Glucocorticoid Receptor Mechanisms of Traumatic Stress Pathology

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，大约有13%的人受到影响

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.