Fxr1 regulates sleep and synaptic homeostasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA580288 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Circadian rhythms are present across almost all species and affect several physiological and behavioral aspects of living organisms. The evolutionary advantage conferred by these rhythms could be their anticipatory properties. In the nervous system, anticipation is particularly interesting due to the spatiotemporal constraints derived by the highly compartmentalized neuronal structure. Previous work has confirmed that 900 genes are expressed in the mouse forebrain in robustly rhythmic fashion, and 180 transcripts are equally robustly circadian at the synapse. Interestingly, mRNAs are found in higher amounts at the end of the dark phase, and decrease exponentially during the first hours of light. This pattern resembles the “sawtooth” pattern of homeostatic sleep pressure. To further characterize this phenotype we propose to compare the synaptic transcriptome of sleep deprived mice to its control base line. This work would shed light into the emerging field of synaptic RNA transport and translation and its regulatory inputs. Hopefully, the results will yield to two different findings: the circadian and activity potential to regulate synaptic transport of RNA and the classification of transcripts deferentially regulated by both processes.
2019-02-28 | E-MTAB-7347 | biostudies-arrayexpress
Project description:The circadian clock drives daily changes of physiology, including sleep-wake cycles, by regulating transcription, protein abundance and function. Circadian phosphorylation controls cellular processes in peripheral organs, but little is known about its role in brain function and synaptic activity. We applied advanced quantitative phosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24h, accurately quantifying almost 8,000 phosphopeptides. Remarkably, half of the synaptic phosphoproteins, including numerous kinases, had large-amplitude rhythms peaking at rest-activity and activity-rest transitions. Bioinformatic analyses revealed global temporal control of synaptic function via phosphorylation, including synaptic transmission, cytoskeleton reorganization and excitatory/inhibitory balance. Remarkably, sleep deprivation abolished 98% of all phosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are main drivers of synaptic phosphorylation, responding to both sleep and wake pressures.
2019-10-14 | PXD010697 | Pride
Project description:Circadian and Sleep regulation of synaptic RNA
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Project description:Every day, we sleep for a third of the day. Sleep is important for cognition, brain waste clearance, metabolism, and immune responses. Homeostatic regulation of sleep is maintained by progressively rising sleep need during wakefulness, which then dissipates during sleep. The molecular mechanisms governing sleep are largely unknown. Here, we used a combination of single-cell RNA sequencing and cell-type specific proteomics to interrogate the molecular and functional underpinnings of sleep. Different cell-types in the brain regions show similar transcriptional response to sleep need whereas sleep deprivation changes overall expression indicative of altered antigen processing, synaptic transmission and cellular metabolism in brainstem, cortex and hypothalamus, respectively. Increased sleep need enhances expression of transcription factor Sox2, Mafb, and Zic1 in brainstem; Hlf, Cebpb and Sox9 in cortex, and Atf3, Fosb and Mef2c in hypothalamus. Results from cell-type proteome analysis suggest that sleep deprivation changes abundance of proteins in cortical neurons indicative of altered synaptic vesicle cycles and glucose metabolism whereas in astrocytes it alters the abundance of proteins associated with fatty acid degradation. Similarly, phosphoproteomics of each cell type demonstrates large shifts in site-specific protein phosphorylation in neurons and astrocytes of sleep deprived mice. Our results indicate that sleep deprivation regulates transcriptional, translational and post-translational responses in a cell-specific manner and advances our understanding of the cellular and molecular mechanisms that govern sleep-wake homeostasis in mammals.
2022-10-13 | PXD018334 | Pride
Project description:Comparison of ribosome associated RNA between Ctrl vs EW (or SD) and EW (or SD) vs EWFxr1 (or SDFxr1)
2020-08-14 | GSE139576 | GEO
Project description:In Alzheimer’s disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment. Hippocampal hyperactivity and decreased sleep quality are associated with early AD, but their basis is poorly understood. We find that homeostatic mechanisms transiently counteract increased excitatory drive of hippocampal CA1 neurons in AppNL-G-F mice, but fail to stabilize it at control levels. Spatial transcriptomics (ST) analysis identifies the Pmch gene encoding Melanin-Concentrating Hormone (MCH) as part of the adaptive response in AppNL-G-F mice. Hypothalamic MCH peptide is produced in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission and modulates firing rate homeostasis in hippocampal neurons. Moreover, MCH reverses the increased excitatory drive of CA1 neurons in AppNL-G-F mice. Consistent with our finding that a reduced fraction of MCH-neurons is active in AppNL-G-F mice, these animals spend less time in rapid eye movement (REM) sleep. In addition, MCH-axons projecting to CA1 become progressively impaired in both AppNL-G-F mice and AD patients. Our findings identify the MCH-system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampal-dependent functions.
2023-09-07 | GSE225181 | GEO
Project description: Not available
| S-EPMC7604579 | biostudies-literature
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 abnormalities are common with aging. Studies show that sleep plays important roles in brain functions, and loss of sleep is associated with increased risks for neurological diseases. In this study, we used next generation RNA-sequencing to explore effects of age on transcriptome changes between sleep and sleep deprivation in medial prefrontal cortex. Old mice showed a 30% reduction in the number of genes significantly altered between sleep/wake, and, in general, had smaller magnitudes of changes in differentially expressed genes compared to young. Gene ontology analysis revealed differential age-effects on certain pathways. Compared to young mice, many of the wake-active functions were similarly induced by sleep deprivation in old mice, whereas many of the sleep-active pathways were attenuated in old mice. We found similar magnitude of changes in a number of synaptic homeostasis genes (Fos, Arc, and Bdnf) induced by sleep deprivation, suggesting intact synaptic upscaling during extended wakefulness with aging. However, sleep-activated processes, such as DNA repair, synaptogenesis, and axon guidance, were sensitive to the effect of aging. Old mice expressed elevated levels of immune-related genes when compared to young mice, and enrichment analysis using cell-type specific markers indicated up-regulation of microglia and oligodendrocyte genes in old mice. Moreover, gene sets of the two cell types showed age-specific sleep/wake regulation. This study indicates alteration of molecular changes with sleep in old mice.
2020-01-03 | GSE128770 | GEO
Project description:Homeostatic scaling is a global form of synaptic plasticity used by neurons to adjust overall synaptic weight and maintain neuronal firing rates while protecting information coding. While homeostatic scaling has been demonstrated in vitro, a clear physiological function of this plasticity type has not been defined. Sleep is an essential process that modifies synapses to support cognitive functions such as learning and memory. Evidence suggests that information coding during wake drives synapse strengthening which is offset by weakening of synapses during sleep .Here we use biochemical fractionation, proteomics and in vivo two-photon imaging to characterize wide-spread changes in synapse composition in mice through the wake/sleep cycle. We find that during the sleep phase, synapses are weakened through dephosphorylation and removal of synaptic AMPA-type glutamate receptors (AMPARs) driven by the immediate early gene Homer1a and signaling from group I metabotropic glutamate receptors (mGluR1/5), consistent with known mechanisms of homeostatic scaling-down in vitro. Further, we find that these changes are important in the consolidation of contextual memories. While Homer1a gene expression is driven by neuronal activity during wake, Homer1a protein targeting to synapses serves as an integrator of arousal and sleep need through signaling by the wake-promoting neuromodulator noradrenaline (NA) and sleep-promoting modulator adenosine. During sleep or periods of increased sleep need Homer1a enters synapses where it remodels mGluR1/5 signaling complexes to promote AMPAR removal. Thus, we have characterized widespread changes occurring at synapses through the wake/sleep cycle and demonstrated that known mechanisms of homeostatic scaling-down previously demonstrated only in vitro are active in the brain during sleep to remodel synapses, contributing to memory consolidation.
2017-02-13 | PXD004537 | Pride