Publications

2024 PUBLICATIONS

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) Science. 384(6691):53-59. DOI: 10.1126/science.adf3481

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Samavat, M., Bartol, T.M., Harris, K.M., Sejnowski, T.J. Synaptic Information Storage Capacity Measured With Information Theory. (2024) Neural Computation. 36(5):781-802. DOI: 10.1162/neco_a_01659

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Husar, A., Ordyan, M., Garcia, G.C., Yancey, J.G., Saglam, A.S., Faeder, J.R., Bartol, T.M., Kennedy, M.B., Sejnowski, T.J. MCell4 with BioNetGen: A Monte Carlo simulator of rule-based reaction-diffusion systems with Python interface. (2024) PLOS Computational Biology. 20(4):e1011800. DOI: 10.1371/journal.pcbi.1011800

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Adusei, M., Callaway, E.M., Usrey, W.M., Briggs, F. Parallel streams of direct corticogeniculate feedback from mid-level extrastriate cortex in the macaque monkey. (2024) eNeuro. DOI: 10.1523/ENEURO.0364-23.2024

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First order thalamic nuclei receive feedforward signals from peripheral receptors and relay these signals to primary sensory cortex. Primary sensory cortex, in turn, provides reciprocal feedback to first order thalamus. Because the vast majority of sensory thalamocortical inputs target primary sensory cortex, their complementary corticothalamic neurons are assumed to be similarly restricted to primary sensory cortex. We upend this assumption by characterizing morphologically diverse neurons in multiple mid-level visual cortical areas of the primate () brain that provide direct feedback to the primary visual thalamus, the dorsal lateral geniculate nucleus (LGN). Although the majority of geniculocortical neurons project to primary visual cortex (V1), a minority, located mainly in the koniocellular LGN layers, provide direct input to extrastriate visual cortex. These "V1-bypassing" projections may be implicated in blindsight. We hypothesized that geniculocortical inputs directly targeting extrastriate cortex should be complemented by reciprocal corticogeniculate circuits. Using virus-mediated circuit tracing, we discovered corticogeniculate neurons throughout three mid-level extrastriate areas: MT, MST, and V4. Quantitative morphological analyses revealed non-uniform distributions of unique cell types across areas. Many extrastriate corticogeniculate neurons had spiny stellate morphology, suggesting possible targeting of koniocellular LGN layers. Importantly though, multiple morphological types were observed across areas. Such morphological diversity could suggest parallel streams of V1-bypassing corticogeniculate feedback at multiple stages of the visual processing hierarchy. Furthermore, the presence of corticogeniculate neurons across visual cortex necessitates a reevaluation of the LGN as a hub for visual information rather than a simple relay. First order thalamic nuclei are most strongly connected in feedforward and feedback directions with primary sensory cortex. In the visual system, direct feedforward circuits link the visual thalamus with higher-order, extrastriate visual areas, although the function of these less-common pathways remains unknown. Here we demonstrate for the first time the presence of complementary direct feedback connections between multiple extrastriate visual cortical areas and the visual thalamus in the primate brain. Although sparse, extrastriate corticogeniculate circuits are consistently present and contain morphologically diverse neurons, suggesting parallel streams of extrastriate feedback. These findings indicate an evolutionary conservation of circuits that integrate information from throughout the visual processing hierarchy within the visual thalamus.

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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Newman, L.E., Weiser Novak, S., Rojas, G.R., Tadepalle, N., Schiavon, C.R., Grotjahn, D.A., Towers, C.G., Tremblay, M., Donnelly, M.P., Ghosh, S., Medina, M., Rocha, S., Rodriguez-Enriquez, R., Chevez, J.A., Lemersal, I., Manor, U., Shadel, G.S. Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal. (2024) Nature Cell Biology. DOI: 10.1038/s41556-023-01343-1

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Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.

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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Bartol, T.M., Ordyan, M., Sejnowski, T.J., Rangamani, P., Kennedy, M.B. A spatial model of autophosphorylation of CaMKII in a glutamatergic spine suggests a network-driven kinetic mechanism for bistable changes in synaptic strength. (2024) bioRxiv. DOI: 10.1101/2024.02.02.578696

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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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Wang, H., Dey, O., Lagos, W.N., Behnam, N., Callaway, E.M., Stafford, B.K. Parallel pathways carrying direction-and orientation-selective retinal signals to layer 4 of the mouse visual cortex. (2024) Cell Reports. 43(3):113830. DOI: 10.1016/j.celrep.2024.113830

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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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Iyer, M., Kantarci, H., Cooper, M.H., Ambiel, N., Novak, S.W., Andrade, L.R., Lam, M., Jones, G., Münch, A.E., Yu, X., Khakh, B.S., Manor, U., Zuchero, J.B. Oligodendrocyte calcium signaling promotes actin-dependent myelin sheath extension. (2024) Nature Communications. 15(1):265. DOI: 10.1038/s41467-023-44238-3

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Sameni, S., Bartol, T.M., Corey-Bloom, J., Sejnowski, T.J. Computer simulations predict the impact of neuronal atrophy on the calcium dynamics in Huntington's disease. (2024) PNAS Nexus. 3(1):pgad443. DOI: 10.1093/pnasnexus/pgad443

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Samavat, M., Bartol, T.M., Bromer, C., Hubbard, D.D., Hanka, D.C., Kuwajima, M., Mendenhall, J.M., Parker, P.H., Bowden, J.B., Abraham, W.C., Sejnowski, T.J., Harris, K.M. Long-Term Potentiation Produces a Sustained Expansion of Synaptic Information Storage Capacity in Adult Rat Hippocampus. (2024) bioRxiv. DOI: 10.1101/2024.01.12.574766

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Zhang, L.A., Li, P., Callaway, E.M. High-Resolution Laminar Identification in Macaque Primary Visual Cortex Using Neuropixels Probes. (2024) bioRxiv. DOI: 10.1101/2024.01.23.576944

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Waitt Advanced Biophotonics Center

Salk Institute for Biological Studies - Waitt Advanced Biophotonics Center - Research

2024 PUBLICATIONS

Publications