A Novel Node in Threat Response Neurocircuitry: VGLUT2 Positive Supramammillary Neurons Projecting to Preoptic Hypothalamus

亚伦·诺里斯博士是一名神经学家和神经麻醉学家，他的长期目标是成为 独立研究人员专注于调节压力和觉醒的神经回路和机制。他的研究 背景包括离子通道生理学、昼夜神经生物学，以及最近的神经回路 调节压力和唤醒。诺里斯博士是Gereau博士麻醉学系实验室的成员 在华盛顿大学。实验室、系和大学提供了卓越的培训环境。在 在Gereau实验室，诺里斯博士将接受最先进的光遗传学、病毒神经回路追踪和小鼠的培训 行为模型。与他的合作导师多尔蒂博士合作，他将获得神经转录学方面的经验。 麻醉科为近20名早期医师提供了丰富的培训环境-- 科学家。该部门还设有活跃的实验室，研究与电路有关的神经科学问题，使用 类似的技术。拟议的项目侧重于乳头上核(SUM)中的神经元群体。 诺里斯博士使用遗传和逆行病毒工具确定了以前未发现的VGLUT2人群 投射到下丘脑视前区的阳性神经元总数(→和POA)。初步数据 提示这种未确定特征的神经元群体是介导主动反应的关键节点。 威胁性的压力源。拟议的实验将使用尖端纤维光度学、化学遗传学、 光遗传学、病毒工具和分子转录切割技术1)从解剖学和转录角度定义 →POA神经种群总和；2)确定先天、环境和后天威胁是否激活 和→POA神经元；3)确定VGLUT2正和→POA神经元是否充分和 对威胁的压力源做出积极反应是必要的。我们将检验这些假设：1)单个神经元在 2)VGLUT2阳性和→POA神经元 在体内被捕食者线索、强迫游泳和习得的威胁线索激活；3)VGLUT2阳性激活 Sum→POA神经元编码负价，唤起积极的先天防御行为，推动工具性 目标导向行为会增加积极应对行为，但不会增加焦虑行为；4) 抑制VGLUT2阳性和→POA神经元降低急性应激诱发的主动应对行为 威胁性刺激。这些实验的结果将从根本上帮助我们理解 参与威胁反应的神经回路。拟议的计划将为诺里斯博士提供培训、指导和 和经验，以及时过渡到独立，并获得R01资金。

Dr. Aaron Norris MD, PhD, is a neuroscientist and neuroanesthesiologist with the long-term goal to be an independent investigator focused on neural circuits and mechanisms regulating stress and arousal. His research background includes ion channel physiology, circadian neurobiology and, most recently, neural circuits regulating stress and arousal. Dr. Norris is a member of Dr. Gereau’s lab in the Department of Anesthesiology at Washington University. The lab, department, and university provide exceptional training environments. In the Gereau lab, Dr. Norris will receive training in state-of-the-art optogenetics, viral neural circuit tracing and mouse behavioral models. Working with his co-mentor, Dr. Dougherty, he will gain experience in neurotranscriptomics. The department of anesthesiology provides a rich training environment with nearly 20 early stage physician– scientists. The department also houses active labs working on circuit related neuroscience questions using similar techniques. The proposed project focuses on a neuronal population in supramammillary nucleus (SuM). Dr. Norris used genetic and retrograde viral tools to identify a previously unrecognized population of VGLUT2 positive neurons in SuM that project to the preoptic area of the hypothalamus (SuM→POA). Preliminary data suggest that this uncharacterized population of neurons is a critical node in mediating active responses to threatening stressors. The proposed experiments will use cutting-edge fiber photometry, chemogenetics, optogenetics, viral tools, and molecular transcriptomic techniques to 1) anatomically and transcriptionally define the SuM→POA neural population; 2) determine whether innate, environmental and learned threats activate SuM→POA neurons; and 3) establish whether VGLUT2 positive SuM→POA neurons are sufficient and necessary for active responses to threatening stressors. We will test the hypotheses: 1) individual neurons in SuM project to POA and anatomically distant brain regions; 2) VGLUT2 positive SuM→POA neurons are activated in vivo by predator cues, force swimming, and learned threat cues; 3) activation of VGLUT2 positive SuM→POA neurons encodes a negative valence, evokes active innate defensive behaviors, drives instrumental goal-directed behaviors, increases active coping behaviors but does not increase anxiety-like behaviors; 4) inhibition of VGLUT2 positive SuM→POA neurons decreases active coping behaviors evoked by acute threatening stimuli. The results of these experiments will fundamentally inform our understanding of the neurocircuitry involved in threat response. The proposed plan will provide Dr. Norris with the training, mentorship, and experience to transition to independence in a timely manner and obtain R01 funding.