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

威胁反应神经回路中的新节点：投射到视前下丘脑的 VGLUT2 阳性乳头上神经元

• 批准号: 9892789
• 负责人: Aaron J Norris
• 金额: $ 19.19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892789
• 关键词: Acute; Affect; Affective; Anatomy; Anesthesiology; Anxiety; Anxiety Disorders; Area; Arousal; Attention; Automobile Driving; Behavior; Behavioral Assay; Behavioral Model; Brain; Brain region; Cell Nucleus; Coping Behavior; Cues; Data; Data Analyses; Distant; Doctor of Philosophy; Emotions; Environment; Exposure to; Fiber; Funding; Gene Expression Profiling; Genetic; Genetic Transcription; Glutamates; Goals; Habenula; Hippocampus (Brain); Human; Hypothalamic structure; Image; Individual; Ion Channel; Lateral; Lead; Learning; Lesion; Measures; Mediating; Memory; Mentors; Mentorship; Methods; Modeling; Molecular; Mood Disorders; Motivation; Mus; Negative Valence; Neurobiology; Neurons; Neurosciences; Odors; Photometry; Physicians; Physiology; Play; Population; Positioning Attribute; Preoptic Areas; Process; Research; Research Personnel; Rodent; Role; Scientist; Shock; Stimulus; Stream; Stress; Structure; Sum; Swimming; Techniques; Testing; Time; Training; Universities; Viral; Washington; anxiety-like behavior; behavioral response; circadian; coping; dentate gyrus; experience; experimental study; foot; in vivo; in vivo calcium imaging; member; negative affect; neural circuit; neuromechanism; neuropsychiatric disorder; novel; optogenetics; photoactivation; relating to nervous system; response; stress disorder; stress related disorder; stressor; tool; transcriptomics

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.

Aaron Norris博士是一名神经科学家和神经麻醉学家，其长期目标是成为一名 独立研究者专注于神经回路和调节压力和唤醒的机制。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 调节压力和兴奋Norris博士是Gereau博士麻醉科实验室的成员 在华盛顿大学。实验室，部门和大学提供卓越的培训环境。在 在Gereau实验室，Norris博士将接受最先进的光遗传学，病毒神经回路追踪和小鼠 行为模型与他的共同导师Doughnut博士合作，他将获得神经转录组学方面的经验。 麻醉科提供了丰富的培训环境，有近20名早期医师- 科学家该部门还拥有活跃的实验室，研究与电路相关的神经科学问题， 类似技术拟议的项目集中在乳头体上核（SuM）的神经元群体。 博士Norris使用遗传和逆行病毒工具鉴定了以前未被识别的VGLUT 2群体 SuM阳性神经元投射至下丘脑视前区（SuM→POA）。初步数据 这表明，这一未表征的神经元群体是介导主动反应的关键节点， 威胁性压力源拟议中的实验将使用尖端的纤维光度学，化学遗传学， 光遗传学、病毒工具和分子转录组学技术，以1）解剖学和转录学定义 SuM→POA神经群; 2）确定先天、环境和习得威胁是否激活 SuM→POA神经元;以及3）确定VGLUT 2阳性SuM→POA神经元是否足够， 积极应对威胁性压力所必需的。我们将测试假设：1）单个神经元在 SuM投射到POA和解剖学上较远的脑区; 2）VGLUT 2阳性的SuM→POA神经元是 在体内被捕食者线索、强迫游泳和习得的威胁线索激活; 3）VGLUT 2阳性 SuM→POA神经元编码负效价，唤起主动的先天防御行为，驱动工具性 目标导向行为，增加积极应对行为，但不增加焦虑样行为; 4） 抑制VGLUT 2阳性的SuM→POA神经元减少急性应激诱发的主动应对行为 威胁性的刺激这些实验的结果将从根本上告知我们对 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， 和经验，以及时过渡到独立，并获得R 01资金。