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Sleep deprivation has far-reaching consequences on the brain and behavior, impacting memory, attention, and metabolism. Previous research has focused on gene expression changes in individual brain regions, such as the hippocampus or cortex. Therefore, it is unclear how uniformly or heterogeneously sleep loss affects the brain. Here, we use spatial transcriptomics to define the impact of a brief period of sleep deprivation across the brain in male mice. We find that sleep deprivation induced pronounced differences in gene expression across the brain, with the greatest changes in the hippocampus, neocortex, hypothalamus, and thalamus. Both the differentially expressed genes and the direction of regulation differed markedly across regions. Importantly, we developed bioinformatic tools to register tissue sections and gene expression data into a common anatomical space, allowing a brain-wide comparison of gene expression patterns between samples. Our results suggest that distinct molecular mechanisms acting in discrete brain regions underlie the biological effects of sleep deprivation., (© 2023. The Author(s).)

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 (SD) is associated with reduced levels of cyclic adenosine monophosphate (cAMP) in the hippocampus and that the reduction of cAMP mediates the diminished memory observed in sleep-deprived animals. 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 Gαs-protein-coupled octopamine receptor (DmOctβ1R) 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 5-h 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 in either the first or second 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., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Walsh et al.)

The mechanisms underlying memory loss associated with Alzheimer's 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 genes encoding chaperones that localize to the endoplasmic reticulum (ER). These chaperones fold and traffic plasticity-related proteins to the cell surface during long-lasting forms of synaptic plasticity and memory. Dysregulation of Nr4a transcription factors and ER chaperones is linked to ADRD, and overexpressing Nr4a1 or the chaperone Hspa5 ameliorates long-term memory deficits in a tau-based mouse model of ADRD, pointing toward innovative therapeutic approaches for treating memory loss. Our findings establish a unique molecular concept underlying long-term memory and provide insights into the mechanistic basis of cognitive deficits in dementia.

Age-associated cognitive impairments affect an individual's quality of life and are a growing problem in society. Therefore, therapeutic strategies to treat age-related cognitive decline are needed to enhance the quality of life among the elderly. Activation of the Nr4a family of transcription factors has been closely linked to memory formation and dysregulation of these transcription factors is thought to be associated with age-related cognitive decline. Previously, we have shown that Nr4a transcription can be activated by synthetic bisindole-derived compounds (C-DIM). C-DIM compounds enhance synaptic plasticity and long-term contextual fear memory in young healthy mice. In this study, we show that activation of Nr4a2 by 1,1-bis(3'-Indolyl)-1-(p-chlorophenyl) methane (C-DIM12), enhances long-term spatial memory in young mice and rescues memory deficits in aged mice. These findings suggest that C-DIM activators of Nr4a transcription may be suitable to prevent memory deficits associated with aging., (Copyright © 2019 Elsevier Inc. All rights reserved.)