Amygdala Circuit Mechanisms for Stress-escalated Aggression

人际暴力是导致创伤后应激障碍（PTSD）的主要原因，这是一种使人衰弱的综合症

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. This K99/R00 will support an important stage of my postdoctoral training in single- cell imaging and closed-loop all-optical approaches which will be necessary to continue exploring cortical underpinnings of dysregulated emotional reactivity. Mastering these versatile methodological approaches will guide my future independent research program in identifying translational connections between stress-sensitive neural systems and the complex orchestration of violent behaviors.