Neural correlates of Sleep Homeostasis

睡眠稳态的神经相关性

基本信息

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
项目类别：
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

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

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项目摘要

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.

这项研究的广泛目的是确定稳态睡眠的基础神经底物反应（HSR），即长时间睡眠剥夺（SD）后的嗜睡增强。 SD经验许多由于生活方式或职业需求，是通过认知受损，冲动性增加，可以实现的，并增加了事故的可能性。此外，睡眠破坏是许多人的共同特征神经精神疾病。这是理解高铁背后的机制对于发展至关重要应对SD的删除后果的措施。具体来说，我们将在这里解决中央问题：“所有神经唤醒系统对于触发HSR是否同样重要？”我们的总体假设是基本前脑（BF）胆碱能神经元（CHAT+）由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中的特权角色，从而增加睡眠抑制启动唤醒的BF神经元，从而将系统状态调节到其设定点。朝向这个目标，AIM 1将测试BF胆碱能神经元，而不是脑干pedunculopontine temental （PPT）胆碱能神经元是HSR所必需的。 AIM 2将检验以下假设：在BF中，只有那些非 - 胆碱能唤醒的神经元投射到令人兴奋的BF CHAT+神经元将诱发HSR。目标3 将测试刺激促进唤醒的bf-vglut2+和ppt-vglut2+神经元，只有在bf时才诱导HSR CHAT+神经元完整，即BF CHAT+神经元的完整性对于触发HSR是必要的。最后，瞄准 4将测试BF CHAT+神经元在促进唤醒和睡眠稳态中的双重作用。我们将使用我们的新颖的鼠标“ optodiaysis”问题（Zant等，2016），结合了选择性神经元的光学操纵体内微透析的种群用于检测局部神经化学变化和/或应用药理剂。这些调查的成功完成将进一步了解我们对诱导HSR所必需的神经底物，因此将有助于开发目标针对睡眠损失的有害影响的药理干预措施。