Similar Datasets
Project description:The fragile X autosomal homolog 1 (Fxr1) is regulated by lithium and has been GWAS-associated with schizophrenia and insomnia. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and involves both cell-autonomous and system-level processes such as sleep. We examined the contribution of Fxr1 to cell-autonomous homeostatic synaptic scaling and neuronal responses to sleep loss, using a combination of gene overexpression and Crispr/Cas9-mediated somatic knockouts to modulate gene expression. Our findings indicate that Fxr1 is downregulated during both scaling and sleep deprivation via a glycogen synthase kinase 3 beta (GSK3β)-dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of surface AMPA receptors and synaptic strength. Preventing the downregulation of Fxr1 during sleep deprivation results in altered EEG signatures. Furthermore, sequencing of neuronal translatomes revealed the contribution of Fxr1 to changes induced by sleep deprivation. These findings uncover a role of Fxr1 as a shared signaling hub between cell-autonomous homeostatic plasticity and system-level responses to sleep loss, with potential implications for neuropsychiatric illnesses and treatments.
| S-EPMC7604579 | biostudies-literature
Project description:Fxr1 regulates sleep and synaptic homeostasis
| PRJNA580288 | ENA
Project description:The response to sleep loss, induced by experimental sleep deprivation (SD), provides insight into the function of sleep. Earlier observations have shown an overall increase in synaptic strength and number of cortical, glutamate, AMPA receptor (AMPAR) synapses in response to SD that is recovered by sleep. However, other aspects of glutamatergic transmission, including NMDA receptor mediated neurotransmission and related upstream synaptic regulators of the glutamate synapse function, have not been well examined. Following SD, we report increased AMPA/NMDA ratio in whole cell recordings of frontal cortical (FC) pyramidal neurons of layers 2-3. Additionally, the ratio of silent/active synapse is decreased after SD reflecting decreased silent synapses and plastic potential to convert silent NMDA to active AMPA synapses. All aspects recover with sleep and are associated with differentially expressed genes (DEGs) affecting glutamatergic synaptic phenotype. The DEGs are enriched for a functional group of synaptic shaping cellular components (SSCs) controling glutamate synapse phenotype, overlap with autism risk genes and are primarily observed in a subtype of excitatory pyramidal neurons that project intra-telencephalically (ExIT neurons). Upstream, sleep-related control is suggested by significant enrichment of genes controlled by transcription factor, MEF2c and nuclear HDAC4, a repressor of MEF2c transcriptional activation. Taken together, we propose a functional role of sleep/wake in FC controlling gene expression, regulating an oscillation of glutamate-synaptic phenotypes that facilitates motor learning and training, and if dysfunctional, increases risk for autism.
2025-02-10 | GSE256140 | GEO
Project description:Sleep supports lifelong brain health and cognition. Sleep loss in early life can drive lasting changes in adult behavior, indicating sleep plays a distinct but poorly understood role supporting brain development. We systematically examined the molecular and behavioral adaptations and synaptic consequences of acute sleep deprivation (SD) in developing and adult mice. Developing mice lack robust adaptations to SD, exacerbating cognitive deficits. Synapse proteome and phosphoproteome analysis revealed profound vulnerability to SD in developing mice, including immediate impacts on synaptogenesis and key aspects of brain development. With maturation, a unified biochemical effect of sleep on synapses emerges, together with robust adaptations and resilience to SD. Our findings show sleep plays a distinct role in early life supporting synapse development, transitioning to homeostatic functions with maturation.
2024-10-08 | PXD047381 | Pride
Project description:Why we sleep is still one of the most perplexing mysteries in biology. Strong evidence, however, indicates that sleep is necessary for normal brain function and that the need to sleep is a tightly regulated process. Surprisingly molecular mechanisms that determine the need to sleep are incompletely described. Moreover, very little is known about transcriptional changes that specifically accompany the accumulation and discharge of sleep need. In this study we present an integrated 2 cross-laboratory analysis of the effects of sleep deprivation (SD) in gene expression in the mouse cortex. We also evaluate changes in gene expression genome-wide following various lengths of subsequent recovery sleep. (RS). We demonstrate that changes in gene expression specifically linked to SD or RS, and not to technical factors (e.g. the assay used), requires a novel analysis methodology not previously utilized in the field of sleep research.
2016-09-07 | GSE78215 | GEO
Project description:The functions of sleep remain elusive, but a strong link exists between sleep need and neuronal plasticity. We tested the hypothesis that plastic processes during wake lead to a net increase in synaptic strength and sleep is necessary for synaptic renormalization. We found that, in three Drosophila neuronal circuits, synapse size or number increases after a few hours of wake and decreases only if flies are allowed to sleep. A richer wake experience resulted in both larger synaptic growth and greater sleep need. Finally, we demonstrate that the gene Fmr1 (fragile X mental retardation 1) plays an important role in sleep-dependent synaptic renormalization.
| S-EPMC3128387 | biostudies-literature
Project description:The hippocampus is essential for consolidating transient experiences into long-lasting memories. Memory consolidation is facilitated by postlearning sleep, although the underlying cellular mechanisms are largely unknown. We took an unbiased approach to this question by using a mouse model of hippocampally mediated, sleep-dependent memory consolidation (contextual fear memory). Because synaptic plasticity is associated with changes to both neuronal cell membranes (e.g., receptors) and cytosol (e.g., cytoskeletal elements), we characterized how these cell compartments are affected by learning and subsequent sleep or sleep deprivation (SD). Translating ribosome affinity purification was used to profile ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different cell populations (whole hippocampus, Camk2a+ neurons, or highly active neurons with phosphorylated ribosomal subunit S6 [pS6+]). We examined how transcript profiles change as a function of sleep versus SD and prior learning (contextual fear conditioning; CFC). While sleep loss altered many cytosolic ribosomal transcripts, CFC altered almost none, and CFC-driven changes were occluded by subsequent SD. In striking contrast, SD altered few transcripts on membrane-bound (MB) ribosomes, while learning altered many more (including long non-coding RNAs [lncRNAs]). The cellular pathways most affected by CFC were involved in structural remodeling. Comparisons of post-CFC MB transcript profiles between sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons and protein synthesis in highly active pS6+ (putative "engram") neurons as biological processes disrupted by SD. These findings provide insights into how learning affects hippocampal neurons and suggest that the effects of SD on memory consolidation are cell type and subcellular compartment specific.
2022-10-25 | GSE216163 | GEO
Project description:Why we sleep is still one of the most perplexing mysteries in biology. Strong evidence, however, indicates that sleep is necessary for normal brain function and that the need to sleep is a tightly regulated process. Surprisingly molecular mechanisms that determine the need to sleep are incompletely described. Moreover, very little is known about transcriptional changes that specifically accompany the accumulation and discharge of sleep need. In this study we present an integrated 2 cross-laboratory analysis of the effects of sleep deprivation (SD) in gene expression in the mouse cortex. We also evaluate changes in gene expression genome-wide following various lengths of subsequent recovery sleep. (RS). We demonstrate that changes in gene expression specifically linked to SD or RS, and not to technical factors (e.g. the assay used), requires a novel analysis methodology not previously utilized in the field of sleep research. Cortical samples from mice were analyzed, from groups that were sleep deprived, sleep deprived and allowed to recover for 1, 2, 3, or 6 hours, and circadian control animals that were not sleep deprived. The experimental protocol began at lights on (ZT0) with 13 mice: 1 sacrificed, 4 control mice left undisturbed, and 8 mice kept awake with gentle brushing when attempting to sleep. After 5 hours of sleep deprivation the mice were randomly assigned to recovery sleep or continued sleep deprivation, and at fixed intervals the mice were sacrificed, dissected and the left cortex retained. The experimental protocol was repeated 7 times, one animal per timepoint per experimental day, so that 7 independent experiments are represented for each timepoint. All animals were acclimated to the brushing and tapping on cages used during sleep deprivationfor 6 days, and dissections and tissue collection were performed by a single experimenter.
2016-09-07 | E-GEOD-78215 | biostudies-arrayexpress
Project description:Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring.
| S-EPMC4447375 | biostudies-literature
Project description:To unravel the underlying mechanisms how neuronal Mettl3 loss induces the activation of microglia, we performed RNA-sequencing (RNA-seq) with the thalamic tissues of 2- and 4-month-old Ctrl and cKO mice, respectively.
2025-02-12 | GSE262033 | GEO