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

睡眠与昏迷的交叉点：Alpha-2 肾上腺素催眠的神经通路

• 批准号: 9293823
• 负责人: Andrew Rich McKinstry-Wu
• 金额: $ 19.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293823
• 关键词: Acute; Address; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Affect; American; Anesthesia procedures; Anesthetics; Animals; Area; Arousal; Behavioral; Binding; Biological Neural Networks; Chronic; Clinical; Coma; Critical Pathways; Data; Development Plans; Dexmedetomidine; Direct Costs; Disease; Drug effect disorder; Engineering; Ensure; Enterobacteria phage P1 Cre recombinase; Future; Genetic; Genetic study; Goals; Head; Hypnosis; Hypothalamic structure; Institution; Investigation; Knock-out; Knockout Mice; Light; Medetomidine; Mediating; Mentors; Microinjections; Modeling; Mus; Neural Pathways; Neurons; Neurosciences; Opsin; Pattern; Pharmacology; Pontine structure; Population; Property; Public Health; Publishing; Receptor Gene; Research; Resistance; Role; Site; Sleep; Sleep Disorders; Sleep Disorders Therapy; Sleeplessness; Slow-Wave Sleep; Structure; Study models; Testing; Transgenic Mice; Uncertainty; Viral; alpha 2 agonist; awake; base; behavioral study; brain pathway; career; career development; experience; hypnotic; insight; knowledge base; life time cost; locus ceruleus structure; multidisciplinary; neural circuit; novel; optogenetics; presynaptic; receptor; sedative

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.

睡眠或唤醒的疾病会影响到一生中的某个时刻，多达三分之一的美国人 遭受慢性问题的人中有超过5000万。要理解和治疗这些疾病，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肾上腺激动剂的催眠作用，该动作激活内源性睡眠电路和 产生看起来类似于慢波睡眠的催眠。我们的数据证实了早期的行为 研究表明，产生α2激动剂催眠的神经元种群在A的鼻孔中 包括基因座的区域。但是，仅位点的肾上腺肾上腺神经元DO 似乎还不够。拟议的调查将确定肾上腺肾上腺素的作用 通过解决这些问题的α2肾上腺激动剂的催眠作用中的蓬蒂因神经元： 可以瞄准鼻孔的α2激动剂的离散和局部作用，并保持 催眠？以前与我们的初步数据一起出版了 α2激动剂到包括基因座的PON的pon足以催眠。我们将使用新颖的α2 肾上腺激动剂光标记以局部调节神经元活性并严格检验该假设。 α2介导的催眠所必需的基因座的肾上腺神经元吗？我们将 在鼻孔中执行α2A肾上腺素受体的肾上腺素特异性敲除，寻找 对α2肾上腺激动剂催眠的抗性。我们还将在光源上驱动肾上腺素的神经元 鼻孔以确定其活性是否可以逆转α2介导的催眠。 是在α2激动剂催眠下LC周围的鼻孔中的神经元发射模式 主要取决于局部或全身影响？可以改变肾上腺神经元活动 反向α2激动剂催眠？我们将在带有α2激动剂的鼻孔中记录单位活性 在野生型和肾上腺素α2A受体敲除小鼠中给药。使用光遗传学和α2 光标记，我们将机械地剖析局部突触前与α2激动剂的全身电路效应。 该项目完成后，我们将确定肾上腺神经元的贡献 to pons toα2介导的催眠。这将洞悉睡眠和 麻醉 - 通往未来睡眠和唤醒疾病的未来疗法。拟议的项目也将 基于PI的基础麻醉药理学知识，并提供新的专业知识 神经科学和遗传学领域。强大的多学科指导团队，同样聪明地 潜水员合作者，一项清晰的职业发展计划以及部门的惊人支持 深入重视世界一流机构的研究将确保PI不仅可以实现科学 该提议的目标是为了成功地调查睡眠和麻醉催眠的事业而做好准备。