Cortical Mechanisms of Traumatic Stress

创伤性应激的皮质机制

• 批准号: 10467187
• 负责人: James P Herman
• 金额: $ 54.9万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467187
• 关键词: Address; Amygdaloid structure; Anatomy; Animals; Anterior; Attenuated; Automobile Driving; Behavior; Behavior Control; Behavioral; Bioinformatics; Biological; Brain; Chemosensitization; Data; Data Set; Development; Disease; Drug Targeting; Electrophysiology (science); Emotional; Exposure to; Extinction (Psychology); Female; Fright; Functional disorder; Gene Proteins; Genomics; Health; Hippocampus (Brain); Homologous Gene; Human; IL2 gene; Image; Immediate-Early Genes; Impairment; Individual; Informatics; Interneurons; Intervention; Knowledge; Learning; Link; Maintenance; Mediating; Modeling; Modification; Molecular; Negative Valence; Neuronal Plasticity; Neurons; Output; Parvalbumins; Pathologic; Pathology; Personal Satisfaction; Pharmacology; Physiological; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevention; Process; Proteome; Proteomics; Rattus; Regimen; Research; Rodent; Role; Signal Transduction; Stress; Synapses; Testing; Viral Vector; Woman; base; behavioral plasticity; biological adaptation to stress; cell type; cingulate cortex; conditioned fear; design; designer receptors exclusively activated by designer drugs; emotion regulation; experimental study; fear memory; human disease; insight; learning extinction; maladaptive behavior; male; men; multiple omics; neural circuit; optogenetics; physical conditioning; prevent; recruit; response; sex; stress resilience; synaptic function; transcriptome sequencing; trauma exposure; traumatic stress

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.

概括 创伤性压力暴露会引发行为和生理反应，从而损害健康和 幸福感，产生大脑和身体的变化，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，都具有相同的行为和生理特征 创伤性应激暴露的典型功能障碍，表明压力与疾病之间的联系。长- 该研究方向的长期目标是了解控制行为压力的大脑机制 反应，对于设计适应不良行为管理策略至关重要的知识 在与压力相关的疾病中。该提案质疑持久行为病理学背后的神经回路 与严重压力有关，重点关注边缘皮质（IL）连接在驱动病理学中的作用。事先的 研究和我们的初步数据提供了强有力的证据表明严重压力后 IL 兴奋性降低 人 IL 同系物的暴露和功能低下与 PTSD 相关。这个提议是 旨在了解应激引起的 IL 功能减退的机制，重点关注变化 内在过程和传入连接。目标1旨在测试IL的必要性和充分性 传入输入会导致恐惧适应（消退）中长期严重的压力引起的损伤 使用创伤暴露大鼠模型（单次长期暴露）在压力提醒后恢复恐惧 压力）。来自前边缘皮层 (PL) 和腹侧海马 (vHPA) 的 IL 传入连接的作用 SPS 诱导的恐惧病理学将使用病毒载体介导的兴奋性和抑制性表达进行测试 DREADD 和电路映射用于测试 PL-IL 和 vHPC-IL 电路的接合。目标2将使用 电生理学方法探索驱动 IL 活性低下的细胞和连接机制 继 SPS 之后，重点关注 PL 和 vHPC 预测的内在神经元兴奋性和突触驱动 伊利诺伊州。目标 3 将使用多维方法来识别 IL 低兴奋性的分子过程， 使用集成基因组、蛋白质组和激酶组数据的分析平台。研究将使用生物信息学 确定对男性和女性进行干预的可能药物靶点的方法。这些研究的结果 将为开发新的药理学和/或回路靶向干预策略提供信息，以促进 遭受创伤或严重压力的个体的压力恢复能力。