Glucocorticoid Receptor Mechanisms of Traumatic Stress Pathology

创伤后应激障碍的发病率是退伍军人管理局的一个主要问题，大约13%的人受到影响 在OIF或OEF服务。女性似乎比男性更容易患上创伤后应激障碍，通常 发生在性侵犯的情况下(可能发生在服兵役期间)。一线治疗选择 可以改善症状，但目前还不能治愈。为此目的制定进一步的战略是至关重要的。 了解疾病发展过程的基础。该提案旨在测试 荷尔蒙对压力和创伤的反应性是导致易感性的关键假说 与创伤后应激障碍相关的行为病理学的发展。在人类中，创伤后应激障碍与对 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/或其抑制结合伙伴FKBP5的表达减少)。GR和 FKBP5基因变异与创伤后应激障碍的发生率或严重程度相关，表明FKBP5基因变异是影响创伤后应激障碍的特征变量 疾病的发展或进展。创伤后应激障碍相关的GR和HPA轴功能障碍在啮齿动物中的模拟 模型，表明它们促成了与创伤相关的病理行为。病理性的 机制被认为是由前额叶皮质-杏仁核控制连接的中断所驱动的 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。这一建议验证了创伤后糖皮质激素信号干扰前额叶的假设 (边缘以下)负责恐惧调节的大脑皮层和杏仁核回路，导致脑组织持续减少。 神经回路功能和行为。在这里，我们使用药理学、遗传学和生理学方法来 了解糖皮质激素对推动创伤后病理的神经回路机制的控制，使用好- 模拟鼠类核心症状的特征性和可重复性的单次持续应激模型 创伤后应激障碍。目标1使用药理学方法阻断或放大下缘皮质糖皮质激素信号 在SPS之后，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 做决定。新的机器学习方法被用于对行为缺陷的星座进行建模 并确定阻断或放大边缘下GR信号如何改变病理 模特。Aim 2使用最近开发的条件性大鼠GR缺失模型来测试 边缘下GR信号在介导应激病理中的作用，包括直接查询GR跨 下缘-基底外侧杏仁核连接。目标3阐述SPS后GR信令的可能机制 在破坏下缘-杏仁核回路功能的情况下，使用电生理方法来测试其作用 GR信号在导致前额叶兴奋性长期病理性降低中的作用。总的来说，这些数据是 期望定义GR结合在与创伤后应激障碍相关的神经回路病理发生中的作用，提供 评估新的或现有的GR调节剂作为假定的疾病治疗方法的有效性的跳板 或者是预防。

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.