Neural correlates of Sleep Homeostasis

睡眠稳态的神经相关性

• 批准号: 10610147
• 负责人: RADHIKA BASHEER
• 金额: $ 32.38万
• 依托单位: BOSTON VA RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610147
• 关键词: Accidents; Acetylcholine; Acute; Address; Adenosine; Area; Arousal; Attenuated; Brain; Brain Stem; Cholinergic Antagonists; Cholinergic Receptors; Chronic; Data; Drosophila genus; Drowsiness; Electroencephalography; Emotional; Excessive Daytime Sleepiness; Excitatory Amino Acid Antagonists; Felis catus; Glutamates; Goals; Homeostasis; Impaired cognition; Impulsivity; Infusion procedures; Intervention; Investigation; Lead; Lesion; Life Style; Mammals; Measures; Mediating; Mental Health; Microdialysis; Modernization; Mus; Neurons; Neurotransmitters; Nitric Oxide; Optics; Outcome Measure; Parvalbumins; Perception; Performance at work; Pharmacology; Play; Population; Quality of life; Rattus; Reporting; Risk; Role; Sleep; Sleep Deprivation; Sleep disturbances; Societies; System; Testing; Therapeutic Intervention; Wakefulness; Work; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; combat; experience; experimental study; extracellular; gamma-Aminobutyric Acid; in vivo; neural correlate; neurochemistry; neuropsychiatric disorder; non rapid eye movement; novel; optogenetics; physical conditioning; prevent; receptor; relating to nervous system; response

The broad objective of this study is to identify the neural substrate(s) underlying the homeostatic sleep response (HSR), i.e. enhanced sleepiness following prolonged sleep deprivation (SD). SD is experienced by many due to lifestyle or vocational demands and is accompanied by impaired cognition, increased impulsivity, and an increased likelihood of accidents. Furthermore, disrupted sleep is a common feature of many neuropsychiatric disorders. Thus, understanding the mechanisms underlying the HSR is critical to develop measures to combat the deleterious consequences of SD. Specifically, here we will address the central question: “Are all neural wake-promoting systems equally important in triggering the HSR?” Our overarching hypothesis is that basal forebrain (BF) cholinergic neurons (ChAT+) are modulated by glutamate and play a privileged role in the HSR by causing the release of extracellular adenosine (ADex), which increases sleep by inhibiting wake-promoting BF neurons, and thereby adjusts the state of the system towards its' set point. Towards this goal, Aim 1, will test if BF cholinergic neurons, but not the brainstem pedunculopontine tegmental (PPT) cholinergic neurons, are required for HSR. Aim 2 will test the hypothesis that within BF, only those non- cholinergic wake-promoting neurons projecting to, and exciting, BF ChAT+ neurons will induce HSR. Aim 3 will test if stimulation of wake-promoting BF-vGluT2+ and PPT-vGluT2+ neurons will only induce HSR if BF ChAT+ neurons are intact, i.e. the integrity of BF ChAT+ neurons is necessary to trigger the HSR. Finally, Aim 4 will test the dual role of BF ChAT+ neurons in promoting arousal and sleep homeostasis. We will use our novel mouse `optodialysis' probes (Zant et al., 2016) that combine optical manipulation of selective neuronal populations with in vivo microdialysis for detecting local neurochemical changes and/or application of pharmacological agents. The successful completions of these investigations will further our understanding of the neural substrates necessary for inducing the HSR, and thus will help in developing targeted pharmacological interventions against the deleterious effects of sleep loss.

本研究的主要目的是确定内稳态睡眠的神经基质 睡眠反应（HSR），即在长时间睡眠剥夺（SD）后增强的嗜睡。SD经历了 许多是由于生活方式或职业需求，并伴有认知受损，冲动增加， 以及增加发生事故的可能性。此外，睡眠中断是许多人的共同特征。 神经精神障碍因此，了解HSR的潜在机制对于开发 采取措施消除可持续发展的有害后果。具体来说，我们将在这里讨论中央 问题：“所有的神经唤醒促进系统在触发HSR方面都同样重要吗？”我们的总体 一种假说认为，基底前脑胆碱能神经元（ChAT+）受谷氨酸调节， 通过引起细胞外腺苷（ADex）的释放，在HSR中发挥特殊作用， 抑制促进唤醒的BF神经元，从而将系统的状态调节到其设定点。 为了实现这一目标，目标1，将测试BF胆碱能神经元，但不是脑干脚桥被盖 (PPT)胆碱能神经元是HSR所必需的。目标2将检验假设，即在BF中，只有那些非 投射到BF ChAT+神经元并兴奋BF ChAT+神经元的胆碱能促醒神经元将诱导HSR。目标3 将测试刺激促醒BF-vGluT 2+和PPT-vGluT 2+神经元是否仅在BF ChAT+神经元是完整的，即BF ChAT+神经元的完整性是触发HSR所必需的。最后，Aim 4将测试BF ChAT+神经元在促进觉醒和睡眠稳态中的双重作用。我们将用我们 新的小鼠“视透析”探针（Zant等，该联合收割机将选择性神经元的光学操作 用于检测局部神经化学变化的体内微透析和/或应用 药理学试剂。这些调查的成功完成将使我们进一步了解 诱导HSR所必需的神经基质，因此将有助于开发靶向的 药物干预对睡眠不足的有害影响。