Calcineurin is a central regulator of process S and governs sleep homeostasis in locus coeruleus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1079795 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28074062.fastq.gz | Fastqsanger.gz | |||
| SRR28074063.fastq.gz | Fastqsanger.gz | |||
| SRR28074064.fastq.gz | Fastqsanger.gz | |||
| SRR28074065.fastq.gz | Fastqsanger.gz | |||
| SRR28074066.fastq.gz | Fastqsanger.gz |
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Project description:Sleep need accumulates during waking and dissipates during sleep to maintain sleep homeostasis (process S). Besides regulation of daily sleep amount, a hallmark of process S is the homeostatic sleep regulation: sleep loss causes increased amount and intensity of subsequent recovery sleep. The central regulators of process S and specific brain regions that govern sleep homeostasis in mammals remain unclear. Here, we report that enhanced calcineurin activity in the mouse brain neurons sharply increases non-rapid eye movement sleep (NREMS) to average ~17-h/day. Knockout of calcineurin in adult mouse brain diminishes baseline NREMS to average ~4-h/day, but also abolishes recovery NREMS owing to inability to accumulate sleep need during wakefulness. Calcineurin promotes baseline NREMS in both excitatory and inhibitory neurons and by antagonizing PKA and activating SIK3 via S551 dephosphorylation. Moreover, calcineurin is specifically required in the locus coeruleus-noradrenergic (LCNA) neurons for the transcriptomic and homeostatic responses to sleep loss. While chemo-/optogenetic activation of LCNA neurons increases the amount and intensity of NREMS, ablation and inhibition of LCNA neurons diminish recovery NREMS following sleep deprivation. These results establish calcineurin as a central regulator of process S and identify LC as a potential sleep need center that governs NREMS homeostasis in mice.
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Project description:Research into mechanisms underlying sleep traditionally relies on electrophysiology and genetics. Because sleep can only be measured on whole animals by behavioral observations and physical means, no sleep research was initiated by biochemical and chemical biological approaches. We used phosphorylation sites of kinases important for sleep as targets for biochemical and chemical biological approaches. Sleep was increased in mice carrying a threonine-to-alanine substitution at residue T469 of salt inducible kinase 3 (SIK3). Our biochemical purification and photo-crosslinking revealed calcineurin dephosphorylation, both in vitro and in vivo, of SIK3 at T469 and S551, but not T221. Knocking down calcineurin regulatory subunit reduced daily sleep by more than 5 hours, exceeding all known mouse mutants. Our work uncovered a critical physiological role for calcineurin in sleep and pioneered biochemical purification and chemical biology as effective approaches to study sleep.
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Project description:Analysis of the effects of sleep deprivation, recovery sleep, and three time-of-day controls on seven brain regions laser microdissected from mouse brain. The regions include the locus coeruleus, suprachiasmatic nucleus, hypocretin area, tuberomammillary nucleus, orbital cortex, posteromedial cortical amygdala, and entorhinal cortex.
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Project description:Analysis of the effects of sleep deprivation, recovery sleep, and three time-of-day controls on seven brain regions laser microdissected from mouse brain. The regions include the locus coeruleus, suprachiasmatic nucleus, hypocretin area, tuberomammillary nucleus, orbital cortex, posteromedial cortical amygdala, and entorhinal cortex. In this study, 7 brain regions were collected by laser microdissection from brain tissue of mice from 5 different treatment groups and used for microarray experiments. Four biological replicates were generated for each regionxcondition. Conditions are: SD, sleep deprivation for 6 hours from ZT0 - 6; SDC, time-of-day control for SD at ZT6; RS, recovery sleep for 4 hours following SD; RSC, time-of-day control for RS at ZT10; W, spontaneous waking at ZT18.
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Project description:Sleep disturbances are common in patients with neurodegeneration, including Alzheimer's disease (AD), which can occur at early stages of AD and are proposed as potent risk factors for disease onset and progression. The underlying causes of this early-onset sleep disturbances remain unclear. Here we found that 5xFAD transgenic mice display significantly reduced sleep and prolonged wakefulness as early as 2 months of age. This early-onset sleep disruption correlates with increased tonic neuronal activity in the Locus Coeruleus (LC), which is mediated by heightened neuronal excitability due to impaired Kv4 and Kv7 channel conductance. Notably, we discovered that these young transgenic mice develop brain region-specific tau hyperphosphorylation (p-tau) in the LC. To investigate the pathological role of LC p-tau, we induce p-tau by inoculating synthetic human tau fibril into the LC of wild-type mice. This fibril inoculation replicated the reduction in Kv conductance and increased LC neuronal excitability in a tau-dependent manner. Modulating Kv4 and Kv7 channels restored normal excitability in both fibril-inoculated wild-type mice and young 5xFAD mice. Furthermore, fibril inoculation was sufficient to induce 5xFAD-like sleep disruptions in wild-type mice. Finally, pharmacological reduction of p-tau, both ex vivo and in vivo, effectively restored normal electrophysiological properties of LC neurons and normalized sleep/wake patterns in fibril-inoculated wild-type mice and young 5xFAD mice. Therefore, our findings identify a neural mechanism underlying early-onset sleep disturbances in a mouse model of AD amyloidosis and highlight the pathological consequences of LC tau hyperphosphorylation.
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