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， 其特征是睡眠障碍、闪回和情绪反应失调。因为一些创伤- 暴露的个体，情绪调节的缺陷可以升级为攻击性，从而使一个循环永久化。 人际暴力和创伤。了解压力源如何影响攻击性的神经回路， 这是为这种形式的暴力制定有效疗法的基础。中央杏仁核（CeA）神经元， 表达特征明确的应激信号神经肽促肾上腺皮质激素释放激素（Crh）， 介质的恐惧引起的反应，并通过我的博士后单细胞钙成像培训， Ressler实验室，我已经确定了一个独特的Crh+ CeA细胞活动的签名，在出现进攻 侵略在目标1（K99）中，我将使用闭环光遗传学来扩展这些初步发现，以了解 Crh+ CeA细胞在发起攻击中的因果作用。使用我的小说和最近验证的社会模型， 创伤诱导的攻击-实验小鼠在其家庭环境中受到攻击， 主导入侵者-有可能探索暴力对恐惧回路的影响。这种创伤暴露的小鼠 采取强化的防御策略，包括非典型的，对非威胁性社会的普遍攻击 伙伴在目标2（R 00）中，这个社会创伤模型将用于确定压力是否会招募亲攻击性 Crh+ CeA细胞活性，并通过实验阻断这种募集和创伤诱导的 侵略目标3（R 00）将开始探索这种翻译应力诱导的自上而下的皮质调节。 攻击型岛叶皮质（IC）支配Crh+ CeA细胞，并且这种投射在功能上与 临床实验中的敌意目标3将确定社会创伤是否通过放大IC来增加攻击性 Crh+ CeA神经元的输入。这个K99/R 00将支持我的博士后培训的一个重要阶段，在单- 细胞成像和闭环全光学方法，这将是必要的，继续探索皮层 情绪反应失调的基础掌握这些通用的方法论方法将 指导我未来的独立研究计划，以确定压力敏感之间的翻译联系， 神经系统和暴力行为的复杂协调。

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.