Glucocorticoid Receptor Mechanisms of Traumatic Stress Pathology

创伤应激病理学的糖皮质激素受体机制

• 批准号: 10480199
• 负责人: James P Herman
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480199
• 关键词: Address; Affect; Amygdaloid structure; Animal Model; Anterior; Anxiety; Automobile Driving; Behavior; Behavioral; Binding; Brain; Cells; Data; Decision Making; Development; Disease; Electrophysiology (science); Emotional; Emotions; Endocrine; Exposure to; Extinction (Psychology); Foundations; Fright; Functional disorder; Future; Gene Deletion; General Population; Generations; Genetic; Glucocorticoid Receptor; Glucocorticoids; Hormonal; Hormones; Human; Hydrocortisone; Impaired cognition; Impairment; Impulsivity; Incidence; Individual; Infusion procedures; Link; Machine Learning; Mediating; Memory; Memory impairment; Modeling; Modification; Nature; Neurons; Pathologic; Pathology; Pharmacology; Physiological; Pituitary Gland; Population; Post-Traumatic Stress Disorders; Predisposing Factor; Predisposition; Prefrontal Cortex; Prevention; Process; Pyramidal Cells; Rattus; Receptor Signaling; Regulation; Reproducibility; Research; Risk; Rodent; Rodent Model; Role; Selective Serotonin Reuptake Inhibitor; Severities; Signal Transduction; Stress; Stress Tests; Symptoms; Testing; Time; Trauma; Veterans; Viral Vector; Withdrawal; Woman; antagonist; anxiety symptoms; anxiety-related behavior; base; cellular pathology; cingulate cortex; conditioned fear; design; experimental study; fear memory; genetic variant; hormonal signals; hypothalamic-pituitary-adrenal axis; inattention; insight; memory process; men; military service; novel; patch clamp; post-trauma; receptor; receptor binding; receptor expression; receptor sensitivity; response; sexual assault; social; symptomatic improvement; trait; trauma exposure; traumatic stress

Incidence of post-traumatic stress disorder is a major problem for the VA, affecting roughly 13% of individuals serving in OIF or OEF. Women appear to be more susceptible to development of PTSD than men, often occurring in the context of sexual assault (which can occur during military service). Frontline treatment options can improve symptoms but do not currently offer a cure. To develop further strategies to this end, it is critical to understand the foundations of the disease process as it develops. The proposal is designed to test the hypothesis that hormonal responsiveness to stress and trauma are critical for driving susceptibility to development of behavior pathologies relevant to PTSD. In humans, PTSD is linked to heightened sensitivity to glucocorticoid signals, due to enhanced glucocorticoid receptor (GR) signaling (due to increased glucocorticoid receptor expression and/or decreased expression of its inhibitory binding partner FKBP5). Both GR and FKBP5 gene variants are linked to PTSD incidence or severity, indicating of a role as trait variable influencing disease development or progression. PTSD-related GR and HPA axis dysfunction are emulated in rodent models, suggesting that they contribute to pathological behaviors associated with trauma. Pathological mechanisms are thought to be driven by disruption of prefrontal cortex-amygdala connections controlling expression of fear, anxiety and emotional memory, processes that are in turn subject to regulation by stress hormones. This proposal tests the hypothesis that post-trauma glucocorticoid signaling disrupts prefrontal (infralimbic) cortex and amygdala circuitry responsible for fear regulation, causing lasting decrements in neurocircuit function and behavior. Here we employ pharmacological, genetic and physiological approaches to understand glucocorticoid control of neurocircuit mechanisms driving posttraumatic pathologies, using a well- characterized and reproducible rodent single prolonged stress (SPS) model to emulate core symptoms of PTSD. Aim 1 uses pharmacological approach to either block or amplify infralimbic cortex glucocorticoid signals in the aftermath of SPS, testing the impact of altered glucocorticoid receptor binding on generation of enhanced anxiety related behaviors, social withdrawal, impaired extinction of fear memories and impaired decision making. Novel machine learning approaches are used to model the constellation of behavioral deficits following SPS and determine how blocking or amplifying infralimbic GR signaling modifies the pathology model. Aim 2 uses a recently-developed conditional rat GR deletion model to test the specific role of the infralimbic GR signaling in mediating stress pathologies, including direct query of GR action across the infralimbic-basolateral amygdala connection. Aim 3 addresses possible mechanisms of post-SPS GR signaling in disruption of infralimbic-amygdala circuit function, employing electrophysiological approaches to test the role of GR signaling in causing long-term pathological reductions in prefrontal excitability. Overall, these data are expected to define the role GR binding in generation of neurocircuit pathology related to PTSD, providing a springboard for evaluating the utility of new or existing GR modulating agents as a putative disease treatment or prevention.

创伤后应激障碍的发病率是退伍军人事务部的一个主要问题，影响了大约 13% 的人 在 OIF 或 OEF 任职。女性似乎比男性更容易患上创伤后应激障碍（PTSD），通常 发生在性侵犯的背景下（可能发生在服兵役期间）。一线治疗选择 可以改善症状，但目前无法治愈。为此制定进一步的战略至关重要 了解疾病发展过程的基础。该提案旨在测试 假设荷尔蒙对压力和创伤的反应对于驱动易感性至关重要 与 PTSD 相关的行为病理学的发展。在人类中，创伤后应激障碍 (PTSD) 与对以下因素的高度敏感有关： 糖皮质激素信号，由于糖皮质激素受体（GR）信号增强（由于糖皮质激素增加） 受体表达和/或其抑制性结合伴侣 FKBP5 表达减少）。 GR 和 FKBP5 基因变异与 PTSD 发生率或严重程度相关，表明其作为性状变量的影响作用 疾病的发展或进展。在啮齿动物中模拟与 PTSD 相关的 GR 和 HPA 轴功能障碍 模型，表明它们有助于与创伤相关的病理行为。病理性的 机制被认为是由前额皮质-杏仁核连接的破坏驱动的 恐惧、焦虑和情绪记忆的表达，这些过程反过来又受到压力的调节 荷尔蒙。该提案测试了创伤后糖皮质激素信号传导破坏前额叶的假设 （边缘下）皮层和杏仁核电路负责恐惧调节，导致恐惧持续减少 神经回路的功能和行为。在这里，我们采用药理学、遗传和生理学方法来 使用良好的方法了解糖皮质激素对驱动创伤后病理的神经回路机制的控制 特征化且可重复的啮齿动物单一长期应激（SPS）模型，用于模拟核心症状 创伤后应激障碍。目标 1 使用药理学方法阻断或放大边缘下皮层糖皮质激素信号 在 SPS 后，测试改变的糖皮质激素受体结合对产生 焦虑相关行为增强、社交退缩、恐惧记忆消退受损和受损 决策。新颖的机器学习方法用于对一系列行为缺陷进行建模 遵循 SPS 并确定阻断或放大边缘下 GR 信号传导如何改变病理学 模型。 Aim 2使用最近开发的条件性大鼠GR缺失模型来测试GR的具体作用 边缘下 GR 信号在介导应激病理学中的作用，包括直接询问整个大脑的 GR 作用 下边缘-基底外侧杏仁核连接。目标 3 解决 SPS 后 GR 信令的可能机制 在边缘下杏仁核回路功能中断中，采用电生理学方法来测试其作用 GR 信号传导导致前额叶兴奋性长期病理性降低。总的来说，这些数据是 有望定义 GR 结合在与 PTSD 相关的神经回路病理学产生中的作用，提供 评估新的或现有的 GR 调节剂作为假定疾病治疗的效用的跳板 或预防。