PROJECT SUMMARY / ABSTRACT Studying the circuit basis of fear in psychiatric disorders has relied on learned associations between stimuli and threatening experiences. Stimuli which are innately threatening represent an alternative approach to this problem, and may elicit different neural circuit mechanisms to promote survival. The neurotransmitter norepinephrine serves an important role in threat response, and recent studies have demonstrated the existence of multiple subtypes of norepinephrine cells within the locus coeruleus (LC). The scientific objective of this project is to determine how subtypes of norepinephrine neurons in LC contribute to the encoding of threat, so that in the future we can develop improved therapies for trauma-related disorders based on that knowledge. Our specific aims employ fluorescent biosensors of norepinephrine, miniature head-mounted microscopes for recording LC norepinephrine cells, optogenetics, and single cell transcriptomics. In our preliminary data, we identify a computational framework in which to consider the problem of learning from innate threat, then show the feasibility of these approaches. By employing these methods, we can collectively identify the relationship between norepinephrine cell-types and the encoding of threat at molecular, cellular, and circuit scales. This will generate a parts list for future studies into the nature of threat processing. In addition to the proposed studies, this proposal develops a plan to train Dr. Kaye for an independent research career as a circuit psychiatrist. This plan is mentored by Dr. Alex Kwan, an expert in optical approaches to neural circuit dissection and computational approaches to behavior, with the co-mentorship of Dr. Kerry Ressler, an expert in the neurobiology of posttraumatic stress disorder and Dr. Ronald Duman, an expert in the neurobiology of stress. This proposal relies on additional training in transcriptomics from Dr. Nenad Sestan, in optogenetics from Dr. Ralph DiLeone, and in the physiology of the norepinephrine system from Dr. Gary Aston-Jones.