Biology subjects

Walsh, E. N.

Publications and source records attributed to Walsh, E. N..

4 recordsLinked to original sources

bioRxiv2025

Sleep deprivation selectively reactivates hippocampal CA1 pyramidal neurons.

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

neuroscience↗

bioRxiv2024

Differential effects of PDE4A5 on cAMP-dependent forms of long-term potentiation

cAMP signaling is critical for memory consolidation and certain of forms long-term potentiation (LTP). Phosphodiesterases (PDEs), enzymes that degrade the second messenger cAMP and cGMP, are highly conserved during evolution and represent a unique set of drug targets, given the involvement of these enzymes in several pathophysiological states including brain disorders. The PDE4 family of cAMP selective PDEs, exert regulatory roles in memory and synaptic plasticity, but the specific roles of distinct PDE4 isoforms in these processes are poorly understood. Building on our previous work demonstrating that spatial and contextual memory deficits were caused by expressing selectively the long isoform of the PDE4A subfamily, PDE4A5, in hippocampal excitatory neurons, we now investigate the effects of PDE4A isoforms on different cAMP-dependent forms of LTP. We find that PDE4A5 impairs long-lasting LTP induced by theta burst stimulation (TBS) while sparing long-lasting LTP induced by spaced 4-train stimulation (4X100Hz). This effect requires the unique N-terminus of PDE4A5 and is specific to this long isoform. Targeted overexpression of PDE4A5 in area CA1 is sufficient to impair TBS-LTP, suggesting that cAMP levels in the postsynaptic neuron are critical for TBS-LTP. Our results shed light on the inherent differences among the PDE4A subfamily isoforms, emphasizing the importance of the long isoforms, which have a unique N-terminal region. Advancing our understanding of the function of specific PDE isoforms will pave the way for developing isoform-selective approaches to treat the cognitive deficits that are debilitating aspects of psychiatric, neurodevelopmental, and neurodegenerative disorders. Key PointsO_LIHippocampal overexpression of a PDE4A subfamily long isoform, PDE4A5, but not a short isoform PDE4A1, impairs spatial and contextual fear memory and the N-terminus of PDE4A5 is important for this effect. C_LIO_LIHippocampal overexpression of PDE4A isoforms, PDE4A1 and PDE4A5 do not impair LTP induced by spaced tetanic stimulation at the CA3-CA1 synapses. C_LIO_LIHippocampal overexpression of PDE4A5, but not PDE4A1 or the N-terminus truncated PDE4A5 (PDE4A5{Delta}4) selectively impairs LTP induced by theta burst stimulation (TBS) at the CA3-CA1 synapses and expression of PDE4A5 in area CA1 is sufficient for the TBS-LTP deficit. C_LIO_LIThese results suggest that PDE4A5, through its N-terminus, regulates cAMP pools that are critical for memory consolidation and expression of TBS-LTP at the CA3-CA1 synapses. C_LI O_FIG O_LINKSMALLFIG WIDTH=148 HEIGHT=200 SRC="FIGDIR/small/592525v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1ee4ccdorg.highwire.dtl.DTLVardef@1f43c3corg.highwire.dtl.DTLVardef@19eb64dorg.highwire.dtl.DTLVardef@d2bab0_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT Spaced tetanic stimulation and TBS induce cAMP synthesis and activation of PKA to promote signaling cascades that facilitate expression of long-lasting LTP at the CA3-CA1 synapses. PDE4A5 overexpression in the hippocampus selectively impairs cAMP and PKA dependent TBS-LTP at the CA3-CA1 synapses, while sparing LTP induced by spaced tetanization. C_FIG

neuroscience↗

bioRxiv2022

Chemogenetic enhancement of cAMP signaling renders hippocampal synaptic plasticity resilient to the impact of acute sleep deprivation

Sleep facilitates memory storage and even brief periods of sleep loss lead to impairments in memory, particularly memories that are hippocampus dependent. In previous studies, we have shown that the deficit in memory seen after sleep loss is accompanied by deficits in synaptic plasticity. Our previous work has also found that sleep deprivation is associated with reduced levels of cyclic adenosine monophosphate (cAMP) in the hippocampus, and that the reduction of cAMP mediates the diminished memory performance. Based on these findings, we hypothesized that cAMP acts as a mediator for not only the cognitive deficits caused by sleep deprivation, but also the observed deficits in synaptic plasticity. In this study, we expressed the heterologous Drosophila melanogaster Gs-protein coupled octopamine receptor (DmOct{beta}1R) in mouse hippocampal neurons. This receptor is selectively activated by the systemically injected ligand (octopamine), thus allowing us to increase cAMP levels in hippocampal neurons during a five-hour sleep deprivation period. Our results show that chemogenetic enhancement of cAMP during the period of sleep deprivation prevents deficits in a persistent form of long-term potentiation (LTP) that is induced at the Schaffer collateral synapses in the hippocampal CA1 region. We also found that elevating cAMP levels only in the early or later half of sleep deprivation successfully prevented LTP deficits. These findings reveal that cAMP-dependent signaling pathways are key mediators of sleep deprivation at the synaptic level. Targeting these pathways could be useful in designing strategies to prevent the impact of sleep loss. Significance statementInsufficient sleep is an issue with significant health and socioeconomic implications. This includes a negative impact on memory consolidation. Previous studies in mice found that acute sleep deprivation leads to deficits in hippocampal synaptic plasticity and memory, which are associated with reduced levels of the signaling molecule cAMP. In this study, we used a chemogenetic strategy to enhance cAMP levels in specific hippocampal neurons during sleep deprivation. We found that this made synaptic plasticity resilient to the negative effects of sleep deprivation. These findings reveal that cAMP-dependent signaling pathways are key mediators of sleep deprivation and that targeting these pathways could be useful in designing strategies to prevent the impact of sleep loss.

neuroscience↗

bioRxiv2021

Endoplasmic Reticulum Chaperone Genes Encode Effectors of Long-Term Memory

The mechanisms underlying memory loss associated with Alzheimers disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of a group of genes encoding chaperones that localize to the endoplasmic reticulum (ER), which function to traffic plasticity-related proteins to the cell surface during long lasting forms of synaptic plasticity and memory. Nr4a transcription factors and ER chaperones are linked to ADRD in human samples as well as mouse models, and overexpressing Nr4a1 or the ER chaperone Hspa5 ameliorates the long-term memory deficits in a tau-based mouse model of ADRD, pointing towards novel therapeutic approaches for treating memory loss. Thus, our findings establish protein folding in the ER as a novel molecular concept underlying long-term memory, providing new insights into the mechanistic basis of cognitive deficits in dementia. One-Sentence SummaryMolecular approaches establish protein folding in the endoplasmic reticulum as a novel molecular concept underlying synaptic plasticity and memory, serving as a switch to regulate protein folding and trafficking, and driving cognitive deficits in neurodegenerative disorders.

neuroscience↗