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起行为和生理反应，这些反应会损害健康和 幸福感，产生大脑和身体变化，可以侵入适当的情绪调节。 许多疾病状态，最著名的是创伤后应激障碍，具有行为和生理性 创伤性压力暴露的典型功能障碍，表明压力与疾病之间存在联系。长期 该研究线的术语目标是了解控制行为压力的大脑机制 回应，知识对于设计管理不良行为的策略至关重要 在压力连接的疾病中。该建议查询持久行为病理的神经通路 与严重的压力有关，重点是内边皮质（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有力的证据，证明了严重压力后IL兴奋性降低 人IL同源物的暴露和功能性低与PTSD有关。该提议是 旨在了解应力引起的IL功能障碍的基础机制，集中于变化 在内在过程和传入连接性中。 AIM 1旨在测试IL的必要性和充分性 传入的输入，导致持续持续的严重压力引起的恐惧适应（灭绝）和 使用大鼠的创伤暴露模型恢复应力提醒之后的恐惧（单一延长 压力）。 IL参与连接的作用来自前Bic皮层（PL）和腹侧海马（VHPA）在 SPS诱导的恐惧病理将使用病毒载体介导的兴奋性和抑制性表达进行测试 可怕的以及用于测试参与度PL-IL和VHPC-IL电路的电路映射。 AIM 2将使用 电生理方法探索驱动IL降低性的细胞和连接机制 遵循SPS，专注于PL和VHPC投影的固有神经元激发和突触驱动 il。 AIM 3将使用多维方法来识别IL缺点性的分子过程， 使用集成基因组，蛋白质组和Kinome数据的分析平台。研究将使用生物信息学 确定可能对男性和女性进行干预的药物靶标的方法。这些研究的结果 将告知开发新的药理和/或涉及电路的干预策略以促进 受到创伤或严重压力的个体的压力弹性。