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

描述(申请人提供)：创伤后应激障碍(PTSD)在一些人暴露于导致极端恐惧或无助的事件后发生。世界各地战区的发生和美国大城市中心的暴力盛行增加了暴露在创伤事件中的可能性。在这些事件中幸存下来的人中，大约10%会患上这种既影响个人又影响家庭的衰弱障碍。个别患者出现不同症状群的程度可能有所不同，因此“一刀切”的治疗往往是不够的。这种个体变异可能与增加疾病易感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人患创伤后应激障碍的风险，但尚不清楚这些因素如何塑造潜在的神经生物学，从而导致观察到的失调。创伤后应激障碍的特点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，这是应激反应的常见途径。皮质醇在这些大脑结构中发挥着重要的调节功能，并参与记忆的形成、处理和恢复，特别是恐惧记忆。此外，创伤后应激障碍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轴上的高度敏感反馈。虽然杏仁核和皮质醇反馈功能在创伤后应激障碍中已经被分开研究，但这两个系统的相互作用在同一患者中还没有被研究过。这项拟议的研究将提供创新的工具，在人类临床人群中梳理杏仁核和HPA轴之间的关系。我们最近发现的HPA轴抑制和恐惧失调，再加上新的恐惧条件反射范式的发展，为我们提供了一个独特的机会来询问杏仁核-HPA的相互作用，以确定与创伤后应激障碍相关的病理的神经生物学基础。

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.