Asytrocytes, sleep and neuroinflammation

星形胶质细胞、睡眠和神经炎症

• 批准号: 8974165
• 负责人: MARK R OPP
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974165
• 关键词: Acetylcholine; Achievement; Affinity; Astrocytes; Attenuated; Award; Behavior; Binding; Bioavailable; Brain; Cell physiology; Circadian Rhythms; Clozapine; Communication; Coupled; Data; Designer Drugs; Development; Electroencephalography; Engineering; Excision; Fostering; Funding Mechanisms; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glial Fibrillary Acidic Protein; Goals; Human Engineering; Immune; Immune system; Inflammatory; Interleukin-1; Interleukins; Knowledge; Learning; Ligands; Link; Lipopolysaccharides; Mediating; Mediator of activation protein; Memory; Mental Depression; Methods; Microglia; Mus; Muscarinics; Neuroglia; Neurons; Oxides; Paper; Participant; Pathology; Pattern; Process; Proteins; Publications; Rattus; Regulation; Relative (related person); Reporting; Research; Research Project Grants; Role; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Source; Stimulus; Substance abuse problem; System; Technology; Temperature; Testing; Time; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Use of New Techniques; adeno-associated viral vector; cell type; cytokine; feeding; immune activation; immune function; in vivo; meetings; neuroinflammation; neuronal circuitry; non rapid eye movement; novel; public health relevance; receptor; research study; response; selective expression; sleep regulation; tool; vesicular release

 DESCRIPTION (provided by applicant): Sleep research has historically been neuron-centric; much effort has focused on determining neuronal circuits and/or actions of transmitter substances produced by neurons. Historically, glia were thought to be merely passive brain residents, yet new research demonstrates that glial cells, particularly astrocytes and microglia, are active participants in sleep regulation and in sleep-immune interactions. For example, recent studies demonstrate that inhibiting vesicular release from astrocytes reduces EEG slow wave activity and attenuates sleep deprivation-induced increases in non-rapid eye movement (NREM) sleep. However, much remains to be learned about the relative contribution of astrocytes to mechanisms underlying alterations in sleep during immune challenge. The cytokines interleukin-1β (IL-1) and tumor necrosis factor-α (TNF) are involved in the regulation of sleep and in the alterations in sleep that occur during immune challenge. Importantly, IL-1 and TNF are produced by neurons and glia, their receptors are present on neurons and glia, and they constitute an important mechanistic link in neuronal-glial communication. Our knowledge about astrocyte contributions to sleep-immune interactions will be advanced if actions of this cell type can be specifically, independently, and reversibly modulated in vivo. Thus, the overall objective of this R21 Exploratory / Developmental Research Grant Award is to selectively stimulate G protein-coupled signaling cascades in astrocytes to elucidate their contributions to the regulation of sleep during immune challenge. To accomplish this task we will use designer receptors exclusively activated by designer drugs (DREADDs). DREADDs are engineered human muscarinic G protein-coupled receptors that are unable to bind their endogenous ligand, acetylcholine. Instead, they bind a chemically inert synthetic ligand, clozapine-N-oxide (CNO), which then stimulates intracellular signaling. To date, DREADDs have almost exclusively been used to modulate activity of neurons. The central hypothesis to be tested by experiments proposed in this application is that stimulating G protein-coupled signaling cascades in astrocytes will attenuate changes in sleep that are induced by immune challenge. We will use the Cre-loxP system, commercially-available GFAP:Cre mice, and adeno-associated virus vectors to selectively express DREADDs on astrocytes. We will then test our overall hypothesis by conducting experiments within the context of two Aims. In Aim 1 we will stimulate Gq or Gi G protein-coupled signaling in the absence of immune challenge and quantify regional changes in mouse brain cytokine protein. In Aim 2 we will activate these same signaling cascades and determine the impact of this manipulation on lipopolysaccharide (LPS)-induced alterations in mouse sleep patterns and brain cytokine protein. Upon completing these studies we will not only possess a new toolkit, but we will have novel data that will contribute to our understanding of mechanisms and functions for sleep-immune interactions. These achievements will have a prolonged and sustained impact on the field by filling a gap in our knowledge of sleep and gliotransmission during immune challenge.