Wakefulness and Forebrain Activation by Orexin Neurons

食欲素神经元的觉醒和前脑激活

基本信息

批准号：
7798783
负责人：
THOMAS E SCAMMELL
金额：
$ 45.77万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7798783
关键词：
AMPA Receptors Address Affect Anatomy Animals Arousal Automobile Driving Behavior Brain region Chronic Clinical Code Disease Drowsiness Dynorphins Electrophysiology (science)Exposure to Figs - dietary Foundations Genetic Glutamates Goals Hypercapnia Hypothalamic structure In Situ Hybridization Lateral Lead Life Maintenance Maps Medial Mediating Modeling Molecular Biology Mus Neurobiology Neurons Neuropeptides Obstructive Sleep Apnea Pathway interactions Patients Peptides Phenotype Physiological Play Prefrontal Cortex Prosencephalon Protocols documentation Receptor Gene Research Personnel Resources Role Signal Transduction Site Sleep Sleep Apnea Syndromes Sleep Disorders Slice Techniques Testing Thalamic structure Time Wakefulness adeno-associated viral vector basal forebrain benefit sharing cholinergic cholinergic neuron dynorphin receptor effective therapy experience hypocretin improved insight kappa opioid receptors multidisciplinary neural circuit neurochemistry neuromechanism neurotransmission novel parabrachial nucleus patch clamp postsynaptic presynaptic prevent programs receptor receptor expression recombinase relating to nervous system research study response

项目摘要

Arousal from obstructive sleep apnea (OSA) plays a life-saving role, and we hypothesize that it is supported by the same circuitry that produces arousal during normal wakefulness. The orexin neurons in the lateral hypothalamus play a critical role in producing arousal, and lack of orexin neurotransmission produces a chronic state of hypoarousal. These studies will provide key insights into an important aspect of this Program Project: Defining the mechanisms through which the orexin neurons ultimately activate the cortex. We present a testable model in which the orexin neurons promote arousal by exciting basal forebrain neurons that activate the cortex. In addition to the orexin peptides, the orexin neurons probably co-release the inhibitory neuropeptide dynorphin, and we hypothesize that dynorphin and orexin act synergistically in the basal forebrain to promote full arousal. We will use powerful genetic, anatomic, and physiologic techniques to identify the neural circuits through which the orexin neurons promote arousal. To define the brain regions through which orexin promotes arousal, we will study sleep/wake behavior in mice that express orexin receptors only in the basal forebrain, thalamus, or cortex. Using slice recordings, we will determine the pre- and postsynaptic effects of orexin and dynorphin on neurochemically-defined basal forebrain neurons, including those projecting to prefrontal cortex. We will also map the basal forebrain pathways through which orexin and dynorphin promote wakefulness. Collectively, these multidisciplinary experiments will define the pathways through which orexin, in combination with dynorphin, promotes cortical activation, thus providing an anatomic and physiologic framework to better understand the neurobiology of arousal and the clinical problem of sleepiness.

阻塞性睡眠呼吸暂停（OSA）的唤醒起着挽救生命的作用，我们假设它受到在正常清醒期间产生唤醒的相同电路的支持。下丘脑中的Orexin神经元在产生唤醒中起着至关重要的作用，缺乏Orexin Neurotransersiss会产生慢性低神经状态。这些研究将为该计划项目的一个重要方面提供关键的见解：定义Orexin神经元最终激活皮质的机制。我们提出了一个可测试的模型，其中Orexin神经元通过令人兴奋的基础前脑促进唤醒激活皮质的神经元。除Orexin肽外，Orexin神经元可能会共释放抑制性神经肽dynorphin，我们假设dynorphin和Orexin ACT在基础前脑中协同作用，以促进完全唤醒。我们将使用强大的遗传，解剖学和生理技术来识别奥列克雷蛋白神经元促进唤醒的神经回路。为了定义奥列生石促进唤醒的大脑区域，我们将研究仅在基础前脑，丘脑或皮质中表达奥雷敦素受体的小鼠的睡眠/唤醒行为。使用切片记录，我们将确定Orexin和dynorphin对神经化学定义的基础前脑神经元（包括投射到前额叶皮层的那些基底神经元）的前和突触后作用。我们还将绘制Orexin和Dynorphin促进清醒的基础前脑途径。总的来说，这些多学科实验将定义Orexin，in 与dynorphin结合，促进皮质激活，从而提供解剖和生理学更好地了解唤醒的神经生物学和嗜睡的临床问题。