Amygdala Circuit Mechanisms for Stress-escalated Aggression

Tufts University Boston, Boston MA

Investigators

Abstract

PROJECT SUMMARY (See instructions): Pathway to Independence: The R00 phase of this project will support my independent research program examining the mechanistic underpinnings of trauma-induced aggression and violence in the Tufts University School of Medicine Department of Neuroscience. Project Summary: Interpersonal violence is a leading cause of posttraumatic stress disorder (PTSD), a debilitating syndrome characterized by sleep disturbances, flashbacks, and dysregulated emotional reactivity. For some trauma-exposed individuals, deficits in emotion regulation can escalate to aggression, thereby perpetuating a cycle of interpersonal violence and trauma. Understanding how stressors affect the neural circuitry of aggression is fundamental to developing effective therapies for this form of violence. Central amygdala (CeA) neurons that express the well-characterized stress signaling neuropeptide, corticotropin releasing hormone (Crh), are critical mediators of fear-induced reactions, and through my postdoctoral single-cell calcium imaging training in the Ressler Lab, I have identified a distinct Crh+ CeA cell activity signature during the emergence of offensive aggression. In Aim 1 (K99), I will use closed-loop optogenetics to extend these preliminary findings to understand the causal role of Crh+ CeA cells in initiating aggression. Using my novel and recently validated model for social trauma-induced aggression – where experimental mice are attacked inside of their home environment by a dominant intruder – it is possible to explore the impact of violence on fear circuitry. Such trauma-exposed mice adopt heightened defensive tactics including atypical, generalized aggression toward non-threatening social partners. In Aim 2 (R00), this model for social trauma will be used to determine if stress recruits pro-aggressive Crh+ CeA cell activity, and to experimentally block this recruitment and the development of trauma-induced aggression. Aim 3 (R00) will begin to explore top-down cortical regulation of this translational stress-induced aggressive phenotype. The insular cortex (IC) innervates Crh+ CeA cells and this projection is functionally linked to hostility in clinical experiments. Aim 3 will establish if social trauma increases aggression by amplifying IC inputs to Crh+ CeA neurons. The K99 phase of this project will support an important stage of my postdoctoral training in single-cell imaging and closed-loop all-optical