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.

总结 创伤性压力暴露会诱发行为和生理反应，可能危及健康， 健康，产生大脑和身体的变化，可以侵入适当的情绪调节。 许多疾病状态，最明显的是创伤后应激障碍， 创伤应激暴露的典型功能障碍，表明压力和疾病之间的联系。很长的- 这项研究的长期目标是了解控制行为压力的大脑机制 反应，知识，将是必不可少的设计策略，管理适应不良的行为 与压力有关的疾病这项提议质疑持久的行为病理背后的神经回路 与严重压力有关，重点是边缘皮层（IL）连接在驱动病理学中的作用。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 暴露和人IL同系物的功能性低活动与PTSD相关。这项建议是 旨在了解应激诱导的IL功能低下的机制， 内在过程和传入连接。目的1是为了检验信息学习的必要性和充分性 传入输入导致长期严重的压力诱导的恐惧适应障碍（灭绝）， 使用大鼠创伤暴露模型（单次延长）， 应力）。来自前边缘皮层（PL）和腹侧海马（vHPA）的IL传入联系在 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神经元的表达来测试。 DREADDs和电路映射用于测试接合PL-IL和vHPC-IL电路。目标2将使用 电生理学方法探索驱动IL低活性的细胞和连接机制 SPS后，专注于内在神经元兴奋性和突触驱动PL和vHPC投射到 IL.目的3将使用多维方法来识别IL低兴奋性的分子过程， 使用整合基因组、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。这些研究结果 将为新的药理学和/或靶向回路干预策略的开发提供信息， 压力恢复力在个人暴露于创伤或严重的压力。