Cortical Mechanisms of Traumatic Stress

摘要 创伤应激暴露引起的行为和生理反应可能危及健康和 健康，产生大脑和身体的变化，这可能会干扰适当的情绪调节。 许多疾病状态，尤其是创伤后应激障碍，具有共同的行为和生理特征 创伤应激暴露的典型功能障碍，表明压力和疾病之间存在联系。长的- 这项研究的目标是了解控制行为压力的大脑机制。 应对，这是设计管理不良适应行为的策略所必需的知识 与压力相关的障碍。这一提议质疑持久行为病理背后的神经回路。 与严重的压力有关，重点关注边缘内皮质(IL)连接在驱动病理中的作用。之前 研究和我们的初步数据提供了强有力的证据，表明严重应激后IL兴奋性降低 暴露，人类IL同系物的功能低下与创伤后应激障碍有关。这项建议是 旨在了解应激导致IL功能低下的潜在机制，专注于变化 在内在过程和传入连接方面。目标1旨在测试IL的必要性和充分性 传入输入导致恐惧适应(消退)和长期严重应激诱导的损害 使用创伤暴露的大鼠模型(单次延长)，在压力提醒后恢复恐惧 压力)。大鼠前脑皮质(PL)和腹侧海马区(VHPA)的IL传入联系在脑损伤中的作用 将利用病毒载体介导的兴奋性和抑制性表达来检测SPS诱导的恐惧病理 DREADD，以及用于测试接合PL-IL和vHPC-IL电路的电路映射。AIM 2将使用 探索导致IL活性低下的细胞和连接机制的电生理方法 SP后，重点研究PL和vHPC投射到丘脑的固有神经元兴奋性和突触驱动。 伊。AIM 3将使用多维方法来确定IL低兴奋性背后的分子过程， 使用一个整合了基因组、蛋白质组和基因组数据的分析平台。研究将使用生物信息学 确定男性和女性干预的可能药物靶点的方法。这些研究的结果 将为开发新的药理和/或环路靶向干预策略提供信息，以促进 暴露在创伤性或严重压力下的个体的压力恢复能力。

Summary Traumatic stress exposure elicits behavioral and physiological responses that can compromise health and well-being, generating brain and bodily changes that can intrude on appropriate emotional regulation. Numerous disease states, most notably post-traumatic stress disorder, share behavioral and physiological dysfunctions typical of traumatic stress exposure, indicative of a link between stress and disease. The long- term objective of this research line is to understand brain mechanisms that control behavioral stress responses, knowledge that will be essential for designing strategies for management of maladaptive behaviors in stress-linked disorders. This proposal queries the neurocircuitry underlying lasting behavioral pathologies linked to severe stress, focusing on the role of intralimbic cortex (IL) connections in driving pathology. Prior research and our preliminary data present strong evidence for reduced IL excitability following severe stress exposure, and functional hypoactivity of the human IL homolog is associated with PTSD. This proposal is designed to understand the mechanisms underlying stress-induced IL hypofunction, concentrating on changes in intrinsic processes and afferent connectivity. Aim 1 is designed to test the necessity and sufficiency of IL afferent input in causing long-lasting severe stress-induced impairments in fear adaptation (extinction) and reinstatement of fear following stress reminders, using a rat model of trauma exposure (single prolonged stress). The role of IL afferent connections from the prelimbic cortex (PL) and ventral hippocampus (vHPA) in SPS-induced fear pathology will be tested using viral vector mediated expression of excitatory and inhibitory DREADDs, and circuit mapping employed to test engagement PL-IL and vHPC-IL circuitry . Aim 2 will use electrophysiological approaches to explore cellular and connectional mechanisms driving IL hypoactivity following SPS, focusing on intrinsic neuronal excitabilty and synaptic drive by PL and vHPC projections to the IL. Aim 3 will use a multi-dimensional approach to identify molecular processes underlying IL hypoexcitability, using an analysis platform integrating genomic, proteome and kinome data. Studies will use bioinformatic approaches to determine possible drug targets for intervention in males and females. Results of these studies will inform development of new pharmacological and/or circuit-targeting intervention strategies to promote stress resilience in individuals exposed to traumatic or severe stress.