An Excitatory Circuit in Perioculomotor Midbrain for Non-REM Sleep Control
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PROVIDER: PRJNA513052 | ENA |
REPOSITORIES: ENA
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Project description:The perioculomotor (pIII) region of the midbrain was postulated as a sleep-regulating center in the 1890s but largely neglected in subsequent studies. Using activity-dependent labeling and gene-expression profiling, we identified pIII neurons that promote non-REM (NREM) sleep.
2019-05-01 | GSE124681 | 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: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
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:Although at the organismal level sleep is defined as a behavioral state, at the level of the cerebral cortex sleep has a distinct local and use-dependent aspect. This observation raises the question whether sleep is a functional property of a complex brain or occurs at the level of neuronal assemblies with populations that were active more during wakefulness needing more intense sleep to recover. Here we show that primary cortical cultures have the capacity to change between sleep- and wake-like states that share key signatures with their in vivo counterparts. Cortical cultures initially exhibit random firing activity that is gradually replaced by a M-bM-^@M-^\sleep-likeM-bM-^@M-^] synchronized burst-pause firing activity as neurons mature and make connections. When stimulated with excitatory neurotransmitters, transient tonic firing is observed, followed by the reappearance of a M-bM-^@M-^\sleep-likeM-bM-^@M-^] state. Besides electrophysiological similarities also the transcriptional profile of stimulated cortical cultures greatly resembles that of the cortex of sleep deprived animals. We then used our in vitro model to map the metabolic pathways activated by the M-bM-^@M-^\wake-likeM-bM-^@M-^] state and found evidence for increased lysolipid release, strongly suggesting that sleep plays a role in neuronal membrane homeostasis. With our in vitro model the cellular and molecular consequences of sleep loss and the genetic determinants of disturbed sleep can now be investigated in a dish. Keywords: stress response For the in vivo transcriptome analyses mice were sleep deprived for 6 hours and brain harvested immediately afterwards. For the in vitro analyses, cortical cultures were stimulated with a neurotransmitter cocktail and cells harvested 3 hours afterwards. Control mice were kept undisturbed in their home cage and control cultures were sham stimulated with water. Also, another set of sleep deprived mice as well as stimulated cultures were allowed to recover before being sampled the next day at the time of day at which sleep deprivation or stimulation started the day before).
2012-08-31 | E-GEOD-33491 | biostudies-arrayexpress
Project description:Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABAARs). BZ clinical use is hampered by tolerance and withdrawal symptoms, which include heightened seizure susceptibility, panic, and sleep disturbances. Here, we undergo a comprehensive investigation of inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Using quantitative proteomics approaches, we reveal cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways, highlighted by Ca2+/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling.
2023-10-24 | PXD041332 | Pride
Project description:The preoptic area (POA) of the hypothalamus is known to be crucial for sleep generation, but the spatial intermingling of sleep- and wake-promoting neurons makes it difficult to dissect the sleep control circuit. Here we identified a population of POA sleep-promoting neurons based on their projection target. Using a lentivirus for retrograde labeling with channelrhodopsin-2 (ChR2) followed by optogenetic manipulation and recording, we found that the POA GABAergic neurons projecting to the tuberomammillary nucleus (TMN) are both sleep active and sleep promoting. Cell type- and projection-specific rabies tracing revealed the presynaptic inputs to these neurons, including an amygdala GABAergic input that promotes wakefulness. Using single-cell RNA-seq, we identified several molecular markers for these neurons, and optogenetic activation of the POA neurons labeled by these markers confirmed their sleep-promoting effects. Together, these findings define a group of sleep-promoting neurons functionally, anatomically, and genetically.
2017-05-23 | GSE79108 | GEO
Project description:Although at the organismal level sleep is defined as a behavioral state, at the level of the cerebral cortex sleep has a distinct local and use-dependent aspect. This observation raises the question whether sleep is a functional property of a complex brain or occurs at the level of neuronal assemblies with populations that were active more during wakefulness needing more intense sleep to recover. Here we show that primary cortical cultures have the capacity to change between sleep- and wake-like states that share key signatures with their in vivo counterparts. Cortical cultures initially exhibit random firing activity that is gradually replaced by a “sleep-like” synchronized burst-pause firing activity as neurons mature and make connections. When stimulated with excitatory neurotransmitters, transient tonic firing is observed, followed by the reappearance of a “sleep-like” state. Besides electrophysiological similarities also the transcriptional profile of stimulated cortical cultures greatly resembles that of the cortex of sleep deprived animals. We then used our in vitro model to map the metabolic pathways activated by the “wake-like” state and found evidence for increased lysolipid release, strongly suggesting that sleep plays a role in neuronal membrane homeostasis. With our in vitro model the cellular and molecular consequences of sleep loss and the genetic determinants of disturbed sleep can now be investigated in a dish. Keywords: stress response
2012-08-31 | GSE33491 | GEO
Project description:Neurons in the arcuate nucleus (ARC) sense the fed/fasted state and regulate hunger. ARCAgRP neurons release GABA, NPY and the melanocortin-4 receptor (MC4R) antagonist, AgRP, and are activated by fasting1-4. When stimulated, they rapidly and potently drive hunger5,6. ARCPOMC neurons, in contrast, release the MC4R agonist, α-MSH, and are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and their activity leads to decreased hunger2,4,7. Together, ARCAgRP and ARCPOMC neurons constitute the ARC feeding center. Against this, however, is the finding that ARCPOMC neurons, unlike ARCAgRP neurons, fail to affect food intake over the timescale of minutes to hours following opto- or chemogenetic stimulation5,8. This suggests a rapidly acting component of the ARC satiety pathway is missing. Here, we show that excitatory ARC neurons identified by expression of vesicular glutamate transporter 2 (VGLUT2) and the oxytocin receptor, unlike ARCPOMC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARCAgRP projections on MC4R-expressing neurons in the paraventricular hypothalamus (PVHMC4R neurons), which are known to mediate satiety9. ARCPOMC neurons also send dense projections to the PVH. Importantly, the α-MSH they release post-synaptically potentiates glutamatergic synaptic activity onto PVHMC4R neurons – including that emanating from ARCVglut2 neurons. This suggests a means by which α-MSH can bring about satiety – via postsynaptic potentiation of this novel ARCVglut2 to PVHMC4R satiety circuit. Thus, while fast (GABA and NPY) and slow (AgRP) ARC hunger signals are delivered together by ARCAgRP neurons10,11, the temporally analogous satiety signals from the ARC, glutamate and α-MSH, are delivered separately by two parallel, interacting projections (from ARCVGLUT2 and ARCPOMC neurons). Discovery of this rapidly acting excitatory ARC → PVH satiety circuit, and its regulation by α-MSH, provides new insight into regulation of hunger/satiety.
2016-11-21 | GSE81789 | GEO
Project description:Training-induced excitatory synaptogenesis in a prefrontal cortex circuit is required for effort/reward evaluation
| PRJNA716510 | ENA