Effects of Cortisol Suppression on Fear-Potentiated Startle in Trauma & PTSD

描述（由申请人提供）：创伤后应激障碍（PTSD）发生在一些人暴露于导致极端恐惧或无助的事件后。世界各地的战区发生率和美国大城市中心暴力的普遍存在增加了暴露于创伤事件的可能性。在这些事件中幸存下来的人中，约有10%会发展出这种影响个人和家庭的衰弱性疾病。个体患者表现出不同症状群的程度可能不同，因此“一刀切”的治疗往往是不够的。这种个体差异可能与增加对疾病的脆弱性或阻碍治疗的生物风险因素有关。虽然基因和环境相互作用会增加个体患创伤后应激障碍的风险，但尚不清楚这些因素如何影响潜在的神经生物学，从而导致观察到的失调。创伤后应激障碍的特征是边缘系统的皮质控制受损，特别是杏仁核和海马体。此外，杏仁核投射还调节神经内分泌系统，即下丘脑-垂体-肾上腺（HPA）轴，这是应激反应的共同途径。皮质醇在这些大脑结构中起着重要的调节作用，并参与记忆的形成、加工和检索，特别是恐惧记忆。此外，PTSD的另一个神经生物学发现是地塞米松（一种皮质醇类似物）在HPA轴上的超敏感反馈。虽然杏仁核和皮质醇反馈功能在PTSD中已被单独研究，但这两个系统的相互作用尚未在同一患者中研究。这项拟议中的研究将提供创新的工具来梳理人类临床人群中杏仁核和HPA轴之间的关系。我们最近发现的HPA轴抑制和恐惧失调，加上新的恐惧条件反射范式的发展提供了一个独特的机会，询问杏仁核-HPA相互作用，以确定方面的神经生物学基础的病理创伤后应激障碍。

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) occurs in some people after exposure to events that cause extreme fear or helplessness. The incidence of war zones worldwide and the prevalence of violence in large urban centers in the U.S. increases the likelihood of exposure to traumatizing events. Of those who survive such events, approximately 10% will develop this debilitating disorder that affects both the individual and their family. Individual patients can vary in the degree to which they present with the different symptom clusters, such that a "one size fits all" treatment is often inadequate. This individual variation may be associated with biological risk factors that increase vulnerability to the disorder or impede treatment. While both genes and environment interact to increase an individual's risk of developing PTSD, it is unclear how the underlying neurobiology is shaped by these factors to result in the observed dysregulations. PTSD is marked by impaired cortical control of the limbic system, specifically the amygdala and hippocampus. Moreover, amygdala projections modulate neuroendocrine systems, namely the hypothalamic-pituitary-adrenal (HPA) axis, which is the common pathway of the stress response. Cortisol performs important regulatory functions in these brain structures, and participates in the formation, processing, and retrieval of memories, particularly fearful ones. Furthermore, another neurobiological finding in PTSD is hyper-sensitive feedback of dexamethasone, a cortisol analogue, on the HPA axis. Although amygdala and cortisol feedback function have been studied separately in PTSD, the interaction of these two systems has not been studied in the same patients. The proposed study will provide innovative tools to tease apart the relationship between the amygdala and the HPA axis in a human clinical population. Our recent discovery of HPA axis suppression and fear dysregulation coupled with the development of new fear conditioning paradigms provides a unique opportunity to interrogate the amygdala-HPA interactions to determine aspects of the neurobiological underpinnings of the pathology related to PTSD.