Defining the brain mechanisms that mediate multidimensional representation of emotion states, such as fear, is an important problem in neuroscience with high relevance to human health, including psychiatric disorders such as anxiety and depression. The study of fear in animal models has been dominated by the Pavlovian fear conditioning paradigm, and a focus on the amygdala. However there is a need to extend the study of fear circuitry to extra-amygdala systems, as well as to paradigms for innate fear where emotion states can be studied without the additional complexities introduced by learning. There is also a need to expand the study of such circuits from a focus on single nuclei to meso-scale connectivity and function. The medial hypothalamic defensive circuit mediates innate defensive responses to predators. Recent data have identified neurons in the ventromedial hypothalamic nucleus (VMH) expressing the transcription factor SF1 as necessary and sufficient for defensive behavioral and autonomic responses to a predator. However little is known about the precise role of these neurons, and their targets, in representing threatening stimuli, and transforming this representation into emotion states and defensive responses. To fill this gap, we are using state-of-the-art tools for recording, imaging and perturbing neural activity in this system, using SF1+ neurons as a point-of-entry. Our broad, long-term objective is to understand how emotional stimuli are represented and transformed into internal states and behavioral responses. The central objective of this proposal is to determine how VMHdm/c SF1+ neurons, and associated circuitry, represent multi-modal threatening stimuli, and generate defensive responses. The rationale for this research is that the study of evolutionarily ancient brain circuits that control conserved emotion states such as fear is likely to yield general principles of multidimensional emotional representation. To achieve our objective, we will characterize how SF1+ neurons represent multi-modal threatening sensory cues (Aim 1); determine the relationship of neuronal activity in VMHdm/c SF1+ neurons to observable responses to threatening stimuli (Aim 2); investigate meso-scale circuit interactions controlling defensive responses by recording simultaneously from multiple regions during exposure to threatening stimuli (Aim 3); and investigate the circuit-level mechanisms underlying experience-dependent influences on acute responses to threatening stimuli (Aim 4). The contribution will be to apply state-of-the-art genetically based tools to study the representation of multimodal threatening stimuli and their causal functions. This contribution is significant because it will advance our understanding of the micro- and meso-scale circuit dynamics underlying emotional representations and responses. The contribution is innovative, because it represents the first time that this circuitry has been studied using such multidimensional systems-level approaches. The work proposed in this application will therefore increase our understanding of fundamental brain mechanisms of emotion representation, with potential relevance to understanding and treating human psychiatric disorders.

Public Health Relevance

The proposed research is relevant to public health because it addresses the study of the brain circuitry that transforms signals from the external world into internal emotion states and responses. Dysfunction of this complex process is thought to underlie disorders such as PTSD, anxiety and depression. Because the brain mechanisms underlying the normal function of such processes are conserved and ancient, their study in animal models will inform our understanding of the human brain. The research described in this proposal will apply powerful genetic tools to the high-resolution analysis of basic neural circuit mechanisms, and is therefore relevant to NIH's mission of achieving a ?deeper understanding of fundamental neurobiology? (Insel, T.R. and Landis, S.C., Neuron (2013)).

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Vicentic, Aleksandra
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California Institute of Technology
Schools of Arts and Sciences
United States
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Zelikowsky, Moriel; Hui, May; Karigo, Tomomi et al. (2018) The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress. Cell 173:1265-1279.e19
Remedios, Ryan; Kennedy, Ann; Zelikowsky, Moriel et al. (2017) Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex. Nature 550:388-392