Amygdala Circuit Mechanisms for Stress-escalated Aggression

杏仁核回路应对压力升级攻击的机制

基本信息

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
项目类别：
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

项目摘要

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，这是一种衰弱的综合征其特征是睡眠障碍，倒叙和情绪反应失调。对于某些创伤 - 暴露的个人，在情绪调节中定义可以升级为侵略性，从而使人际暴力和创伤。了解压力源如何影响侵略性的神经回路为这种形式的暴力开发有效疗法的基础。中央杏仁核（CEA）神经元表达特征良好的应力信号神经肽，皮质激素释放的马酮（CRH）至关重要恐惧引起的反应的介体，以及通过我的博士后单细胞钙成像训练 Ressler Lab，我在出现进攻期间发现了一个独特的CRH+ CEA细胞活动签名侵略。在AIM 1（K99）中，我将使用闭环光遗传学扩展这些初步发现以了解 CRH+ CEA细胞在开始攻击中的因果作用。使用我的小说和最近验证的社会模型创伤引起的侵略性 - 实验小鼠在其家庭环境内部被一个占主导地位的入侵者 - 有可能探索暴力对恐惧巡回赛的影响。这种暴露于创伤的小鼠采取更高的防御策略，包括非典型，广泛的积极对非威胁性社会的积极进取合作伙伴。在AIM 2（R00）中，这种社会创伤模型将用于确定压力是否招募促进性 CRH+ CEA细胞活性，并实验阻止这种募集和创伤引起的发展 AIM 3（R00）将开始探索这种翻译应力引起的自上而下的皮质调节积极的表型。 Intular Cortex（IC）支配CRH+ CEA细胞，并且该投影在功能上链接在临床实验中的敌意。 AIM 3将确定社会创伤是否通过扩增IC来提高侵略性 CRH+ CEA神经元的输入。这款K99/R00将支持我在单一培训的博士后培训的重要阶段细胞成像和闭环全光学方法，这是继续探索皮质的必要条件情绪反应失调的基础。掌握这些多功能的方法论方法将指导我未来的独立研究计划，以识别对压力敏感的转化连接神经系统和暴力行为的复杂编排。