Publications - Salk Institute for Biological Studies

2025 PUBLICATIONS

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Sejnowski, T.J. Dynamical Mechanisms for Coordinating Long-term Working Memory Based on the Precision of Spike-timing in Cortical Neurons. (2025) ArXiv.

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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) Wissenschaft. 390(6773):574-577. DOI: 10.1126/science.aeb1510

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Pinto-Duarte, A., Bogue, K., Sejnowski, T.J., Srinivasan, S. Conservation of glial density and cell-type ratios within a brain region across mammals. (2025) PNAS Nexus. 4(11):pgaf314. DOI: 10.1093/pnasnexus/pgaf314

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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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Zhang, H., Nelken, I., Sharpee, T. Parsing auditory neural code into maximum-entropy packets. (2025) bioRxiv. DOI: 10.1101/2025.11.09.687481

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Klug, J.R., Yan, X., Hoffman, H., Engelhardt, M.D., Osakada, F., Callaway, E.M., Jin, X. Asymmetric cortical projections to striatal direct and indirect pathways distinctly control actions. (2025) Elife. 12. DOI: 10.7554/eLife.92992

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Moore, J.D., Bachmann, L.C., McElvain, L.E., Pfaff, S.L., Dulac, C. A genetically-defined population of amygdalofugal neurons promotes suckling and early postnatal growth. (2025) bioRxiv. DOI: 10.1101/2025.10.18.683193

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Yao, M., Praturu, A., Sharpee, T. Multiscale Hyperbolic Embedding for Cell Hierarchies in Large-Scale Bioinformatics Data. (2025) bioRxiv. DOI: 10.1101/2025.09.29.679407

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Barykina, N.V., Carey, E.M., Oliinyk, O.S., Mendonça-Gomes, J.M., de Oliveira, S., Nimmerjahn, A., Verkhusha, V.V. Synthetic multicolor antigen-stabilizable nanobody platform for intersectional labelling and functional imaging. (2025) bioRxiv. DOI: 10.1101/2025.10.27.684934

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Virlogeux, A., Bollu, T., Ren, X., Palma, A.M., Goulding, M.D. The dorsal column nuclei encode and transmit the network signatures of mechanical allodynia. (2025) Cell Reports. 44(9):116248. DOI: 10.1016/j.celrep.2025.116248

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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.

Nakahira, Y., Liu, Q., Deng, X., Sejnowski, T.J., Doyle, J.C. Diversity Deconstrains Component Limitations in Sensorimotor Control. (2025) Neural Computation.:1-24 DOI: 10.1162/neco.a.24

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Praturu, A., Sharpee, T.O. Distance-Based Logistic Matrix Factorization. (2025) Neural Computation.:1-14 DOI: 10.1162/neco.a.25

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Calatayud, C., Fernandez-Carasa, I., Spataro, N., Mussolino, C., Richaud-Patin, Y., Faella, A., Fernández-Santiago, R., Ezquerra, M., Courtin, T., Bandres-Ciga, S., Miguez, A., Canals, J.M., Chiritoiu, M., Malhotra, V., Garrido, A., Marti, M.J., Tolosa, E., Bosch, E., Cathomen, T., Gage, F.H., Raya, A., Consiglio, A. Low-frequency genetic variants in GAK enhance Golgi function and protect against Parkinson's disease. (2025) medRxiv. DOI: 10.1101/2025.08.13.25333123

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Molokanova, E., Zhou, T., Vasupal, P., Cherkas, V.P., Narute, P., Ferraz, M.S.A., Reiss, M., Almenar-Queralt, A., Chaldaiopoulou, G., de Souza, J.S., Hemati, H., Downey, F., Olajide, O.O., Thörn Perez, C., Puppo, F., Mesci, P., Pfaff, S.L., Kireev, D., Muotri, A.R., Savchenko, A. Non-genetic neuromodulation with graphene optoelectronic actuators for disease models, stem cell maturation, and biohybrid robotics. (2025) Nature Communications. 16(1):7499. DOI: 10.1038/s41467-025-62637-6

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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) Molekulare Psychiatrie. 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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Kang, S.J., Liu, S., Kim, J.H., Kim, D.I., Oh, T.G., Peng, J., Ye, M., Lee, K.F., Evans, R.M., Goulding, M., Han, S. Thalamic CGRP neurons define a spinothalamic pathway for affective pain. (2025) Verhandlungen der Nationalen Akademie der Wissenschaften der Vereinigten Staaten von Amerika. 122(28):e2505889122. DOI: 10.1073/pnas.2505889122

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Moreira, J.P.C., Carvalho, V.R., Mendes, E.M.A.M., Fallah, A., Sejnowski, T.J., Lainscsek, C., Comstock, L. An open-access EEG dataset for speech decoding: Exploring the role of articulation and coarticulation. (2025) Sci Data. 12(1):1017. DOI: 10.1038/s41597-025-05187-2

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Yao, M., Nagamori, A., Campos Maçãs, S., Azim, E., Sharpee, T., Goulding, M., Golomb, D., Gatto, G. The spinal premotor network driving scratching flexor and extensor alternation. (2025) Cell Reports. 44(6):115845. DOI: 10.1016/j.celrep.2025.115845

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Rowekamp, R.J., Sharpee, T.O. Computations that sustain neural feature selectivity across processing stages. (2025) PLOS Computational Biology. 21(6):e1013075. DOI: 10.1371/journal.pcbi.1013075

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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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Rusu, I., Cecere, Z.T., How, J.J., Quach, K.T., Yemini, E., Sharpee, T.O., Chalasani, S.H. A framework for analyzing C. elegans neural activity using multi-dimensional hyperbolic embedding (2025) bioRxiv. DOI: 10.1101/2021.04.09.439242

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Kirk, L.M., Garcia, G.C., Hanka, D.C., Zatyko, K., Bartol, T., Sejnowski, T.J., Harris, K.M. Presynaptic vesicles supply membrane for axonal bouton enlargement during LTP. (2025) bioRxiv. DOI: 10.1101/2025.04.29.651313

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Goulding, M., Bollu, T., Büschges, A. Sensory Feedback and the Dynamic Control of Movement. (2025) Jahresrückblick Neurowissenschaften. DOI: 10.1146/annurev-neuro-112723-042229

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Mi, X., Chen, A.B., Duarte, D., Carey, E., Taylor, C.R., Braaker, P.N., Bright, M., Almeida, R.G., Lim, J.X., Ruetten, V.M.S., Wang, Y., Wang, M., Zhang, W., Zheng, W., Reitman, M.E., Huang, Y., Wang, X., Li, L., Deng, H., Shi, S.H., Poskanzer, K.E., Lyons, D.A., Nimmerjahn, A., Ahrens, M.B., Yu, G. Fast, accurate, and versatile data analysis platform for the quantification of molecular spatiotemporal signals. (2025) Zelle. DOI: 10.1016/j.cell.2025.03.012

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Bartol, T.M., Ordyan, M., Sejnowski, T.J., Rangamani, P., Kennedy, M.B. A spatial model of autophosphorylation of CaMKII predicts that the lifetime of phospho-CaMKII after induction of synaptic plasticity is greatly prolonged by CaM-trapping. (2025) Front Synaptic Neurosci. 17:1547948. DOI: 10.3389/fnsyn.2025.1547948

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Long-term potentiation (LTP) is a biochemical process that underlies learning in excitatory glutamatergic synapses in the Central Nervous System (CNS). A critical early driver of LTP is autophosphorylation of the abundant postsynaptic enzyme, Ca/calmodulin-dependent protein kinase II (CaMKII). Autophosphorylation is initiated by Ca flowing through NMDA receptors activated by strong synaptic activity. Its lifetime is ultimately determined by the balance of the rates of autophosphorylation and of dephosphorylation by protein phosphatase 1 (PP1). Here we have modeled the autophosphorylation and dephosphorylation of CaMKII during synaptic activity in a spine synapse using MCell4, an open source computer program for creating particle-based stochastic, and spatially realistic models of cellular microchemistry. The model integrates four earlier detailed models of separate aspects of regulation of spine Ca and CaMKII activity, each of which incorporate experimentally measured biochemical parameters and have been validated against experimental data. We validate the composite model by showing that it accurately predicts previous experimental measurements of effects of NMDA receptor activation, including high sensitivity of induction of LTP to phosphatase activity and persistence of autophosphorylation for a period of minutes after the end of synaptic stimulation. We then use the model to probe aspects of the mechanism of regulation of autophosphorylation of CaMKII that are difficult to measure . We examine the effects of "CaM-trapping," a process in which the affinity for Ca/CaM increases several hundred-fold after autophosphorylation. We find that CaM-trapping does not increase the proportion of autophosphorylated subunits in holoenzymes after a complex stimulus, as previously hypothesized. Instead, CaM-trapping may dramatically prolong the lifetime of autophosphorylated CaMKII through steric hindrance of dephosphorylation by protein phosphatase 1. The results provide motivation for experimental measurement of the extent of suppression of dephosphorylation of CaMKII by bound Ca/CaM. The composite MCell4 model of biochemical effects of complex stimuli in synaptic spines is a powerful new tool for realistic, detailed dissection of mechanisms of synaptic plasticity.

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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Hur, M., Bartol, T., Rangamani, P., Sejnowski, T., Mjolsness, E. Synaptic Spine Head Morphodynamics from Graph Grammar Rules for Actin Dynamics. (2025) ArXiv.

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There is a morphodynamic component to synaptic learning by which changes in dendritic (postsynaptic) spine head size are associated with the strengthening or weakening of the synaptic connection between two neurons, in response to the temporal correlation of local presynaptic and postsynaptic signals. These morphological factors are in turn sculpted by the dynamics of the actin cytoskeleton. In this paper, we use Dynamical Graph Grammars (DGGs) implemented within a computer algebra system to model how networks of actin filaments can dynamically grow or shrink, reshaping the spine head. Dynamical Graph Grammars (DGGs) provide a well-defined way to accommodate dynamically changing system structure such as active cytoskeleton represented using dynamic graphs, within nonequilibrium statistical physics under the master equation. We show that DGGs can also incorporate biophysical forces between graph-connected objects at a finer time scale, with specialized DGG kinetic rules obeying biophysical constraints of Galilean invariance, conservation of momentum, and dissipation of conserved global energy. We use graph-local energy functions for cytoskeleton networks interacting with membranes, and derive DGG rules from the specialization of dissipative stochastic dynamics - separated into dissipative and thermal noise rule types - to a mutually exclusive and exhaustive collection of graph-local neighborhood types for the rule left hand sides. The dissipative rules comprise a stochastic version of gradient descent dynamics. The thermal noise rules use a Gaussian approximation of each position coordinate to sample jitter-like displacements. For the spine head model we designed and implemented DGG grammar mathematical sub-models including actin network growth, non-equilibrium statistical mechanics, and filament-membrane mechanical interaction to regulate the re-writing of graph objects. We simulate emergent biophysics of simplified networks of actin polymers and their interactions with membranes. From a biological perspective, we observe regulatory effects of three actin-binding proteins (ABPs) on the membrane size and find evidence supporting mechanisms of membrane growth.

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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Rungratsameetaweemana, N., Kim, R., Chotibut, T., Sejnowski, T.J. Random noise promotes slow heterogeneous synaptic dynamics important for robust working memory computation. (2025) Verhandlungen der Nationalen Akademie der Wissenschaften der Vereinigten Staaten von Amerika. 122(3):e2316745122. DOI: 10.1073/pnas.2316745122

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Cassidy, R.M., Macias, A.V., Lagos, W.N., Ugorji, C., Callaway, E.M. Complementary Organization of Mouse Driver and Modulator Cortico-Thalamo-Cortical Circuits. (2025) Journal of Neuroscience. DOI: 10.1523/JNEUROSCI.1167-24.2024

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Corticocortical (CC) projections in the visual system facilitate hierarchical processing of sensory information. In addition to direct CC connections, indirect cortico-thalamo-cortical (CTC) pathways through the pulvinar nucleus of the thalamus can relay sensory signals and mediate cortical interactions according to behavioral demands. While the pulvinar connects extensively to the entire visual cortex, it is unknown whether transthalamic pathways link all cortical areas or whether they follow systematic organizational rules. Because mouse pulvinar neurons projecting to different areas are spatially intermingled, their input/output relationships have been difficult to characterize using traditional anatomical methods. To determine the organization of CTC circuits, we mapped the higher visual areas (HVAs) of male and female mice with intrinsic signal imaging and targeted five pulvinar→HVA pathways for projection-specific rabies tracing. We aligned post-mortem cortical tissue to in vivo maps for precise quantification of the areas and cell types projecting to each pulvinar→HVA population. Layer 5 corticothalamic (L5CT) "driver" inputs to the pulvinar originate predominantly from primary visual cortex (V1), consistent with the CC hierarchy. L5CT inputs from lateral HVAs specifically avoid driving reciprocal connections, consistent with the "no-strong-loops" hypothesis. Conversely, layer 6 corticothalamic (L6CT) "modulator" inputs are distributed across areas and are biased toward reciprocal connections. Unlike previous studies in primates, we find that every HVA receives disynaptic input from the superior colliculus. CTC circuits in the pulvinar thus depend on both target HVA and input cell type, such that driving and modulating higher-order pathways follow complementary connection rules similar to those governing first-order CT circuits. Understanding the function of the pulvinar will require knowledge of its anatomical connections. Using state-of-the-art rabies tracing, we establish a map of brain-wide and CTC pulvinar connections. While the primate tectopulvinar pathway selectively targets dorsal visual areas, we find ubiquitous SC input in the mouse. This extrageniculate projection supports unconscious visually-guided behavior, suggesting that all visual cortical areas contribute to such functions in mice. Our results also unify longstanding anatomical hypotheses. Namely, "driver" CTC inputs are feedforward relays and adhere to the "no-strong-loops" hypothesis. "Modulator" L6CT inputs are overrepresented in the target HVA, reflecting the reciprocal connectivity described in previous bulk tracing studies. Together, these findings constitute a comprehensive map to guide future experimental and theoretical studies of pulvinar function.

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Waitt Advanced Biophotonics Center

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

2025 PUBLICATIONS

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