Neural Correlates of Sleep Homeostasis

睡眠稳态的神经相关性

• 批准号: 10621850
• 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/10621850
• 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; Glutamate Transporter; Glutamates; Goals; Homeostasis; Impaired cognition; Impulsivity; Infusion procedures; Intervention; Investigation; Lesion; Life Style; Mammals; Measures; Mediating; Mental Health; Microdialysis; Modernization; Mus; Neurons; Neurotransmitters; Nitric Oxide; Optics; Outcome Measure; Parvalbumins; Perception; Performance at work; Play; Population; Quality of life; Rattus; Reporting; Risk; Role; Sleep; Sleep Deprivation; Sleep disturbances; Societies; System; Testing; Therapeutic Intervention; Vocation; Wakefulness; Work; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; combat; experience; experimental study; extracellular; gamma-Aminobutyric Acid; in vivo; neural; neural correlate; neurochemistry; neuropsychiatric disorder; non rapid eye movement; novel; optogenetics; pharmacologic; physical conditioning; prevent; receptor; 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.

这项研究的主要目标是确定稳态睡眠背后的神经基质 反应（HSR），即长期睡眠剥夺（SD）后嗜睡增加。 许多是由于生活方式或职业要求造成的，并伴有认知受损、冲动增加、 此外，睡眠中断是许多人的共同特征。 因此，了解 HSR 的机制对于发展至关重要。 具体而言，我们将在此讨论核心问题。 问题：“所有神经唤醒系统在触发 HSR 方面都同样重要吗？” 假设是基底前脑 (BF) 胆碱能神经元 (ChAT+) 受谷氨酸调节并发挥作用 通过引起细胞外腺苷 (ADex) 的释放，在 HSR 中发挥特殊作用，从而增加睡眠 抑制促进唤醒的 BF 神经元，从而将系统的状态调整到其设定点。 为了实现这一目标，目标 1 将测试 BF 胆碱能神经元，而不是脑干脚桥被盖神经元 (PPT) 胆碱能神经元是 HSR 所必需的，目标 2 将检验 BF 内仅那些非胆碱能神经元的假设。 胆碱能促醒神经元投射到并兴奋 BF ChAT+ 神经元将诱导 HSR Aim 3。 将测试刺激唤醒 BF-vGluT2+ 和 PPT-vGluT2+ 神经元是否只会在 BF 的情况下诱导 HSR 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。 4 将测试 BF ChAT+ 神经元在促进唤醒和睡眠稳态方面的双重作用。 新颖的小鼠“光透析”探针（Zant 等人，2016）结合了选择性神经的光学操作 使用体内微透析检测局部神经化学变化和/或应用的人群 这些研究的成功完成将进一步加深我们对药物的理解。 诱导 HSR 所需的神经底物，因此将有助于开发靶向的 针对睡眠不足的有害影响的药物干预。