权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Astroglial mechanisms in sleep homeostasis

星形胶质细胞睡眠稳态机制

基本信息

批准号：
10163932
负责人：
MARCOS G FRANK
金额：
$ 61.65万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10163932
关键词：
Address Anatomy Arousal Astrocytes Attention Biological Brain Cells Circadian Rhythms Coupled Cyclic AMP Data Development Drowsiness Drug Targeting Electroencephalography Equilibrium Etiology Excessive Daytime Sleepiness Exocytosis Feedback G alpha q Protein GTP-Binding Proteins Gene Expression Glial Fibrillary Acidic Protein Glutamate Transporter Heterogeneity Homeostasis Image Impaired cognition In Situ Hybridization Ion Channel Lead Learning Ligands Measurement Measures Mechanics Mediating Memory Mental disorders Metabolic Metabolism Methods Microscopy Molecular Mood Disorders Morbidity - disease rate Morphology Mus Neuroglia Neurons Neurotransmitters Pathway interactions Phospholipase C Plant Roots Play Polysomnography Process Proteins REM Sleep Role STIM1 gene Second Messenger Systems Signal Pathway Signal Transduction Signaling Protein Sleep Sleep Deprivation Sleep Disorders Sleeplessness Synapses Techniques Technology Testing Time Transcript United States Wakefulness awake basal forebrain base brain cell circadian pacemaker designer receptors exclusively activated by designer drugs differential expression digital experimental study frontal lobe in vivo innovation insight miniaturize nervous system disorder neurotransmitter uptake new therapeutic target next generation sequencing non rapid eye movement novel promoter response single-cell RNA sequencing sleep abnormalities transcriptome two photon microscopy two-photon

项目摘要

Summary Sleep problems such as excessive daytime sleepiness and insomnia are common in the United States. They are found in many psychiatric and neurological disorders and cause deficits in attention, learning and memory. Some sleep problems may be caused by disrupted circadian rhythms, but others may reflect changes in sleep homeostasis; an enigmatic regulatory mechanism that increases sleep drive, sleep amounts and sleep intensity as a function of prior time awake. The cellular mechanisms of sleep homeostasis are incompletely described but have traditionally thought to be neuronal. We, however, have shown that glial astrocytes are part of this mechanism. More specifically, we propose that sleep homeostasis arises from interactions between astrocytes and neurons. We therefore hypothesize that the normal compensatory response to sleep loss involves intracellular and molecular changes in astrocytes. This A1 submission has been extensively revised in accordance with initial review. New experiments and preliminary data are included (indicated by red font). We will test this overall hypothesis with three innovative approaches in vivo. In Aim 1, we combine genetically encoded Ca2+ indicator (GECI) astrocyte imaging with simultaneous polysomnographic recording in unanesthetized mice in vivo. This allows us to measure astrocyte Ca2+ dynamics in natural states of rapid- eye-movement (REM) sleep, non(N)REM sleep and wakefulness using both 2-photon and epiflorescent microscopy. We also more directly test the necessity of intracellular Ca2+ in sleep homeostasis by inducibly reducing this signal in vivo and measuring changes in sleep expression and homeostasis. In Aim 2, we use inducible molecular techniques to alter the major signaling pathways known to exist in astrocytes (i.e. Gq, Gi and Gs proteins) and examine the resulting changes in sleep expression and homeostasis. In Aim 3, we use next generation sequencing technology (single-cell RNA sequencing (scRNA-seq)) to isolate additional (but currently unknown) signaling pathways that are involved in astrocyte-mediated sleep homeostasis. Mammalian astrocytes are highly diverse based on morphology, cell-specific markers (e.g. GFAP+), ion channels, glutamate transporters and metabolic substrates. The relative contribution of these different astrocytes to sleep is unknown. scRNA-seq provides a new and powerful method to address this problem. Impact: Our characterization of a novel glial sleep mechanism will provide new insights into the etiology of abnormal sleep and arousal. Our experiments will also provide new insights into the function of non-neuronal brain cells. This in turn can lead to the development of new therapeutics that target glia, rather than neurons.

总结