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

睡眠或性唤醒障碍会在生活中的某个时候影响多达三分之一的美国人， 超过5000万名患有慢性病的人。为了了解和治疗这些疾病，我们 首先必须了解负责唤醒和睡眠的神经回路和网络。我们建议 研究α-2肾上腺素能激动剂的催眠作用，它激活内源性睡眠活动回路和 产生一种类似于慢波睡眠的催眠。我们的数据证实了之前的行为 研究表明，产生α-2激动剂催眠的神经元群(S)位于脑桥。 包括蓝斑在内的区域。然而，仅蓝斑的肾上腺素能神经元 这似乎还不够。拟议的研究将确定肾上腺素能和吻部的作用。 桥脑神经元在α-2肾上腺素能激动剂催眠作用中的作用 靶向脑桥的α-2激动剂的离散和局部作用能否产生和维持 催眠？之前发布的数据和我们的初步数据支持本地交付的想法 α-2激动剂对包括蓝斑在内的脑桥的催眠作用是足够的。我们将使用新颖的α2 肾上腺素能激动剂光标记局部调节神经元活动并严格检验这一假说。 蓝斑的肾上腺素能神经元是α-2介导的催眠所必需的吗？我们会 在吻侧脑桥进行肾上腺素能特异性敲除α2A肾上腺素能受体，寻找 对α-2肾上腺素能激动剂催眠的抵抗。我们还将通过光遗传技术驱动肾上腺素能神经元 以确定它们的活动是否能逆转α-2介导的催眠。 在α-2激动剂催眠状态下，LC吻侧脑桥神经元的放电模式 主要依赖于局部或系统影响？能改变肾上腺素能神经元的活动 逆转α-2激动剂催眠？我们将用α-2激动剂记录吻侧脑桥的单位活动 在野生型和肾上腺素能α2A受体基因敲除小鼠中给药。使用光遗传学和α2 光标记，我们将机械地剖析α2激动剂的局部突触前和全身电路效应。 在这个项目完成时，我们将确定肾上腺素能神经元在 脑桥顶部至α-2介导的催眠。这将使我们深入了解睡眠和睡眠中常见的神经回路 麻醉--通往未来睡眠和觉醒障碍治疗的大门。拟议的项目还将 建立在麻醉药理学基础知识的基础上，并提供新的 神经科学和遗传学领域。强大的、多学科的指导团队，同样智力 多样的合作者，明确的职业发展计划，以及一个 高度重视在世界级机构的研究将确保PI不仅实现科学 这项建议的目标，但准备成功的职业生涯研究睡眠和麻醉催眠。

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.