Intersections of Sleep and Coma: Neural Pathways of Alpha-2 Adrenergic Hypnosis

睡眠或觉醒障碍将影响多达三分之一的美国人在他们生命中的某个时刻， 超过5000万人患有慢性疾病。为了了解和治疗这些疾病，我们 必须首先了解负责唤醒和睡眠的神经回路和网络。我们建议 研究α2肾上腺素能激动剂的催眠作用，其激活内源性睡眠激活回路， 产生类似于慢波睡眠的催眠状态。我们的数据证实了 研究表明，产生α2激动剂催眠的神经元群位于脑桥的喙部， 包括蓝斑的区域。然而，蓝斑的肾上腺素能神经元单独 似乎还不够。拟进行的研究将确定肾上腺素能和吻侧皮质激素的作用。 脑桥神经元在α2肾上腺素能受体激动剂催眠作用中的作用： α2受体激动剂靶向脑桥喙部的离散和局部作用能否产生和维持 催眠？以前发表的与我们的初步数据一起支持本地交付的想法， α2受体激动剂对脑桥包括蓝斑的作用足以达到催眠的目的。我们将使用新的α2 肾上腺素能激动剂光标记以局部调节神经元活性，并严格检验这一假设。 蓝斑的肾上腺素能神经元是α2介导的催眠所必需的吗？我们将 在脑桥喙部进行α2A肾上腺素能受体的肾上腺素能特异性敲除，寻找 对α2肾上腺素能激动剂催眠的抵抗。我们还将通过光遗传学驱动肾上腺素能神经元， 以确定它们的活性是否可以逆转α2介导的催眠。 α2受体激动剂催眠下LC周围脑桥嘴侧神经元的放电模式 主要取决于局部或全身效应？改变肾上腺素能神经元的活动 逆转α2激动剂催眠用α_2受体激动剂记录脑桥嘴侧的单位活动 在野生型和肾上腺素能α2A受体敲除小鼠中施用。利用光遗传学和α2 光标记，我们将机械解剖局部突触前与系统回路的α2受体激动剂的影响。 在这个项目完成后，我们将确定肾上腺素能神经元的贡献， 脑桥嘴侧对α2介导的催眠。这将使我们深入了解睡眠中常见的神经回路， 麻醉--通向未来睡眠和觉醒障碍治疗的大门。拟议项目还将 建立在PI的麻醉药理学的基础知识，以及提供新的专业知识， 神经科学和遗传学领域。强大的多学科指导团队， 多元化的合作者，清晰的职业发展计划，以及部门的惊人支持， 在世界一流的机构进行深入的研究将确保PI不仅实现科学 这个建议的目标，但准备一个成功的职业生涯调查睡眠和麻醉催眠。

Disorders of sleep or arousal will affect up to a third of all Americans at some point in their lives, with upwards of 50 million of those experiencing chronic issues. To understand and treat these disorders, we must first understand the neural circuits and networks responsible for arousal and sleep. We propose to study the hypnotic action of α2 adrenergic agonists, which activate endogenous sleep-active circuits and produce a hypnosis that appears similar to slow-wave sleep. Our data corroborates earlier behavioral studies showing the neuronal population(s) producing α2 agonist hypnosis lies in the rostral pons in a region that includes the locus coeruleus. However, adrenergic neurons of the locus coeruleus alone do not appear to be sufficient. The proposed investigation will determine the role of adrenergic and rostral pontine neurons in hypnotic actions of α2 adrenergic agonists through addressing these questions: Can discrete and localized actions of α2 agonists targeting the rostral pons produce and maintain hypnosis? Previously published together with our preliminary data support the idea that local delivery of α2 agonists to pons including the locus coeruleus is sufficient for hypnosis. We will use novel α2 adrenergic agonist photolabels to locally modulate neuronal activity and rigorously test this hypothesis. Are adrenergic neurons of the locus coeruleus necessary for α2-mediated hypnosis? We will perform adrenergic-specific knockouts of α2A adrenergic receptors in the rostral pons, looking for resistance to α2 adrenergic agonist hypnosis. We will also optogenetically drive adrenergic neurons of the rostral pons to determine if their activity can reverse α2 mediated hypnosis. Is the neuronal firing pattern in the rostral pons around the LC under α2-agonist hypnosis primarily dependent on local or systemic effects? Can changing adrenergic neuron activity reverse α2-agonist hypnosis? We will record unit-activity in the rostral pons with α2 agonist administration in wild-type and adrenergic α2A receptor knockout mice. Using optogenetics and α2 photolabels, we will mechanistically dissect local presynaptic vs. systemic circuit effects of α2 agonists. At the completion of this project, we will have determined the contribution of adrenergic neurons of the rostral pons to α2 mediated hypnosis. This will give insight into the neural circuits common to sleep and anesthesia—a door to future therapies for disorders of sleep and arousal. The proposed project will also build upon the PI's base knowledge of anesthetic pharmacology, as well as providing expertise in new areas of neuroscience and genetics. The strong, multi-disciplinary mentoring team, equally intellectually diverse collaborators, a clear career development plan, and the phenomenal support of a department that deeply values research at a world-class institution will ensure that the PI not only achieves the scientific goals of this proposal, but is prepared for a successful career investigating sleep and anesthetic hypnosis.