Fagan, A.M., Gage, F.H. Cholinergic sprouting in the hippocampus: a proposed role for IL-1. (1990) Exp. Neurol. 110(1):105-20.

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Jinnah, H.A., Gage, F.H., Friedmann, T. Animal models of Lesch-Nyhan syndrome. (1990) Brain Research Bulletin. 25(3):467-75.

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Foster, G.A., Brodin, E., Gage, F.H., Maxwell, D.J., Roberts, M.H., Sharp, T. Restoration of function to the denervated spinal cord after implantation of embryonic 5HT- and substance P-containing raphe neurones. (1990) Progress in Brain Research. 82:247-59.

Shimohama, S., Saitoh, T., Gage, F.H. Differential expression of protein kinase C isozymes in rat cerebellum. (1990) J. Chem. Neuroanat. 3(5):367-75.

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Buzsáki, G., Chen, L.S., Gage, F.H. Spatial organization of physiological activity in the hippocampal region: relevance to memory formation. (1990) Progress in Brain Research. 83:257-68.

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Fisher, L.J., Young, S.J., Groves, P.M., Gage, F.H. Extracellular properties of cells within mesencephalon suspension grafts in rat striatum. (1990) Progress in Brain Research. 82:473-9.

Higgins, G.A., Koh, S., Neve, R.L., Mufson, E.J., Chen, K.S., Gage, F.H. Trophic regulation of basal forebrain gene expression in aging and Alzheimer's disease. (1990) Progress in Brain Research. 86:239-55.

Thal, L.J., Mandel, R.J., Terry, R.D., Buzsaki, G., Gage, F.H. Nucleus basalis lesions fail to induce senile plaques in the rat. (1990) Experimental Neurology. 108(1):88-90.

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Higgins, G.A., Oyler, G.A., Neve, R.L., Chen, K.S., Gage, F.H. Altered levels of amyloid protein precursor transcripts in the basal forebrain of behaviorally impaired aged rats. (1990) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 87(8):3032-6.

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Tuszyński, M.H., Gage, F.H. Potential use of neurotrophic agents in the treatment of neurodegenerative disorders. (1990) Acta Neurobiologiae Experimentalis. 50(4-5):311-22.

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Tuszynski, M.H., Buzsaki, G., Gage, F.H. Nerve growth factor infusions combined with fetal hippocampal grafts enhance reconstruction of the lesioned septohippocampal projection. (1990) Neuroscience. 36(1):33-44.

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Tuszynski, M.H., Armstrong, D.M., Gage, F.H. Basal forebrain cell loss following fimbria/fornix transection. (1990) Brain Research. 508(2):241-8.

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Buzsáki, G., Smith, A., Berger, S., Fisher, L.J., Gage, F.H. Petit mal epilepsy and parkinsonian tremor: hypothesis of a common pacemaker. (1990) Neuroscience. 36(1):1-14.

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Short, M.P., Rosenberg, M.B., Ezzedine, Z.D., Gage, F.H., Friedmann, T., Breakefield, X.O. Autocrine differentiation of PC12 cells mediated by retroviral vectors. (1990) Developmental Neuroscience. 12(1):34-45.

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Shults, C.W., Hashimoto, R., Brady, R.M., Gage, F.H. Dopaminergic cells align along radial glia in the developing mesencephalon of the rat. (1990) Neuroscience. 38(2):427-36.

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Mahanthappa, N.K., Gage, F.H., Patterson, P.H. Adrenal chromaffin cells as multipotential neurons for autografts. (1990) Progress in Brain Research. 82:33-9.

Gage, F.H., Buzsáki, G., Armstrong, D.M. NGF-dependent sprouting and regeneration in the hippocampus. (1990) Progress in Brain Research. 83:357-70.

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Gage, F.H., Rosenberg, M.B., Tuszynski, M.H., Yoshida, K., Armstrong, D.M., Hayes, R.C., Friedmann, T. Gene therapy in the CNS: intracerebral grafting of genetically modified cells. (1990) Progress in Brain Research. 86:205-17.

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Gage, F.H., Fisher, L.J., Jinnah, H.A., Rosenberg, M.B., Tuszynski, M.H., Friedmann, T. Grafting genetically modified cells to the brain: conceptual and technical issues. (1990) Progress in Brain Research. 82:1-10.

Dawson, V.L., Gage, F.H., Hunt, M.A., Wamsley, J.K. Normalization of subtype-specific muscarinic receptor binding in the denervated hippocampus by septodiagonal band grafts. (1989) Exp. Neurol. 106(2):115-24.

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Chen, K.S., Tuszynski, M.H., Gage, F.H. Role of neurotrophic factors in Alzheimer's disease. (1989) Neurobiology of Aging. 10(5):545-6; discussion 552-3.

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Higgins, G.A., Koh, S., Chen, K.S., Gage, F.H. NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat. (1989) Neuron. 3(2):247-56.

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Buzsáki, G., Bayardo, F., Miles, R., Wong, R.K., Gage, F.H. The grafted hippocampus: an epileptic focus. (1989) Exp. Neurol. 105(1):10-22.

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Field potentials and unitary activity were investigated in the grafted and the host hippocampi in freely moving rats and in vitro. The subcortical afferents and efferents of the hippocampus (fimbria-fornix, FF) were removed by aspiration. Solid pieces of hippocampal grafts derived from 15- to 16-day-old fetuses were placed in the lesion cavity in rats with unilateral FF lesions, and cell suspensions prepared from fetal hippocampi were grafted directly into the host hippocampi in animals with bilateral FF lesions. Reciprocal communication between the grafted and the host hippocampi was monitored with a 16-microelectrode probe from 7 to 10 months after grafting. The fluorescent retrograde tracer, Fluorogold, was used to examine graft-host projections and acetylcholinesterase staining to reveal host-derived fibers in the graft. The most typical neuronal pattern of the hippocampal graft was a highly synchronous population burst with concurrent EEG spike. The speed of propagation of the EEG spike within the graft and across the graft-host interface was either fast (greater than 3 m/s) or slow (less than 0.5 m/s). Large amplitude, short duration EEG spikes usually propagated with a high speed, while smaller amplitude, wider spikes with broad population bursts spread at a lower velocity. The direction of propagation was usually uniform indicating that the population burst was triggered by a localized subgroup of highly excitable neurons ("focus"). Spontaneous seizures were also present in the solid graft which frequently invaded the host hippocampus. The incidence of EEG spikes was three times higher in rats with bilateral suspension grafts than in animals with FF lesion only. In about half of the grafted rats spontaneous behavioral seizures were also observed. Intracellular recordings from putative pyramidal cells in the graft and in the host revealed large amplitude (10-12 mV), spontaneously occurring EPSPs. IPSPs were difficult to detect even during depolarizations of up to 20 mV from rest. We suggest that the increased excitability of the hippocampal graft is due to the high incidence of recurrent excitatory collaterals terminating on or close to the somata of pyramidal neurons. Population bursts may spread fast via extensively arborizing axon collaterals or slowly by successively activating new sets of neighboring neurons. Spontaneous behavioral convulsions are explained by assuming that the grafted hippocampus serves as an epileptic focus which is capable of kindling the host brain by repeated seizure induction.(ABSTRACT TRUNCATED AT 400 WORDS)

Batchelor, P.E., Armstrong, D.M., Blaker, S.N., Gage, F.H. Nerve growth factor receptor and choline acetyltransferase colocalization in neurons within the rat forebrain: response to fimbria-fornix transection. (1989) Journal of Comparative Neurology. 284(2):187-204. DOI: 10.1002/cne.902840204

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Although it is well known that magnocellular cholinergic basal forebrain neurons are trophically responsive to nerve growth factor (NGF) and contain NGF receptors (NGFr), the exact distribution of forebrain NGFr-immunoreactive neurons and the degree to which cholinergic neurons are colocalized with them have remained in question. In this study we employed a very sensitive double-labelling method and examined in the same tissue section the distribution and cellular features of NGFr-positive and choline acetyltransferase (ChAT)-immunolabelled neurons within the rat basal forebrain. Throughout this region the majority of magnocellular basal forebrain neurons were immunoreactive for both NGFr and ChAT. However, a small percentage of neurons in the ventral portion of the vertical limb of the diagonal band of Broca were immunoreactive only for NGFr, whereas a larger population of magnocellular neurons in the substantia innominata exhibited only ChAT immunoreactivity. No NGFr-immunoreactive cells were found associated with ChAT-positive neurons in the striatum, neocortex, or hippocampus, and no single-labelled NGFr-immunoreactive neurons were found outside the basal forebrain area, except for a large number of positive-labelled cells along the ventricular walls of the third ventricle. In addition to its function in maintaining the normal integrity of the basal forebrain and cholinergic, peripheral sympathetic, and neural-crest-derived sensory neurons, NGF may also have a role in the growth of these neurons after damage to the nervous system. To examine this postulate the hippocampus was denervated of its septal input and examined 8 weeks later. Two populations of neurons were found to have undergone collateral sprouting--namely, the midline magnocellular cholinergic neurons of the dorsal hippocampus and the sympathetic noradrenergic neurons of the superior cervical ganglion. Both of these neuronal populations also stained strongly for NGFr. In contrast, the small intrinsic cholinergic neurons of the hippocampus exhibited neither sprouting response nor staining for NGFr. In view of these results, we suggest that the differing sprouting responses demonstrated by these three neuronal populations may be due to their responsiveness to NGF, as indicated by the presence or absence of NGF receptors.

Buzsàki, G., Bickford, R.G., Ryan, L.J., Young, S., Prohaska, O., Mandel, R.J., Gage, F.H. Multisite recording of brain field potentials and unit activity in freely moving rats. (1989) Journal of Neuroscience Methods. 28(3):209-17.

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Mandel, R.J., Gage, F.H., Thal, L.J. Spatial learning in rats: correlation with cortical choline acetyltransferase and improvement with NGF following NBM damage. (1989) Exp. Neurol. 104(3):208-17.

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Shimohama, S., Rosenberg, M.B., Fagan, A.M., Wolff, J.A., Short, M.P., Breakefield, X.O., Friedmann, T., Gage, F.H. Grafting genetically modified cells into the rat brain: characteristics of E. coli beta-galactosidase as a reporter gene. (1989) Brain Res. Mol. Brain Res. 5(4):271-8.

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Buzsáki, G., Ponomareff, G.L., Bayardo, F., Ruiz, R., Gage, F.H. Neuronal activity in the subcortically denervated hippocampus: a chronic model for epilepsy. (1989) Neuroscience. 28(3):527-38.

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Spontaneous and evoked field potentials and cellular discharges were studied in the subcortically denervated hippocampus of the freely moving rat. The fimbria fornix, the ventral hippocampal commissure, and the supracallosal afferent fibers were removed by aspiration, and recordings were made 3-5 months after the lesion. Two types of spontaneous interictal spikes were observed. Type 1 interictal spike had identical depth distribution to physiological sharp waves but they were shorter in duration (less than 40 ms), larger in amplitude (greater than 2.5 mV) and population spikes were riding on the main deflection. Type 2 interictal spikes were negative in the stratum oriens and positive in the pyramidal layer and stratum radiatum of both CA1 and CA3. The amplitude of both types of interictal spikes could exceed 6 mV. We suggest that interictal spikes were initiated randomly in different subpopulations of the CA2-3 region and the location of the initiating population burst determined the polarity and amplitude of the extracellular interictal spike. Repetitive stimulation of the perforant path (5 Hz, 6 s) evoked markedly uniform afterdischarges in both intact and fimbria fornix-deprived rats. The threshold of afterdischarges was significantly lower, the seizure spread to the contralateral hippocampus was slower, and secondary afterdischarges lasted significantly longer in the lesioned rats. We suggest that under physiological conditions the electrical stability of the hippocampus is ensured by the feed-forward inhibitory action of subcortical afferents. Removal of tonic inhibitory influences and/or sprouting of local axon collaterals allows extreme synchronization and reverberation of information in the entorhinal-hippocampal-entorhinal cortex circuitry. The presence of interictal spikes and increased susceptibility to seizures for several months after the lesion offers the fimbria-fornix-deprived hippocampus a useful chronic preparation to study the mechanisms of limbic epilepsy.

Shapiro, M.L., Simon, D.K., Olton, D.S., Gage, F.H., Nilsson, O., Björklund, A. Intrahippocampal grafts of fetal basal forebrain tissue alter place fields in the hippocampus of rats with fimbria-fornix lesions. (1989) Neuroscience. 32(1):1-18.

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Gage, F.H., Tuszynski, M.H., Chen, K.S., Armstrong, D., Buzsáki, G. Survival, growth and function of damaged cholinergic neurons. (1989) EXS. 57:259-74.

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Buzsàki, G., Gage, F.H. The cholinergic nucleus basalis: a key structure in neocortical arousal. (1989) EXS. 57:159-71.

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Tuszynski, M.H., Jinnah, H.A., Gage, F.H. Delivery of neuroactive compounds to the brain: potential utility of genetically modified cells. (1989) Neurobiology of Aging. 10(5):644-5; discussion 648-50.

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Gage, F.H., Dunnett, S.B., Bjorklund, A. Age-related impairments in spatial memory are independent of those in sensorimotor skills. (1989) Neurobiology of Aging. 10(4):347-52.

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Phelps, C.H., Gage, F.H., Growdon, J.H., Hefti, F., Harbaugh, R., Johnston, M.V., Khachaturian, Z.S., Mobley, W.C., Price, D.L., Raskind, M. Potential use of nerve growth factor to treat Alzheimer's disease. (1989) Neurobiology of Aging. 10(2):205-7.

Buzsáki, G., Wiesner, J., Henriksen, S.J., Gage, F.H. Long-term potentiation of evoked and spontaneous neuronal activity in the grafted hippocampus. (1989) Exp Brain Res. 76(2):401-8.

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Buzsáki, G., Gage, F.H. Absence of long-term potentiation in the subcortically deafferented dentate gyrus. (1989) Brain Research. 484(1-2):94-101.

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Gage, F.H., Batchelor, P., Chen, K.S., Chin, D., Higgins, G.A., Koh, S., Deputy, S., Rosenberg, M.B., Fischer, W., Bjorklund, A. NGF receptor reexpression and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum. (1989) Neuron. 2(2):1177-84.

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Fischer, W., Gage, F.H., Björklund, A. Degenerative Changes in Forebrain Cholinergic Nuclei Correlate with Cognitive Impairments in Aged Rats. (1989) European Journal of Neuroscience. 1(1):34-45.

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Mandel, R.J., Gage, F.H., Thal, L.J. Enhanced detection of nucleus basalis magnocellularis lesion-induced spatial learning deficit in rats by modification of training regimen. (1989) Behavioural Brain Research. 31(3):221-9.

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Foster, G.A., Roberts, M.H., Wilkinson, L.S., Björklund, A., Gage, F.H., Hökfelt, T., Schultzberg, M., Sharp, T. Structural and functional analysis of raphe neurone implants into denervated rat spinal cord. (1989) Brain Research Bulletin. 22(1):131-7.

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Rosenberg, M.B., Friedmann, T., Robertson, R.C., Tuszynski, M., Wolff, J.A., Breakefield, X.O., Gage, F.H. Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. (1988) Ciencia. 242(4885):1575-8.

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Buzsáki, G., Ponomareff, G., Bayardo, F., Shaw, T., Gage, F.H. Suppression and induction of epileptic activity by neuronal grafts. (1988) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 85(23):9327-30.

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Buzsaki, G., Bickford, R.G., Ponomareff, G., Thal, L.J., Mandel, R., Gage, F.H. Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. (1988) Journal of Neuroscience. 8(11):4007-26.

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EEG and single-unit techniques have been used to study the EEG correlates of cellular firing in the neocortex, n. reticularis (RT) and "specific" thalamic nuclei, and the cholinergic forebrain area (nucleus basalis, NB). Neuronal firing was related to the ongoing behavior of the rat. In addition, using a 16-channel neocortical recording/mapping system, we studied the effects of ibotenic acid lesion of NB, RT, and other thalamic nuclei on the patterns and spatial distribution of neocortical electrical activity. The majority of neurons in neocortex, NB, and RT increased their firing rates during walking, as compared to during immobility, with concurrent decrease of delta power in the neocortical EEG. During immobility, high-voltage spindles (HVS; greater than 1 mV) were occasionally recorded from the neocortex. Depth profiles of HVS and slow delta waves were different in the neocortex. Neocortical cells decreased their discharge frequency during the positive portion of delta waves recorded in layers V and VI. All cells in the neocortex and specific thalamic nuclei fired rhythmically and phase-locked to the spike component of HVS. RT neurons showed an opposite phase relationship and fired mainly during the wave component of HVS. Half of the NB neurons also showed phasic modulation with HVS. Circumscribed lesion of RT and extensive damage of other thalamic regions, including the intralaminar nuclei, suppressed HVS but had no effect on the neocortical EEG correlates of behavior. In sharp contrast, damage to the NB resulted in a dramatic increase of slow delta waves on the side of the lesion, mimicking the effect of scopolamine administration. We suggest that the NB plays a key role in neocortical arousal by directly activating the neocortex and by suppressing the rhythm generation in the RT-thalamocortical circuitry. We further suggest that the NB system may serve as a structural basis for the concept of the generalized ascending activation of Moruzzi and Magoun (1949).

Gage, F.H., Olejniczak, P., Armstrong, D.M. Astrocytes are important for sprouting in the septohippocampal circuit. (1988) Exp. Neurol. 102(1):2-13.

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Buzsáki, G., Bickford, R.G., Armstrong, D.M., Ponomareff, G., Chen, K.S., Ruiz, R., Thal, L.J., Gage, F.H. Electric activity in the neocortex of freely moving young and aged rats. (1988) Neuroscience. 26(3):735-44.

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Brundin, P., Strecker, R.E., Gage, F.H., Lindvall, O., Björklund, A. Intracerebral transplantation of dopamine neurons: understanding the functional role of the mesolimbocortical dopamine system and developing a therapy for Parkinson's disease. (1988) Annals of the New York Academy of Sciences. 537:148-60.

Armstrong, D.M., Hersh, L.B., Gage, F.H. Morphologic alterations of cholinergic processes in the neocortex of aged rats. (1988) Neurobiology of Aging. 9(2):199-205.

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Gage, F.H., Chen, K.S., Buzsaki, G., Armstrong, D. Experimental approaches to age-related cognitive impairments. (1988) Neurobiology of Aging. 9(5-6):645-55.

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Rats exhibit morphological, biochemical, and metabolic changes in their brains, as well as cognitive deficits, with aging. Aged rats were found to be significantly impaired compared to young rats in a water maze task and test of motor coordination, and show reduced locomotor activity and exploration. Although aged rats did exhibit deficits as a group, not all aged rats were impaired. Additionally, the subgroup that was impaired on one task was not necessarily the subgroup that was impaired on another task. The cholinergic projection neurons in the basal forebrain region were significantly atrophied in the aged rodent. The degree of atrophy was highly correlated with the cognitive impairment exhibited on the Morris water maze task. Swollen choline acetyltransferase (ChAT)-positive "plaque-like" structures were observed in the neocortex of the aged but not the young rats. Declines in cholinergic activity in the brain has also been observed during aging. Biochemical measurements of ChAT in the basal forebrain region of aged rats revealed small but consistent decreases in ChAT activity compared to young rats. General metabolic activity, measured by the 2-deoxyglucose method, was also decreased in the hippocampal CA1 and CA3 fields, the dentate gyrus, the medial septal-diagonal band area, and the prefrontal cortex of aged rats. There was a significant correlation between the decrease in glucose utilization and deficits on the Morris water maze. Most aged rats exhibit pathological EEG patterns as reflected by frequent long-duration high voltage neocortical spindles (HVS) during immobility. Bilateral lesions of the nucleus basalis and scopolamine treatment increased the incidence of HVS, thereby mimicking changes in the aged brain. We attempted to ameliorate the cognitive deficits observed in subgroups or impaired rats by either: (1) implanting fetal cells of basal forebrain origin into the hippocampus, or (2) infusing nerve growth factor (NGF) chronically into the lateral ventricle. The grafts appeared to facilitate an improvement in the ability of the impaired aged rats to perform in the Morris water maze. This improved performance was reversed by injections of atropine at doses that did not affect the behavior of young animals that performed well in the same task. These results suggest that enhancement of the cholinergic system could have an effect on the performance of the impaired aged animals. The study of the effects of infusions of NGF clearly demonstrate that the ability of impaired aged rats to remember what they had previously learned was increased after NGF treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Blaker, S.N., Armstrong, D.M., Gage, F.H. Cholinergic neurons within the rat hippocampus: response to fimbria-fornix transection. (1988) Journal of Comparative Neurology. 272(1):127-38. DOI: 10.1002/cne.902720109

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The distribution and morphologic characteristics of choline acetyltransferase (ChAT)-containing neurons were studied throughout the rostrocaudal extent of the rat hippocampus and in a midline area just dorsal to the dorsal hippocampus. Peroxidase reaction product was observed with the aid of immunohistochemical methods and a high-titer polyclonal antibody against ChAT, the acetylcholine biosynthetic enzyme. ChAT-positive cells in the hippocampus were characterized by small, round or oval perikarya with two or more proximal processes. They were located within the caudal and temporal hippocampal formation, predominantly within the subiculum, in the stratum lacunosum moleculare, at the border of the stratum lacunosum moleculare and the stratum radiatum, and in the molecular layer of the dentate gyrus. The cells resembled in morphology the small, bipolar and multipolar neocortical ChAT-immunoreactive cells. In addition to the hippocampus, ChAT-positive neurons were observed caudally in a region just above the dorsal hippocampal commissure and rostrally in the columns of the fornix. These cells were large with an oval perikarya and darkly labeled compared to neurons in the hippocampus. They more closely resembled the ChAT-positive neurons in the midline raphe of the medial septal nucleus. Examination of the rat hippocampus 2 and 8 weeks following unilateral lesioning of the fimbria-fornix and supracallosal striae revealed a sparse innervation of ChAT-positive fibers in the hippocampus ipsilateral to the lesion. ChAT-labeled neurons in the hippocampus did not appear to sprout in response to the lesion. In contrast, ChAT-positive cells in the midline did appear to sprout into the medial dorsal subiculum and dorsal medial hippocampus. We conclude that these two populations of cells are distinct with respect to their response to hippocampal denervation and, furthermore, that this distinction may be attributed to a differential response to nerve growth factor.

Gage, F.H., Blaker, S.N., Davis, G.E., Engvall, E., Varon, S., Manthorpe, M. Human amnion membrane matrix as a substratum for axonal regeneration in the central nervous system. (1988) Experimental Brain Research. 72(2):371-80.

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Human Amnion Membrane Matrix (HAMM) was used as a substratum for the regeneration of neuronal axons in the central nervous system. A large piece of HAMM was bound to nitrocellulose paper (NCP) as a supporting material, and cut into small strips. Aspirative lesions of the fimbria-fornix were made in adult rats leaving a cavity separating the septum from the hippocampus. In the same operation a small piece of HAMM-NCP was placed into the cavity with one end abutting the axotomized septum and the other end abutting the denervated hippocampus. At times between 2 weeks and 3 months after surgery the brains of the animals were examined histologically for 1) host response to the implant; 2) maintenance of HAMM-NCP in the originally implanted orientation; 3) growth of acetylcholinesterase (AChE)-positive fibers on the HAMM; 4) growth of the AChE-positive fibers into the denervated hippocampus; and 5) non-neuronal cells on the HAMM. The NCP remained in place over the 3-month period. In most cases the HAMM and NCP remained apposed and caused no greater reaction in the brain beyond that created in response to the aspirative lesion alone. AChE-positive fibers grew out from the septum onto the HAMM by 2 weeks, and by 8 weeks more extensive growth was observed on the HAMM. By 8-weeks, AChE fibers could be clearly seen coming off the membrane and entering the host hippocampus. By double-labelling for the basement membrane side of the HAMM (using anti-human laminin antibodies) and for cholinergic fibers (using AChE histochemistry) in the same sections, it was possible to see fibers clearly growing on the laminin-positive side of the HAMM but little or no growth on the opposing laminin-negative stromal side. The most important variables for extensive growth appeared to be the accurate placement of the implant and the amount of time following the lesions. The placement of the matrix on NCP prior to implantation in the brain made it easier to orient the membrane between the septum and the hippocampus, and seemed to assist in maintaining the membrane in that orientation. The HAMM represents a useful, regeneration-promoting grafting material for central nervous system repair studies.

Buzsáki, G., Freund, T., Björklund, A., Gage, F.H. Restoration and deterioration of function by brain grafts in the septohippocampal system. (1988) Progress in Brain Research. 78:69-77.

Blaker, S.N., Davis, G.E., Manthorpe, M., Engvall, E., Varon, S., Gage, F.H. Human amnion membrane as a substratum for axonal elongation in vitro and in vivo. (1988) Progress in Brain Research. 78:435-8.

Foster, G.A., Schultzberg, M., Gage, F.H., Björklund, A., Hökfelt, T., Cuello, A.C., Verhofstad, A.A., Visser, T.J., Emson, P.C. Transmitter expression and morphological development of embryonic medullary and mesencephalic raphé neurones after transplantation to the adult rat central nervous system. III. Grafts to the striatum. (1988) Exp Brain Res. 70(2):242-55.

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Foster, G.A., Schultzberg, M., Gage, F.H., Björklund, A., Hökfelt, T., Cuello, A.C., Verhofstad, A.A., Visser, T.J., Emson, P.C. Transmitter expression and morphological development of embryonic medullary and mesencephalic raphé neurones after transplantation to the adult rat central nervous system. II. Grafts to the hippocampu (1988) Experimental Brain Research. 70(2):225-41.

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Suspensions of cells taken from the mesencephalic or medullary raphé regions of the 13-14 day old embryonic rat brain were injected into the hippocampus of adult rats which had previously been denervated of its serotoninergic input by 5,7-dihydroxytryptamine. At periods of up to 14 months after implantation, the brains were taken for immunohistochemical analysis of 5-hydroxytryptamine (5HT)-, substance P (SP)- and thyrotropin releasing hormone (TRH)-like immunoreactivity. Surviving grafts were found in all animals. The implants derived from mesencephalic raphé contained neurones immunoreactive to 5HT, SP or both substances together. On average 19% of the potential number of mesencephalic 5HT neurones were found in the grafts. Outgrowth of 5HT-immunoreactive fibres was extensive, and displayed the typical pattern of 5HT innervation in the normal hippocampus-the densest plexuses were found in the dentate gyrus, with sparser networks in the CA1 and CA2 regions. SP-positive processes were principally found only in the graft itself. Transplants of medullary raphé cells contained 5HT-immunoreactive neurones, some of which also contained SP-and/or TRH-like immunoreactivity, thereby mirroring the situation found in the caudal raphé complex in situ. An average of 18% of the total available medullary serotoninergic neurones were found at each graft site. A rich outgrowth of 5HT-immunoreactive varicose processes was evident, with the same pattern as the 5HT innervation by the mesencephalic raphé grafts, and as in the normal hippocampus. SP- and TRH-positive fibres were essentially detectable only in the graft, but not in the host hippocampus. The present studies indicate that the milieu of the hippocampus does not preferentially attenuate the survival of the serotoninergic cells which do not normally project to it. Nor is the fibre outgrowth of these medullary raphé 5HT neurones significantly different from that of the mesencephalic raphé. However, the hippocampal environment may be responsible for the appearance of SP-LI in the otherwise apparently solely 5HT-containing mesencephalic raphé neurones, and for repressing the outgrowth of fibres containing TRH-, or SP-like immunoreactivity, regardless of their origin.

Buzsáki, G., Gage, F.H. Mechanisms of action of neural grafts in the limbic system. (1988) Can J Neurol Sci. 15(2):99-105.

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Gage, F.H., Wolff, J.A., Rosenberg, M.B., Xu, L., Yee, J.K., Shults, C., Friedmann, T. Implantation of genetically engineered cells to the brain. (1988) Progress in Brain Research. 78:651-8.

Bengtsson, F., Nobin, A., Falck, B., Gage, F.H., Jeppsson, B. Effect of oral branched chain amino acids on behavior and brain serotonin metabolism in portacaval shunted rats. (1988) World Journal of Surgery. 12(2):246-54.

Gage, F.H., Armstrong, D.M., Williams, L.R., Varon, S. Morphological response of axotomized septal neurons to nerve growth factor. (1988) Journal of Comparative Neurology. 269(1):147-55. DOI: 10.1002/cne.902690112

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Gage, F.H., Brundin, P., Strecker, R., Dunnett, S.B., Isacson, O., Bjorklund, A. Intracerebral neuronal grafting in experimental animal models of age-related motor dysfunction. (1988) Annals of the New York Academy of Sciences. 515:383-94.

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The combined morphological, biochemical, electrophysiological, and behavioral data summarized above show that implanted embryonic nerve cells in some cases can substitute quite well for a lost intrinsic neuronal system in mammals. The intracerebral implants probably exert their effects in several ways. The functional effects seen with grafts placed into one of the cerebral ventricles (such as those described in the studies of Perlow et al., Freed et al., and Gash et al.) are thus probably explained on the basis of a diffuse release of an active amine or peptide into the host CSF and adjacent brain tissue. In other instances, as in animals with DA-rich grafts reinnervating the neostriatum, we believe that the available data provide quite substantial evidence that the behavioral recovery is caused by the ability of the grafted neurons to reinnervate relevant parts of the host brain. This is illustrated by the studies mentioned above that show that the degree of functional recovery in 6-OHDA-lesioned rats with nigral transplants is directly correlated with the extent of striatal DA reinnervation and that the "profile" of functional recovery is dependent on that area of the striatal complex that is reinnervated by the graft. This point is particularly well illustrated in a further study in which rats with electrodes implanted into the center of intracortical nigral grafts were allowed to "self-stimulate" via the graft. The results show that the graft can indeed sustain self-stimulation behavior and that the rate of lever-pressing is related to the proximity between the electrode tip and the DA-containing neurons in the graft. This strongly supports the notion that the implanted DA neurons can transmit behaviorally meaningful and temporally organized information to the host brain via their efferent connections. To what extent the intracerebral implants can be functionally integrated with the host brain is still poorly known, though, and it therefore remains an interesting question for further investigation. The chances for extensive integration may be greatest for neuronal suspension grafts implanted as deposits directly into the depth of the brain, but even solid grafts inserted as whole pieces into the brain have, in several cases, been seen to become reinnervated from the host brain in adult and developing recipients. Nevertheless, a recent HRP study failed to detect any host afferents to intracortical solid nigral grafts, despite the fact that these grafts had themselves formed extensive DA connections in the host striatum and had produced behavioral recovery.(ABSTRACT TRUNCATED AT 400 WORDS)

Armstrong, D.M., Bruce, G., Hersh, L.B., Gage, F.H. Development of cholinergic neurons in the septal/diagonal band complex of the rat. (1987) Brain Research. 433(2):249-56.

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Gage, F.H., Wolff, J.A., Rosenberg, M.B., Xu, L., Yee, J.K., Shults, C., Friedmann, T. Grafting genetically modified cells to the brain: possibilities for the future. (1987) Neuroscience. 23(3):795-807.

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Shults, C.W., Johnston, P., Gage, F.H. Comparison of substance K-like and substance P-like fibers and cells in the rat hippocampus. (1987) Brain Research. 426(2):290-6.

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Isacson, O., Pritzel, M., Dawbarn, D., Brundin, P., Kelly, P.A., Wiklund, L., Emson, P.C., Gage, F.H., Dunnett, S.B., Björklund, A. Striatal neural transplants in the ibotenic acid-lesioned rat neostriatum. Cellular and functional aspects. (1987) Annals of the New York Academy of Sciences. 495:537-55.

Armstrong, D.M., Terry, R.D., Deteresa, R.M., Bruce, G., Hersh, L.B., Gage, F.H. Response of septal cholinergic neurons to axotomy. (1987) Journal of Comparative Neurology. 264(3):421-36. DOI: 10.1002/cne.902640309

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In the present study we employed quantitative morphometric techniques to assay the response of septal cholinergic neurons following unilateral transection of the fimbria/fornix and supracallosal stria. Analysis of 50-micron-thick tissue sections with a Quantimet 920 image analysis system demonstrated a reduction in ChAT immunoreactivity as early as 1 day following denervation. This decrease was associated with a drop in the number of labeled cells ipsilateral to the lesion and a decrease in the area of cholinergic perikarya on the lesioned and nonlesioned side of the septum. The response at 1 day, however, was transient, and at 4 days the number of labeled neurons was not significantly different from controls. By 8 days we observed a dramatic reduction in the number and size of ChAT-positive cells ipsilateral to the lesion and a reduction in the size of cholinergic perikarya on the contralateral (i.e., nonlesioned) side. These values persisted throughout the remainder of the study. To assess more completely the morphologic response of neurons to axotomy than can be determined in 50-micron-thick tissue sections, we embedded the adjacent immunolabeled tissue section in Epon and then serially sectioned it to a thickness of 0.75-1.0 micron. By using this method, we were able to measure the area, length, and width of the cell, the area of the nucleus and nucleolus, and the position of the nucleus (i.e., eccentricity). Measurements were performed on ChAT-labeled and nonlabeled cells. The results of our studies demonstrate that cholinergic and noncholinergic cells responded to axotomy in a characteristic yet different fashion from each other and that this response could be quantitatively assayed. In general, labeled and nonlabeled cells on the lesioned side of the septum shrink in response to denervation. This shrunken state was reflected in measurements of cellular area, length, width, and nuclear area. Moreover, other measurements of cellular morphology (i.e., area of the nucleolus, position of the nucleus) indicate that none of the neuronal populations examined in the present study displayed morphologic evidence of regeneration. Our results indicate a dramatic loss of cholinergic perikarya ipsilateral to the lesion. Moreover, although a few neurons do persist they do so in a shrunken state. These data provide an essential baseline for the second study in this series, which will evaluate the effect of nerve growth factor on the survival of denervated septal neurons.

Buzsàki, G., Czopf, J., Kondàkor, I., Björklund, A., Gage, F.H. Cellular activity of intracerebrally transplanted fetal hippocampus during behavior. (1987) Neuroscience. 22(3):871-83.

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Hippocampal tissue derived from 12-, 20-, 25- and 34-mm rat fetuses was placed in a cavity formed by unilateral aspiration of the fimbria-fornix and the overlying neocortical tissue in adult rats. From 4 to 6 months after transplantation the rats were equipped with chronic recording and stimulating electrodes. Single cell activity of the transplant was monitored during running in a wheel, drinking, and sleeping. Both complex-spike cells (n = 151) and single-spike cells (n = 80) were recorded from the graft. A portion of the neurons changed their firing rates and discharge patterns as a function of ongoing behavior. About half of the single-spike cells increased their firing frequency during running. Fifteen per cent of the single-spike cells fired rhythmically at about 8 Hz during running, and the paradoxical phase of sleep and the discharge pattern correlated with rhythmic slow activity (theta) recorded concurrently from the contralateral (intact) hippocampus. These patterns were most frequently obtained from grafts of 20- and 25-mm (16 to 18 embryonic days) fetuses. Graft neurons could be activated by stimulating the ipsilateral hippocampus or the ipsilateral perforant path, with latencies of 8-30 ms. The most common electrical pattern in grafts of all groups was the synchronous bursts of several neighboring cells and concurrent electroencephalogram sharp-waves. Sharp-waves occurred during all behaviors. Large amplitude, high-frequency electroencephalogram spindles (14-18 Hz and 30-50 Hz) and associated neuronal bursts were recorded in grafts of 12-, 20-, and 25-mm fetuses. Based on these findings we suggest that both subcortical afferents and host hippocampal afferents send axons to hippocampal grafts and form viable synaptic connections with a portion of the neurons in the graft. The frequently encountered population bursts are explained by assuming that excitatory collaterals in the graft are more potent in the graft than in the normal hippocampus, and/or GABAergic inhibition is less efficient in the graft.

Isacson, O., Dawbarn, D., Brundin, P., Gage, F.H., Emson, P.C., Björklund, A. Neural grafting in a rat model of Huntington's disease: striosomal-like organization of striatal grafts as revealed by acetylcholinesterase histochemistry, immunocytochemistry and receptor autoradiogr (1987) Neuroscience. 22(2):481-97.

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Grafts of fetal striatum were implanted in the form of a cell suspension into the brains of rats with prior ibotenic acid lesions of the caudate-putamen. The grafts were placed in three different sites: the lesioned caudate-putamen, or the denervated (but otherwise undamaged) globus pallidus and substantia nigra. After 3-6 months survival the grafts were investigated by means of immunohistochemistry and receptor autoradiography in combination with routine histology and acetylcholinesterase histochemistry. The grafts placed within the lesioned caudate-putamen were at least 10-fold larger larger than those placed in the substantia nigra region, with the grafts placed in the globus pallidus being of intermediate size. In all locations the acetylcholinesterase staining had an uneven, patchy distribution, which was most pronounced in the grafts located within the caudate-putamen. These patches did not bear any obvious relationship to variations in density of the neuronal perikarya within the grafted tissue. Many of the neuropeptide-immunoreactive neuron types present in the normal striatum, such as those containing substance P, [Met]enkephalin, somatostatin, cholecystokinin and neuropeptide Y were also detected in the grafted striatum along with acetylcholinesterase-positive staining. Acetylcholinesterase-positive, [Met]enkephalin-positive, substance P-positive and tyrosine hydroxylase-positive markers all showed uneven, patchy distributions in the grafts. This was also the case for the distribution of dopamine D2 and opiate receptors (as revealed by [3H]spiroperidol and [3H]diprenorphine autoradiography, respectively), whereas muscarinic receptor binding was even throughout the grafts. As is the case in the so-called striosomal patches (neurochemically defined compartments) in the immature intact striatum during the early postnatal period, patches of high acetylcholinesterase staining in the grafts showed partial correspondence with patches of high [Met]enkephalin fibre staining, and dopamine receptor density, and (although to a lesser degree) also with patches of high opiate receptor density and high substance P-immunoreactivity. This correspondence of patches also occurred between tyrosine hydroxylase fibre staining and acetylcholinesterase staining as revealed by grafts placed into the substantia nigra. These results suggest that the fetal striatal cell suspension grafts will give rise to a fairly normal range of striatal neuron and receptor types and that they develop at least some of the striosomal features characteristic for the normal striatum.(ABSTRACT TRUNCATED AT 400 WORDS)

Kesslak, J.P., Frederickson, C.J., Gage, F.H. Quantification of hippocampal noradrenaline and zinc changes after selective cell destruction. (1987) Exp Brain Res. 67(1):77-84.

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Nilsson, O.G., Shapiro, M.L., Gage, F.H., Olton, D.S., Björklund, A. Spatial learning and memory following fimbria-fornix transection and grafting of fetal septal neurons to the hippocampus. (1987) Experimental Brain Research. 67(1):195-215.

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The ability of intrahippocampal grafts of fetal septal-diagonal band tissue, rich in developing cholinergic neurons, to ameliorate cognitive impairments induced by bilateral fimbria-fornix transections in rats was examined in three experiments using the Morris water-maze to test different aspects of spatial memory. Experiment 1. Rats with fimbriafornix lesions received either septal cell suspension grafts or solid septal grafts; normal rats and rats with lesions alone were used as controls. Sixteen weeks after surgery, the rats' spatial learning and memory were tested in the water-maze using a place test, designed to investigate place navigation performance, in which rats learned to escape from the water by swimming to a platform hidden beneath the water's surface. After 5 days of training, the rats were given a spatial probe test in which the platform was removed from the tank to test spatial reference memory. Experiment 2. The same rats used in Exp. 1 were tested in a delayed-match-to-sample, working memory version of the water-maze task. The platform was located in one of two possible locations during each trial, which was composed of 2 swims. If the rat remembered the location of the platform on the 2nd swim of a trial, it should find the platform more quickly on that swim, and thereby demonstrate working memory. Experiment 3. Prior to receiving fimbria-fornix lesions, normal rats were trained in a modification of the water-maze task using alternating cue navigation and place navigation trials (i.e., with visible or non-visible escape platforms). The retention and reacquisition of the place task and the spatial probe test were examined in repeated tests up to 6 months after the lesion and intrahippocampal grafting of septal cell suspensions. The effects of central muscarinic cholinergic receptor blockade with atropine were also tested. Normal rats performed well in both the place and spatial probe tests. In contrast, rats with fimbria-fornix lesions only were unable to acquire or retain spatial information in any test. Instead, these rats adopted a random, non-spatial search strategy, whereby their latencies to find the platform decreased in the place navigation tasks. Sixty to 80% of the rats with septal suspension or solid grafts had recovered place navigation, i.e., the ability to locate the platform site in the tank, in Exp. 1 and 3, and they showed a significantly improved performance in the working memory test in Exp. 2. Atropine abolished the recovered place navigation in the grafted rats, whereas normal rats were impaired to a lesser extent.(ABSTRACT TRUNCATED AT 400 WORDS)

Björklund, A., Gage, F.H. Grafts of fetal septal cholinergic neurons to the hippocampal formation in aged or fimbria-fornix lesioned rats. (1987) Progress in Brain Research. 72:333-42.

Gage, F.H., Buzsaki, G., Nilsson, O., Björklund, A. Grafts of fetal cholinergic neurons to the deafferented hippocampus. (1987) Progress in Brain Research. 71:335-47.

Varon, S., Williams, L.R., Gage, F.H. Exogenous administration of neuronotrophic factors in vivo protects central nervous system neurons against axotomy induced degeneration. (1987) Progress in Brain Research. 71:191-201.

Davis, G.E., Blaker, S.N., Engvall, E., Varon, S., Manthorpe, M., Gage, F.H. Human amnion membrane serves as a substratum for growing axons in vitro and in vivo. (1987) Ciencia. 236(4805):1106-9.

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Peterson, G.M., Williams, L.R., Varon, S., Gage, F.H. Loss of GABAergic neurons in medial septum after fimbria-fornix transection. (1987) Neuroscience Letters. 76(2):140-4.

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Gage, F.H., Björklund, A. Denervation-induced enhancement of graft survival and growth. A trophic hypothesis. (1987) Annals of the New York Academy of Sciences. 495:378-95.

Clarke, D.J., Gage, F.H., Dunnett, S.B., Nilsson, O.G., Björklund, A. Synaptogenesis of grafted cholinergic neurons. (1987) Annals of the New York Academy of Sciences. 495:268-83.

Steinbusch, H.W., Beek, A., Frankhuyzen, A.L., Tonnaer, J.A., Gage, F.H., Björklund, A. Functional activity of raphe neurons transplanted to the hippocampus and caudate-putamen. An immunohistochemical and neurochemical analysis in adult and aged rats. (1987) Annals of the New York Academy of Sciences. 495:169-84.

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Björklund, A., Gage, F.H. Grafts of fetal septal cholinergic neurons to the hippocampal formation in aged or fimbria-fornix-lesioned rats. (1987) Annals of the New York Academy of Sciences. 495:120-37.

Gage, F.H., Björklund, A. Trophic and growth-regulating mechanisms in the central nervous system monitored by intracerebral neural transplants. (1987) Ciba Foundation Symposium. 126:143-59.

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Williams, L.R., Vahlsing, H.L., Lindamood, T., Varon, S., Gage, F.H., Manthorpe, M. A small-gauge cannula device for continuous infusion of exogenous agents into the brain. (1987) Exp. Neurol. 95(3):743-54.

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Fischer, W., Wictorin, K., Björklund, A., Williams, L.R., Varon, S., Gage, F.H. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. (1987) Naturaleza. 329(6134):65-8. DOI: 10.1038/329065a0

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Buzsáki, G., Gage, F.H., Czopf, J., Björklund, A. Restoration of rhythmic slow activity (theta) in the subcortically denervated hippocampus by fetal CNS transplants. (1987) Brain Research. 400(2):334-47.

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Solid pieces of the fetal septal region (SG) or hippocampus (HPC) were implanted in a cavity formed by aspiration of the fimbria fornix (FF) and the overlying cingulate cortex on one side in adult rats. In other lesioned animals cell suspensions obtained from the fetal septal area (SS) or the locus coeruleus region of the brainstem (LC) were injected stereotaxically into the deafferented host hippocampus. Six to 9 months after transplantation the animals had chronic recording electrodes implanted into both hippocampi. EEG and unit activity were monitored during running in a wheel, drinking and immobility. Unilateral fimbria-fornix lesions abolished rhythmic slow activity (RSA or theta, theta) in the ipsilateral hippocampus and no recovery was seen up to 9 months later in either the control FF-lesioned animals or in the rats with LC suspension grafts. Recovery of RSA, however, was observed in all animals with solid septal grafts and in some rats with solid HPC grafts. Similar to normal rats, RSA was present only during running and absent during drinking and sitting still. Coherence measurements of RSA between the transplanted and intact hemispheres resulted in high values (0.70-0.95). Concurrent with RSA, interneurons and granule cells in the host hippocampus fired rhythmically at RSA frequency (6-9 Hz). The depth profile and the antero-posterior distribution of the power of RSA correlated with the amount and distribution of the graft-induced acetylcholinesterase-positive reinnervation of the host hippocampus. In contrast to the animals with solid septal grafts, placed within the FF lesion cavity, the rats with intrahippocampal septal suspension grafts displayed only short duration bursts of RSA, and mainly during immobility. Based on these findings it is suggested that at least a proportion of the RSA 'pacemaker' cells of the host septum survives the transection of the fimbria-fornix fibers and that a graft of fetal septal or hippocampal tissue implanted into the lesion cavity may be capable of relaying this pacemaker activity to the host hippocampus. This effect may be due to the ability of the grafted tissue to promote the regeneration of new, direct or indirect, septo-hippocampal connections across the lesion cavity.

Buzsáki, G., Gage, F.H., Kellényi, L., Björklund, A. Behavioral dependence of the electrical activity of intracerebrally transplanted fetal hippocampus. (1987) Brain Research. 400(2):321-33.

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Williams, L.R., Varon, S., Peterson, G.M., Wictorin, K., Fischer, W., Bjorklund, A., Gage, F.H. Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. (1986) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 83(23):9231-5.

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Clarke, D.J., Gage, F.H., Nilsson, O.G., Björklund, A. Grafted septal neurons form cholinergic synaptic connections in the dentate gyrus of behaviorally impaired aged rats. (1986) Journal of Comparative Neurology. 252(4):483-92. DOI: 10.1002/cne.902520405

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Gage, F.H., Björklund, A. Cholinergic septal grafts into the hippocampal formation improve spatial learning and memory in aged rats by an atropine-sensitive mechanism. (1986) Journal of Neuroscience. 6(10):2837-47.

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Behaviorally impaired old rats were selected from a population of 75 21- to 23-month-old rats on the basis of the place-investigated abilities in the Morris' water-maze task. After the pretransplant test, half of the old impaired rats received bilateral intrahippocampal cell suspension grafts prepared from the fetal septal-diagonal band region, which is rich in developing cholinergic neurons; the other half were left as sham-operated controls. Twelve weeks after grafting, the rats were retested in the water-maze using alternating cue-navigation and place-navigation trials (i.e., with visible or nonvisible escape platform). While the old impaired controls had deteriorated further between the 2 tests and showed poor retention of the pretransplant performance level, the grafted rats were significantly improved in comparison with both their pretransplant performance and the performance of the old impaired controls in the posttransplant test. The graft-induced effect was due both to an improved retention of the performance level acquired in the test performed prior to transplantation surgery, and to an improved acquisition of spatial memory of the escape platform site during the posttransplant test week (measured as an improved focusing of search over the platform site after platform removal). The acetylcholine esterase inhibitor physostigmine had no or only marginal effects on the performance of any of the young or aged rat groups. By contrast, the recovered navigational abilities and spatial memory in the grafted animals were completely abolished after administration of the muscarinic receptor antagonist atropine. A similar atropine-sensitivity was seen in behaviorally nonimpaired aged rats but not in the well-trained young control rats. The results show that cholinergic septal grafts, implanted into the hippocampal formation, improved spatial learning in the impaired aged rats primarily, or perhaps exclusively, by a recovery of the rats' ability to use spatial cues for place-navigation in the water-maze, while other aspects of the performance deficits in the water-maze task in the aged rats were left unaffected by the septal grafts. On the basis of parallel morphological studies, it is proposed that the effects of the septal grafts on the spatial learning impairments in the aged rats are critically dependent on the direct action of cholinergic neurons in the grafts via synapses formed onto neuronal elements in the host by their ingrowing axons.

Gage, F.H., Wictorin, K., Fischer, W., Williams, L.R., Varon, S., Bjorklund, A. Retrograde cell changes in medial septum and diagonal band following fimbria-fornix transection: quantitative temporal analysis. (1986) Neuroscience. 19(1):241-55.

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Complete unilateral fimbria-fornix transections, including the overlying cingulate cortex, were administered to female rats. At time points from 1 day to 6 weeks, the septal-diagonal band region was examined using acetylcholinesterase histochemistry, Cresyl Violet cell staining, and choline acetyltransferase biochemistry. As early as 1 day following the transection a decrease in acetylcholinesterase positive cell body staining was observed in the medial septum; however, no loss of Nissl-stained neurons was measured in Cresyl Violet stained sections until 1 week after the lesion. Maximal loss of acetylcholinesterase-positive cells, as visualized after irreversible acetylcholinesterase inhibition, was measured at 1 week, and no further change was observed at time points up to 6 weeks after operation. The loss of acetyltransferase-positive cells was greatest in the medial septal area (-65%) and the vertical limb of the diagonal band (-55%). Little cell loss was measured in the horizontal limb of the diagonal band. This is consistent with the known projections of these cell bodies. Remaining acetylcholinesterase-positive cell bodies in the medial septum had shrunk by about 20% (measured as the diameter along the major axis). A marked neuronal cell loss (about 50%) was demonstrable in the medial septum and vertical limb of the diagonal band in the Cresyl Violet-stained sections, too. A pile-up of acetylcholinesterase-stained material was observed in the dorsal-lateral quadrant of the septal area just proximal to the lesion at 1 day following transection. This pile-up occurred in the medial septum and diagonal band area up to 1 week following the transection, and had nearly disappeared by 2 weeks post-transection. Choline acetyltransferase biochemical activity, measured in samples of whole septum, decreased significantly at 1 day but subsequently returned to control levels. By 2 weeks following transection, an increase in acetylcholinesterase-positive stained fibers was observed in the dorsal-lateral quadrant of the septum, ipsilateral to the lesion relative to the contralateral septum. This response, which was interpreted as sprouting from the lesioned axons proximal to the transection, probably accounted for the rise in choline acetyltransferase biochemical activity in the whole septum following the reduction on the first day.

Gage, F.H., Björklund, A. Neural grafting in the aged rat brain. (1986) Annual Review of Physiology. 48:447-59. DOI: 10.1146/annurev.ph.48.030186.002311

Björklund, A., Nornes, H., Gage, F.H. Cell suspension grafts of noradrenergic locus coeruleus neurons in rat hippocampus and spinal cord: reinnervation and transmitter turnover. (1986) Neuroscience. 18(3):685-98.

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Fetal noradrenergic neurons from the brain stem locus coeruleus region can be successfully grafted as a dissociated cell suspension provided that the dissociation is done in the absence of any trypsin digestion step. The survival, fiber outgrowth and biochemical function of locus coeruleus neurons, taken from 13- to 15-day-old rat embryos, have been studied after injection into the dorsal hippocampal formation and the thoracolumbar spinal cord in adult rats. All rats were treated with an i.v. injection of 6-hydroxydopamine prior to grafting to remove the intrinsic locus coeruleus projections to these areas, and they were taken for fluorescence histochemical or biochemical analyses 2-7 months after transplantation. Up to 330 surviving noradrenaline neurons were found at each implantation site (injected with 2-3 microliters of cell suspension) which represents an estimated survival rate of about 40%. In the most successful cases the entire dorsal hippocampal formation, and an approximately 4 cm long segment of the thoracolumbar spinal cord, was supplied with a new noradrenaline-containing terminal network, which reached normal densities in the regions closest to the grafts. In the hippocampal formation, in particular, the ingrowing axons re-established a laminar innervation pattern which resembled that of the normal locus coeruleus afferents. In the hippocampus, two 2-microliters injections of locus coeruleus cell suspension restored the total hippocampal noradrenaline content to an average of 55%, and the noradrenaline synthesis rate (as assessed by the rate of DOPA accumulation after synthesis inhibition) was found to be close to normal in the graft-reinnervated specimens. In the spinal cord, two 3-microliters injections restored the noradrenaline level in the thoracolumbar cord (a 4.5 cm long segment) to an average of 22% of normal, with the highest individual levels being close to normal. Determinations of the noradrenaline metabolite 3,4-dihydroxy-phenylethyleneglycol indicated that the rate of noradrenaline metabolism in the graft-reinnervated spinal cord was close to that of the normal intact spinal cord. The results demonstrate the potential of the suspension grafting technique for extensive noradrenergic reinnervation of the hippocampal formation or large portions of the spinal cord. Fetal locus coeruleus neurons implanted in this way can re-establish fairly normal terminal innervation patterns and reinstate noradrenaline turnover and metabolism in a previously denervated central target.

Bengtsson, F., Nobin, A., Falck, B., Gage, F.H., Jeppsson, B. Portacaval shunt in the rat: selective alterations in behavior and brain serotonin. (1986) Pharmacology, Biochemistry, and Behavior. 24(6):1611-6.

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Björklund, A., Gage, F.H. Transplantation of basal forebrain cholinergic neurons in the aged rat brain. (1986) Progress in Brain Research. 70:499-512.

Acsádi, G., Buzsáki, G., Keszthelyi, T., Királyfalvi, L., Gage, F.H. Effects of confinement, previous experience and hippocampal damage on the DRL schedule. (1986) Behavioural Brain Research. 20(2):241-8.

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Lindvall, O., Ingvar, M., Gage, F.H. Short term status epilepticus in rats causes specific behavioral impairments related to substantia nigra necrosis. (1986) Experimental Brain Research. 64(1):143-8.

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Schultzberg, M., Foster, G.A., Gage, F.H., Björklund, A., Hökfelt, T. Coexistence during ontogeny and transplantation. (1986) Progress in Brain Research. 68:129-45.

Kesslak, J.P., Gage, F.H. Recovery of spatial alternation deficits following selective hippocampal destruction with kainic acid. (1986) Behavioral Neuroscience. 100(2):280-3.

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Clarke, D.J., Gage, F.H., Björklund, A. Formation of cholinergic synapses by intrahippocampal septal grafts as revealed by choline acetyltransferase immunocytochemistry. (1986) Brain Research. 369(1-2):151-62.

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Brundin, P., Isacson, O., Gage, F.H., Prochiantz, A., Björklund, A. The rotating 6-hydroxydopamine-lesioned mouse as a model for assessing functional effects of neuronal grafting. (1986) Brain Research. 366(1-2):346-9.

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Zetterström, T., Brundin, P., Gage, F.H., Sharp, T., Isacson, O., Dunnett, S.B., Ungerstedt, U., Björklund, A. In vivo measurement of spontaneous release and metabolism of dopamine from intrastriatal nigral grafts using intracerebral dialysis. (1986) Brain Research. 362(2):344-9.

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Gage, F.H., Björklund, A. Enhanced graft survival in the hippocampus following selective denervation. (1986) Neuroscience. 17(1):89-98.

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The trophic effects of denervation on the survival of fetal cholinergic neuronal cell suspensions grafted to the hippocampal formation of the rat were assessed in the present study. Young adult female rats were injected with cell suspensions of neurons obtained from the fetal basal forebrain region into the hippocampal formation simultaneously with (or without) a fimbria-fornix transection, which removes the hippocampal cholinergic afferents. Four to six months later, one group of grafted animals was evaluated histochemically for: transplant volume; number of acetylcholinesterase-positive cells, and size of acetylcholinesterase-positive cells in the graft. A parallel study was conducted to determine the total number and size of the acetylcholinesterase-positive cells in the septal-diagonal band-substantia innominata complex of the adult rat, to match with the cell survival and growth in the grafts. A second group of grafted rats was taken in parallel for biochemical analysis of choline acetyltransferase activity in the grafted hippocampus. The transplant volume in the rats with fimbria-fornix transection was greater than twice the volume seen in animals without fimbria-fornix lesion. In addition, the number of acetylcholinesterase-positive cells in the transplant was twice as great in the denervated animals as in the non-denervated ones. However, the number of acetylcholinesterase-positive cells per mm3 of graft volume did not differ between the two groups, suggesting that the trophic effect of the denervation was not specific for the cholinergic neurons, but affected the entire grafted tissue. The hippocampal choline acetyltransferase activity of the animals that received the fimbria-fornix lesion simultaneously with transplantation was about three times higher than that of the rats that received grafts but no simultaneous fimbria-fornix transection. A control experiment with animals that received an aspirative lesion of the retrosplenial cortex, transecting the perforant path input, revealed no enhancing effect of hippocampal choline acetyltransferase activity over non-lesioned grafted animals. Thus, the denervation-enhancing effects of the fimbria-fornix lesion appear to be selective and not the result of a general wound-induced mechanism. These results strongly support the contention that neurotrophic factors are released as a result of denervation in the adult hippocampal formation, and that these neurotrophic factors can support survival and growth of central cholinergic neurons. However, the factors involved do not appear to be specific for the cholinergic neurons, but rather have their trophic effects on many types of cells.

Brundin, P., Isacson, O., Gage, F.H., Björklund, A. Intrastriatal grafting of dopamine-containing neuronal cell suspensions: effects of mixing with target or non-target cells. (1986) Brain Research. 389(1-2):77-84.

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Isacson, O., Brundin, P., Gage, F.H., Björklund, A. Neural grafting in a rat model of Huntington's disease: progressive neurochemical changes after neostriatal ibotenate lesions and striatal tissue grafting. (1985) Neuroscience. 16(4):799-817.

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The acute and long-term changes following large neostriatal ibotenic acid lesions and intrastriatal striatal neuronal grafting have been studied neurochemically by determinations of the gamma-aminobutyrate (GABA) and acetylcholine-synthetic enzymes, glutamate decarboxylase and choline acetyltransferase, and of dopamine and its primary acidic metabolite, 3,4-dihydroxyphenylacetic acid. The neurochemical data have been matched with estimates of tissue volume changes and striatal graft development through tissue weight and protein content analysis and histological volumetric measurements. Injections of 20 micrograms ibotenic acid, deposited over four injection sites in the head of the caudate-putamen, had by one week caused a 70-85% reduction in glutamate decarboxylase and choline acetyltransferase activity. With time there was a progressive recovery of the specific enzyme activities in the lesioned areas (expressed per microgram protein or per mg wet weight) to 40-60% of control levels as determined at 20 weeks post-lesion in the caudate-putamen. This increase was, however, largely if not exclusively due to the long-term shrinkage of the lesioned caudate-putamen, amounting to 50-70% at 20 weeks. Thus, the total glutamate decarboxylase and choline acetyltransferase activity levels in the lesioned caudate-putamen remained virtually unchanged (between 15 and 25% of control) over the 20 week experimental period. Glutamate decarboxylase activity was also markedly reduced (35-70%) in the two primary striatal projection areas, globus pallidus and substantia nigra, and there were no signs of recovery over time. Striatal dopamine levels, which were acutely unaffected by the lesion, showed a slow decline so that the total dopamine content in the area was reduced by about 80% at 20 weeks. Suspended striatal neurons obtained from the striatal primordia of 14-15-day-old rat fetuses, injected into the previously lesioned caudate-putamen, survived and established a new striatum-like structure at the site of the ibotenic acid lesion. The final volume of the graft tissue reached up to about 10 mm3 in volume and reduced striatal atrophy on average from about 50 to 70% of normal control in the rats with lesions to about 30-40% in the animals with grafts. In the rats with grafts, there was a significant recovery of glutamate decarboxylase and choline acetyltransferase activities not only in the lesioned caudate-putamen, containing the graft (from 20-25% to 40-50%, when expressed as total enzyme activity levels), but also the glutamate decarboxylase activity in the globus pallidus, a structure located at a distance from the graft.(ABSTRACT TRUNCATED AT 400 WORDS)

Brundin, P., Barbin, G., Isacson, O., Mallat, M., Chamak, B., Prochiantz, A., Gage, F.H., Björklund, A. Survival of intracerebrally grafted rat dopamine neurons previously cultured in vitro. (1985) Neurosci. Lett. 61(1-2):79-84.

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Bengtsson, F., Gage, F.H., Jeppsson, B., Nobin, A., Rosengren, E. Brain monoamine metabolism and behavior in portacaval-shunted rats. (1985) Experimental Neurology. 90(1):21-35.

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Gage, F.H., Brundin, P., Isacson, O., Björklund, A. Rat fetal brain tissue grafts survive and innervate host brain following five day pregraft tissue storage. (1985) Neuroscience Letters. 60(2):133-7.

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Segal, M., Bjorklund, A., Gage, F.H. Transplanted septal neurons make viable cholinergic synapses with a host hippocampus. (1985) Brain Research. 336(2):302-7.

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Brundin, P., Nilsson, O.G., Gage, F.H., Björklund, A. Cyclosporin A increases survival of cross-species intrastriatal grafts of embryonic dopamine-containing neurons. (1985) Experimental Brain Research. 60(1):204-8.

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Shapiro, M.L., Simon, D., Olton, D.S., Gage, F.H., Bjorklund, A., Stenevi, U. Brain transplants: can they restore single unit activity in the hippocampus? (1985) Annals of the New York Academy of Sciences. 444:536-7.

Foster, G.A., Schultzberg, M., Gage, F.H., Björklund, A., Hökfelt, T., Nornes, H., Cuello, A.C., Verhofstad, A.A., Visser, T.J. Transmitter expression and morphological development of embryonic medullary and mesencephalic raphé neurones after transplantation to the adult rat central nervous system. I. Grafts to the spinal cord (1985) Experimental Brain Research. 60(3):427-44.

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Suspensions of cells derived from the mesencephalic raphé or medullary raphé regions of the 13-14 day old embryonic rat brain were injected into the spinal cord of adult rats which had been previously denervated with 5,7-dihydroxytryptamine. At periods of up to 12 months after grafting, the spinal cords were taken for immunohistochemical analysis of 5-hydroxytryptamine (5HT), substance P (SP) and thyrotropin releasing hormone (TRH). In nearly all cases, surviving transplants were found. The grafts derived from mesencephalic raphé cells contained neurones which were immunoreactive to 5HT, or SP, but not both together. On average 4% of the total possible number of the available embryonic mesencephalic serotoninergic cells were found. A very dense outgrowth of 5HT positive fibres from the transplant was observed, extending up to 1.5 cm in both the caudal and rostral directions from the graft locus. Some SP immunoreactive fibres were also apparent near the implant. The grafts derived from the medullary transplant also contained 5HT-immunoreactive cells, comprising on average 25% of the total 5HT neurones available from the embryonic medullary primordium. In addition, neurones co-localizing 5HT together with SP and TRH were visible, closely reflecting the situation found in the medullary raphé in situ. Dense plexi of fibres containing 5HT-LI extended both caudally and rostrally up to 12-15 mm from the transplant. Outgrowth of SP and TRH varicose fibres was also demonstrable, although to a lesser degree than for 5HT. It was also possible to find many motoneurones surrounded by varicose fibres containing both 5HT and SP, in contrast to the situation with the mesencephalic grafts, where no such patterns of innervation were seen. The experiments indicate that the milieu of the spinal cord may compromise the survival of mesencephalic raphé 5HT neurones far more than of medullary serotonin cells. However, despite this effect on cell survival, the outgrowth of fibres from the remaining mesencephalic 5HT neurones was apparently unaffected by their ectopic position. Similarly, the transmitter content of both classes of raphé cells was largely unaltered, either by the transplantation process or by the environment into which they were placed. It is concluded that although the adult denervated spinal cord can selectively affect neuronal survival, it is incapable either of inducing in other serotoninergic cells placed within it the transmitter phenotype typical of medullary raphé neurones, or of causing those ectopically located 5HT cells to form connections appropriate to the descending serotonin fibres.

Wieloch, T., Lindvall, O., Blomqvist, P., Gage, F.H. Evidence for amelioration of ischaemic neuronal damage in the hippocampal formation by lesions of the perforant path. (1985) Neuroscience Letters. 7(1):24-6.

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Kelly, P.A., Gage, F.H., Ingvar, M., Lindvall, O., Stenevi, U., Björklund, A. Functional reactivation of the deafferented hippocampus by embryonic septal grafts as assessed by measurements of local glucose utilization. (1985) Experimental Brain Research. 58(3):570-9.

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Transection of the septo-hippocampal connections through fimbria-fornix damage in the rat results in profound hippocampal cholinergic deafferentation, and, when applied bilaterally, leads to severe and long-lasting impairments in learning and memory. Previous studies have shown that intrahippocampal septal grafts can reestablish a new cholinergic in the initially denervated hippocampal formation and at least partly compensate for the lesion-induced learning impairments in fimbria-fornix lesioned rats. The purpose of the present study was to determine the magnitude of lesion-induced alterations in cerebral function as reflected in local glucose use measured by (14C)-2-deoxyglucose (2-DG) autoradiography, and the degree to which this index of functional activity could be normalized following reinnervation from transplants of fetal cerebral tissue from the primordial septal region. Six months after unilateral fimbria-fornix transection the rate of glucose utilization was reduced markedly throughout the ipsilateral hippocampus when compared to the intact contralateral side, while in the neocortex only the cingulate cortex showed long-lasting reductions in glucose use. Rats that received a transplant of fetal septal-diagonal band tissue at the time of fimbria-fornix transection, and were sacrificed 6 months later, displayed significantly greater glucose utilization in the ipsilateral hippocampus and cingulate cortex than was measured in these areas in rats with lesion alone. The recovery in glucose use was paralleled by a significant increase in acetylcholinesterase (AChE) staining in several areas of the ipsilateral hippocampal formation and cingulate cortex. This index of graft-induced cholinergic reinnervation was, moreover, significantly correlated with the rate of glucose use. Thus, in the fimbria-fornix transected animals the magnitude of glucose depression correlated with the extent of reduction in AChE staining, and in the grafted animals the degree of normalization of glucose use was correlated with the graft-induced increase in AChE-staining density. These results thus indicate that the 2-DG autoradiographic technique can provide a unique opportunity to map both altered functional activity in localized areas of the brain following specific lesions and the extent to which transplant-derived reinnervation of the host may induce a return to normal functional levels in the target site.

Björklund, A., Gage, F.H., Stenevi, U., Dunnett, S.B., Kelly, P.A. Intracerebral neural grafting in animal models of aging brain: strategies, rationale and preliminary results. (1985) Danish Medical Bulletin. 32 Suppl 1:35-9.

Gage, F.H., Stenevi, U., Carlstedt, T., Foster, G., Björklund, A., Aguayo, A.J. Anatomical and functional consequences of grafting mesencephalic neurons into a peripheral nerve "bridge" connected to the denervated striatum. (1985) Exp Brain Res. 60(3):584-9.

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Björklund, A., Gage, F.H. Neural grafting in animal models of neurodegenerative diseases. (1985) Annals of the New York Academy of Sciences. 457:53-81.

Gage, F.H., Kelly, P.A., Björklund, A. Regional changes in brain glucose metabolism reflect cognitive impairments in aged rats. (1984) Journal of Neuroscience. 4(11):2856-65.

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Aged rats (22 to 24 months) and young control rats (3 months) were tested in a battery of behavioral tests which included tests of learning, place navigation, sensorimotor integration, motor coordination, activity, and exploration. Following testing all animals were analyzed in an unanesthetized state for their local glucose utilization. Significant differences in glucose utilization were found between the aged and young groups on some behaviors and in some brain regions. There was considerable variability in the aged group in both their behavioral performance and their glucose utilization scores; thus, attempts were made to determine whether the variability in the degree of impairment within any particular behavioral test was correlated to the regional glucose utilization scores in any of the 45 brain regions analyzed. In two of the behavioral tests employed (i.e., one for learning and one for place navigation), the decline in performance correlated significantly with the decrement in regional glucose utilization. Moreover, the performance in these two tests showed significant correlation with glucose use in only five regions (dentate gyrus, medial septum-diagonal band area, hippocampal CA1, hippocampal CA3, and prefrontal cortex). These results show that the learning impairments in the aged rats are related to the extent of decrease in glucose utilization in restricted areas of the limbic system. In addition, the results show that the individual rats within an aged rat population develop cognitive impairments to a variable degree and that the aged rats with the most pronounced learning impairments are the ones exhibiting the most severe functional decrements, in terms of glucose utilization, in the septohippocampal system and the prefrontal cortex. This suggests that aging rats may be interesting not only for the study of the normal aging process, but also as a model of dementia.

Isacson, O., Brundin, P., Kelly, P.A., Gage, F.H., Björklund, A. Functional neuronal replacement by grafted striatal neurones in the ibotenic acid-lesioned rat striatum. (1984) Naturaleza. 311(5985):458-60.

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Evans, S.H., Chafetz, M.D., Gage, F.H. Taxonomic abstraction in psychobiology. (1984) Journal of General Psychology. 111(2ND Half):209-27. DOI: 10.1080/00221309.1984.9921111

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Gage, F.H., Björklund, A. Intracerebral grafting of neuronal cell suspensions into the adult brain. (1984) Central Nervous System Trauma. 1(1):47-56.

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Gage, F.H., Björklund, A., Stenevi, U., Dunnett, S.B., Kelly, P.A. Intrahippocampal septal grafts ameliorate learning impairments in aged rats. (1984) Ciencia. 225(4661):533-6.

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Dunnett, S.B., Bunch, S.T., Gage, F.H., Björklund, A. Dopamine-rich transplants in rats with 6-OHDA lesions of the ventral tegmental area. I. Effects on spontaneous and drug-induced locomotor activity. (1984) Behavioural Brain Research. 13(1):71-82.

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Gage, F.H., Björklund, A., Stenevi, U. Denervation releases a neuronal survival factor in adult rat hippocampus. (1984) Naturaleza. 308(5960):637-9.

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Gage, F.H., Dunnett, S.B., Björklund, A. Spatial learning and motor deficits in aged rats. (1984) Neurobiology of Aging. 5(1):43-8.

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Dunnett, S.B., Gage, F.H., Björklund, A., Stenevi, U., Low, W.C., Iversen, S.D. Hippocampal deafferentation: transplant-derived reinnervation and functional recovery. (1984) Acta psychiatrica Scandinavica. Supplementum. 313:46-56.

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Gage, F.H., Björklund, A., Stenevi, U. Cells of origin of the ventral cholinergic septohippocampal pathway undergoing compensatory collateral sprouting following fimbria-fornix transection. (1984) Neuroscience Letters. 44(2):211-6.

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Barker, D.J., Howard, A.J., Gage, F.H. Functional significance of sympathohippocampal sprouting: changes in single cell spontaneous activity. (1984) Brain Research. 291(2):357-63.

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Stewart, G.R., Frederickson, C.J., Howell, G.A., Gage, F.H. Cholinergic denervation-induced increase of chelatable zinc in mossy-fiber region of the hippocampal formation. (1984) Brain Research. 290(1):43-51.

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Gage, F.H., Björklund, A., Stenevi, U. Local regulation of compensatory noradrenergic hyperactivity in the partially denervated hippocampus. (1983) Naturaleza. 303(5920):819-21.

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Björklund, A., Stenevi, U., Schmidt, R.H., Dunnett, S.B., Gage, F.H. Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites. (1983) Acta physiologica Scandinavica. Supplementum. 522:9-18.

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Gage, F.H., Björklund, A., Stenevi, U., Dunnett, S.B. Intracerebral grafting of neuronal cell suspensions. VIII. Survival and growth of implants of nigral and septal cell suspensions in intact brains of aged rats. (1983) Acta physiologica Scandinavica. Supplementum. 522:67-75.

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Björklund, A., Gage, F.H., Schmidt, R.H., Stenevi, U., Dunnett, S.B. Intracerebral grafting of neuronal cell suspensions. VII. Recovery of choline acetyltransferase activity and acetylcholine synthesis in the denervated hippocampus reinnervated by septal suspension imp (1983) Acta physiologica Scandinavica. Supplementum. 522:59-66.

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Björklund, A., Gage, F.H., Stenevi, U., Dunnett, S.B. Intracerebral grafting of neuronal cell suspensions. VI. Survival and growth of intrahippocampal implants of septal cell suspensions. (1983) Acta physiologica Scandinavica. Supplementum. 522:49-58.

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Björklund, A., Stenevi, U., Schmidt, R.H., Dunnett, S.B., Gage, F.H. Intracerebral grafting of neuronal cell suspensions. I. Introduction and general methods of preparation. (1983) Acta physiologica Scandinavica. Supplementum. 522:1-7.

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Gage, F.H., Dunnett, S.B., Brundin, P., Isacson, O., Björklund, A. Intracerebral grafting of embryonic neural cells into the adult host brain: an overview of the cell suspension method and its application. (1983) Developmental Neuroscience. 6(3):137-51.

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Gage, F.H., Björklund, A., Stenevi, U., Dunnett, S.B. Functional correlates of compensatory collateral sprouting by aminergic and cholinergic afferents in the hippocampal formation. (1983) Brain Research. 268(1):39-47.

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Selective lesions of discrete aminergic and cholinergic afferent pathways to the hippocampal formation have been studied as an experimental model of behavioral recovery after partial hippocampal deafferentation in adult rats. The noradrenergic, serotoninergic and cholinergic afferents reach the hippocampal formation along three routes: a supracallosal pathway, a subcallosal pathway (along the fimbria-fornix), and a ventral pathway (along the ansa lenticularis and the ventral amygdaloid pathway). Bi-lateral lesion of the supracallosal pathway resulted in significant reductions in biochemical markers of the hippocampal noradrenergic, serotoninergic and cholinergic innervations. Within 6 weeks following lesion these markers were found to have recovered to levels close to normal. A more substantial deafferentation, obtained by a bilateral lesion of both dorsal pathways, resulted in a more profound initial decrease in the biochemical marker levels, and a less complete recovery in the long-term animals. Concomitant with the initial phase of deafferentation, rats with lesions of one or both of the dorsal afferent pathways exhibited an equally profound behavioral deficit in acquisition of a forced choice alternation learning task in a T-maze. However, while rats subjected to the combined supracallosal-fimbria-fornix lesion remained impaired, the ones with lesions of the supracallosal pathway alone exhibited a significant recovery of the capacity to perform the maze task. The correlation between behavioral recovery and recovery of the biochemical markers in the supracallosal pathway-lesioned group was significant for the serotoninergic innervation of the hippocampus. The present results suggest that reinnervation of the partially deafferented hippocampus through compensatory collateral sprouting is a valuable new experimental model system within which to analyze mechanisms underlying functional recovery after lesions in the CNS.

Gage, F.H., Björklund, A., Stenevi, U. Reinnervation of the partially deafferented hippocampus by compensatory collateral sprouting from spared cholinergic and noradrenergic afferents. (1983) Brain Research. 268(1):27-37.

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Whipple, M.R., Reinecke, M.G., Gage, F.H. Inhibition of synaptosomal neurotransmitter uptake by hallucinogens. (1983) Journal of Neurochemistry. 40(4):1185-8.

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Chafetz, M.D., Gage, F.H. Pineal and habenula innervation altered by septal lesions. (1983) Brain Research Bulletin. 10(1):27-31.

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Schmidt, R.H., Björklund, A., Stenevi, U., Dunnett, S.B., Gage, F.H. Intracerebral grafting of neuronal cell suspensions. III. Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism. (1983) Acta physiologica Scandinavica. Supplementum. 522:19-28.

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Turner, F.D., Gage, F.H. Behavioral kinetics: dynamics of the unconditioned response to footshock. (1982) Physiology & Behavior. 29(5):957-60.

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Chafetz, M.D., Evans, S., Gage, F.H. Fluorescence measurement of lesion-induced fiber growth. II. Measurement of sympathohippocampal sprouting using a new microfluorometric method. (1982) Brain Research. 247(2):217-25.

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Chafetz, M.D., Gage, F.H. Fluorescence measurement of lesion-induced fiber growth. I. A microfluorometric technique to measure density and intensity of varicosities and fibers. (1982) Brain Research. 247(2):209-16.

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Björklund, A., Stenevi, U., Dunnett, S.B., Gage, F.H. Cross-species neural grafting in a rat model of Parkinson's disease. (1982) Naturaleza. 298(5875):652-4.

Dunnett, S.B., Gage, F.H., Björklund, A., Stenevi, U., Low, W.C., Iversen, S.D. Hippocampal deafferentation: transplant-derived reinnervation and functional recovery. (1982) Scandinavian Journal of Psychology. Suppl 1:104-11.

Gage, F.H., Dunnett, S.B., Björklund, A., Stenevi, U. Functional recovery following brain damage: conceptual frameworks and biological mechanisms. (1982) Scandinavian Journal of Psychology. Suppl 1:112-20.

Thompson, R.G., Valdes, J.J., Gage, F.H. Reversible alterations in hypothalamic uptake of biogenic amines after septal lesions. (1981) Experimental Neurology. 74(2):356-69.

Gage, F.H., Springer, J.E. Behavioral assessment of norepinephrine and serotonin function and interaction in the hippocampal formation. (1981) Pharmacology, Biochemistry, and Behavior. 14(6):815-21.

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Chafetz, M.D., Thompson, R.G., Evans, S.H., Gage, F.H. Biochemical specificity of septal hyperreactivity: a behavioral discrimination. (1981) Behavioural Brain Research. 2(3):409-20.

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Gage, F.H., Thompson, R.G. Differential distribution of norepinephrine and serotonin along the dorsal-ventral axis of the hippocampal formation. (1980) Brain Research Bulletin. 5(6):771-3.

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Gage, F.H., Valdes, J.J., Thompson, R.G. Morphine injections into the periaqueductal-periventricular gray attenuate septal hyperreactivity. (1980) Psychopharmacology. 70(1):113-4.

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Valdes, J.J., Cameron, W.R., Evans, S., Gage, F.H. Regional brain morphine injections selectively attenuate aspects of septal hyperreactivity: a multivariate assessment. (1980) Pharmacology, Biochemistry, and Behavior. 12(4):563-72.

Gage, F.H., Armstrong, D.R., Thompson, R.G. Behavioral kinetics: a method for deriving qualitative and quantitative changes in sensory responsiveness following septal nuclei damage. (1980) Physiology & Behavior. 24(3):479-84.

Cameron, W.R., Gage, F.H., Hitt, J.C., Popolow, H.B. The influence of the anterodorsal hippocampus on feminine sexual behavior in rats. (1979) Behavioral and Neural Biology. 27(1):72-86.

Babitch, J.A., Gage, F.H., Valdes, J.J. Effects of phalloidin on K+-dependent, Ca2+-independent neurotransmitter efflux and K+-facilitated, Ca2+-dependent neurotransmitter release. (1979) Life Sciences. 24(2):117-24.

Gage, F.H., Thompson, R.G., Valdes, J.J. Endogenous norepinephrine and serotonin within the hippocampal formation during the development and recovery from septal hyperreactivity. (1978) Pharmacology, Biochemistry, and Behavior. 9(3):359-67.

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Gage, F.H., Olton, D.S., Bolanowski, D. Activity, reactivity, and dominance following septal lesions in rats. (1978) Behavioral Biology. 22(2):203-10.

Olton, D.S., Walker, J.A., Gage, F.H. Hippocampal connections and spatial discrimination. (1978) Brain Research. 139(2):295-308.

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Johnson, C.T., Olton, D.S., Gage, F.H., Jenko, P.G. Damage to hippocampus and hippocampal connections: effects on DRL and spontaneous alternation. (1977) Journal of Comparative and Physiological Psychology. 91(3):508-22.

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Jenko, P.G., Gage, F.H., Olton, D.S. Time-dependent fornix influence on increased light aversion induced by septal lesions. (1976) Behavioral Biology. 17(4):607-14.

Gage, F.H., Olton, D.S. L-Dopa reduces hyperreactivity induced by septal lesions in rats. (1976) Behavioral Biology. 17(2):213-8.

Gage, F.H., Olton, D.S. Hippocampal influence on hyperreactivity induced by septal lesions. (1975) Brain Research. 98(2):311-25.

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Olton, D.S., Gage, F.H. Role of the fornix in the septal syndrome. (1974) Physiology & Behavior. 13(2):269-79.

Woodruff, M.L., Gage, F.H., Isaacson, R.L. Changes in focal epileptic activity produced by brain-stem sections in the rabbit. (1973) Electroencephalography and Clinical Neurophysiology. 35(5):475-86.

Isaacson, R.L., Gage, F.H. Hypothalamic stimulation and the persistence of epileptiform discharges. (1973) Brain Research. 49(1):194-9.

Rusty Gage, doctor

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