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

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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.