Inhibitory Control of Hypothalamic Circuit for Aggression

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Many diverse neural disorders as well as certain types of cortical trauma can result in increased aggression. These behavioral effects can take the form of increased proactive aggression-seeking behavior, increased reactive aggressive action, or both, suggesting that these behaviors may be independently regulated. While these effects are believed to result from “top-down” disinhibition of aggression-relevant circuits, there is little direct circuit-level or physiological evidence to support this. Our recent work has shown that the ventrolateral hypothalamus, ventrolateral area (VMHvl) controls the expression of both reactive and proactive aggressive behaviors and may represent a common pathway for functional inhibitory control of aggression. During the K99 phase of this proposal, we identified how an undescribed source of local inhibition to the VMHvl selectively gates aggression-seeking behavior. In addition to this local inhibition, the VMHvl receives inhibition from a number of upstream structures in the hypothalamus, amygdala and forebrain. These inputs likely have dissociable roles in the regulation of reactive and proactive aggression and may represent multiple independent pathways to dysregulate the circuit. Newly developed techniques for cell-type specific imaging of deep neural structures now allow interrogation of individual circuit components and can also be used to detect real-time changes in inhibition. This proposal leverages recent advances in cell-type and pathway specific targeting in mice in tandem with new strategies for optical recording, chloride FRET sensing, and functional manipulation to describe brain-wide circuits for inhibitory control of aggression. In this proposal, we aim to 1) Characterize and map the regulatory roles of sources of long-range inhibition onto the VMHvl and model their effects on the output of excitatory aggression-relevant neurons, 2) Using a novel optical chloride sensor, explore whether activation of these upstream inhibitory control inputs results in functional inhibitory drive, and 3) Test whether upstream inputs for inhibitory control selectively target subsets of VMHvl neurons for proactive and reactive aggression. Together, these data will potentially lead to a broad new understanding of how activity within canonical circuits for aggression is shaped and gated by inhibition and how these processes may go awry during social dysfunction.