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bioRxiv · 10.1101/2025.07.30.665413

Sleep deprivation selectively reactivates hippocampal CA1 pyramidal neurons.

Wang, Y.·Walsh, E. N.·Resch, J. M.·Lyons, L. C.·Abel, T.
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Abstract

Sleep supports a variety of physiological processes, ranging from metabolic to immune system homeostasis, and plays a critical role in cognition and memory. A brief period of sleep loss impairs memory, particularly hippocampus-dependent memories, and alters molecular signaling and synaptic plasticity in the hippocampus. Studies have shown that sleep deprivation (SD), alters neuronal activation as indicated by broad changes in gene expression signatures and by the altered expression of c-Fos, an immediate early gene that functions as a molecular marker of neuronal activity. In the present study, we examined hippocampal subregion-specific c-Fos induction patterns via immunohistochemical staining. We find that CA1 pyramidal neurons exhibit the most robust c-Fos induction after SD. Using an activity-driven ribosomal tagging system and a repeated SD model, we labeled sleep deprivation activated CA1 neurons and observed a population of excitatory neurons in area CA1 that are reactivated by repeated SD. Using the c-Fos-RiboTag system that enables the isolation of ribosomes attached mRNA from labeled neurons, we performed fosTRAP-seq and identified activity-dependent gene expression changes in c-Fos+ CA1 neurons. Our results revealed that synapse organization, protein dephosphorylation, cellular response to endogenous stimulus (such as insulin) are upregulated, whereas mRNA processing and splicing being downregulated. In summary, our study provides a detailed view of the activation of hippocampal neurons after SD, revealing a subset of CA1 pyramidal neurons that have higher sensitivity to the effect of sleep loss, shown as reactivation during repeated SD, allows investigation of molecular changes in neurons specifically impacted by repeated sleep loss. Our work uncovers a population of CA1 pyramidal neurons that are sensitive to repeated sleep loss and sheds light on a possible connection between acute and chronic sleep loss at the cellular and molecular levels. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/665413v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1cfa351org.highwire.dtl.DTLVardef@eb387dorg.highwire.dtl.DTLVardef@c9cf6forg.highwire.dtl.DTLVardef@1518b12_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wang, Y., Walsh, E. N., Resch, J. M., Lyons, L. C., Abel, T.. 2025-07-31. Sleep deprivation selectively reactivates hippocampal CA1 pyramidal neurons.. https://doi.org/10.1101/2025.07.30.665413

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