Amygdala Circuit Mechanisms for Stress-escalated Aggression

杏仁核回路应对压力升级攻击的机制

• 批准号: 10722577
• 负责人: Emily L Newman
• 金额: $ 12.77万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722577
• 关键词: Acute; Adopted; Affect; Aggressive behavior; Amygdaloid structure; Brain; Brain region; Breeding; CRH gene; Calcium; Cells; Clinical; Complex; Corticotropin-Releasing Hormone; Data; Decision Making; Deep Brain Stimulation; Detection; Development; Emotional; Ensure; Exhibits; Exposure to; Female; Fright; Future; Generations; Goals; Home; Home environment; Hostility; Hybrids; Image; Impairment; Individual; Interpersonal Violence; Investigation; Link; Maps; Mediating; Mediator; Methodology; Modeling; Molecular; Mus; Neurons; Neuropeptides; Operative Surgical Procedures; Optics; Pathologic; Phase; Phenotype; Play; Population; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Prevention; Process; Protocols documentation; Reaction; Regulation; Research; Role; Sensory; Signal Transduction; Sleep disturbances; Social Behavior; Social Controls; Specificity; Stress; Stress Tests; Structure; Synapses; Syndrome; System; Time; Training; Translational Regulation; Trauma; Violence; Work; behavioral response; career development; cellular imaging; data hub; design; effective therapy; emotion regulation; experience; experimental study; fighting; interpersonal trauma; machine learning algorithm; male; neural; neural circuit; novel; novel therapeutics; offspring; optogenetics; post-doctoral training; prevent; programs; recruit; response; sex; social; social defeat; social stress; stressor; supervised learning; theories; translational model; trauma exposure

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.

人际暴力是创伤后应激障碍(PTSD)的主要原因，PTSD是一种令人衰弱的综合征 以睡眠障碍、闪回和情绪反应失调为特征。对于一些创伤- 暴露在风险中的个体，情绪调节的缺陷可能升级为攻击性，从而使 人际暴力和精神创伤。了解应激源如何影响攻击性的神经回路 这是为这种形式的暴力开发有效疗法的基础。中央杏仁核(CEA)神经元 表达具有良好特性的应激信号神经肽，促肾上腺皮质激素释放激素(CRH)是至关重要的 恐惧诱导反应的媒介，并通过我的博士后单细胞钙成像培训 Ressler Lab，我在攻击性疾病的出现过程中发现了一个明显的CRH+CEA细胞活动特征 攻击性。在目标1(K99)中，我将使用闭合环光遗传学来扩展这些初步发现，以理解 CRH+CEA细胞在启动攻击中的因果作用。使用我最近验证的新的社交模型 创伤诱导的攻击--实验小鼠在其家庭环境中受到 强势入侵者--探索暴力对恐惧回路的影响是可能的。这样的创伤暴露小鼠 采取强化防御策略，包括对不具威胁性的社会群体进行非典型的、普遍的攻击 合伙人。在目标2(R00)中，这个社会创伤模型将被用来确定应激招募的人是否具有攻击性 CRH+CEA细胞活性，并实验阻断这种募集和创伤诱导的发展 攻击性。目标3(R00)将开始探索这种翻译应激诱导的自上而下的皮质调节 攻击性表型。岛叶皮质(IC)支配CRH+CEA细胞，这种投射在功能上是相连的 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神经元的传入。这款K99/R00将支持我的博士后培训的一个重要阶段-- 细胞成像和闭路全光学方法，这将是继续探索皮质所必需的 情绪反应失调的基础。掌握这些多才多艺的方法将会 指导我未来的独立研究计划，识别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。