Glucocorticoid modulation of contextual processing and its neurocircuitry: Testing a new model of PTSD pathophysiology

项目总结/摘要 50%到90%的美国人遭受过创伤，这可能导致创伤后应激障碍（PTSD）。 只有少数人会患上PTSD。识别弱势群体并改变将风险转化为疾病的过程 可以减轻这种严重疾病的公共卫生负担。危险因素和神经生物学机制是 正在确认，但仍有许多未知数。新兴模型识别相关基因，环境，大脑 电路和行为，将我们的关注点从简单的恐惧学习扩展到更复杂的神经网络学习。 调节对威胁的反应的电路。研究这些电路及其功能产生了一种新的 创伤后应激障碍病理生理学模型，重点是在上下文处理（CP）和海马- 前额叶回路支持CP功能。越来越多的证据支持这一模型， 创伤后应激障碍的现象学，并整合了它的神经生物学。该项目的目的是进一步 开发和测试这一模型，并探索治疗和潜在预防的意义。 创伤后应激障碍患者对模糊的线索反应恐惧（例如，大噪声）即使在安全环境中（例如， 家庭后院）。对他们来说，难以将线索与背景联系起来可能是一个核心问题， 应该调节适应性反应的上下文信息。海马体（Hpc）在 这个过程，调解核心CP功能，如模式分离（PS）和模式完成（PC）。PS/PC 缺陷可能是PTSD中CP困难的基础，导致无法记住曾经发生的事情。 威胁现在是安全的（灭绝回忆），或者当危险信号是上下文时识别潜在的危险 (fear更新）。Hpc中的糖皮质激素（GC）信号传导可损害CP功能，因此GC增加的证据 PTSD中的受体敏感性与CP模型一致。已知的遗传和发育因素 形状GC敏感性可能通过影响CP功能（如PS/PC）而导致PTSD风险， 由HPC-前额叶（PFC）回路内的活动/连接介导。 该项目将测试CP模型，检查CP功能（如PS/PC和Hpc-PFC）之间的联系 神经通路subserving这些功能，糖皮质激素信号在调节这些途径的作用 和功能，以及GC改善或破坏CP功能的能力。它将通过研究120 在低皮质醇、生理皮质醇、 和升高的（中度和高度）皮质醇水平。GC信号传导的“基线”水平将通过 整合皮质醇分泌（毛发皮质醇）和GC受体敏感性（体外溶菌酶抑制）。项目 我们还将以同样的模式研究150名PTSD患者，以确定PS/PC过程是否是核心 PTSD的缺陷，与症状严重程度和通过Hpc-PFC的灭绝回忆/恐惧更新缺陷相关 功能障碍，并测试GC的能力，以“拯救”CP赤字在PTSD，通过影响Hpc-PFC途径。

Project Summary/Abstract Fifty to 90% of Americans are exposed to trauma that can lead to Post-traumatic Stress Disorder (PTSD). Only a few develop PTSD. Identifying the vulnerable and modifying the processes that translate risk into illness could reduce the public health burden of this serious disease. Risk factors and neurobiological mechanism are being identified, but much remains unknown. Emerging models identify relevant genes, environments, brain circuits and behavior, expanding our focus beyond simple fear learning to incorporate more complex neural circuits that modulate responses to threat. Studying these circuits and their functions has generated a novel model of PTSD pathophysiology that focuses on deficits in context processing (CP) and on the hippocampal- prefrontal circuitry that subserves CP functions. This model is supported by growing evidence, explains much of PTSD's phenomenology, and integrates much of its neurobiology. The aim of this project is to further develop and test this model, and explore implications for treatment and, potentially, for prevention. PTSD patients respond fearfully to ambiguous cues (e.g., loud noise) even when in safe contexts (e.g., home backyard). Difficulty linking cues to contexts may be a core problem for them, undermining access to contextual information that should modulate adaptive responses. The hippocampus (Hpc) plays a key role in this process, mediating core CP functions like pattern separation (PS) and pattern completion (PC). PS/PC deficits may underlie CP difficulties in PTSD, contributing to an inability to remember that something once threatening is now safe (extinction recall) or to recognize potential danger when danger signals are contextual (fear renewal). Glucocorticoid (GC) signaling in Hpc can impair CP functions, so evidence of increased GC receptor sensitivity in PTSD is consistent with the CP model. Genetic and developmental factors known to shape GC sensitivity may contribute to PTSD risk through impact on CP functions like PS/PC, perhaps mediated by activity/connectivity within Hpc-prefrontal (PFC) circuits. This project will test the CP model, examining links between CP functions like PS/PC and the Hpc-PFC neural pathways subserving these functions, the role of glucocorticoid signaling in moderating these pathways and functions, and the ability of GCs to improve or undermine CP functions. It will do so by studying 120 healthy subjects performing PS/PC and fear learning tasks in fMRI, under low cortisol, physiological cortisol, and elevated (moderate and high) cortisol levels. “Baseline” levels of GC signaling will be assessed via integrated cortisol secretion (hair cortisol) and GC receptor sensitivity (in vitro lysozyme inhibition). The project will also study 150 PTSD patients in the same paradigm, to determine whether PS/PC processes are core deficits in PTSD, linked to symptom severity and extinction recall/fear renewal deficits via Hpc-PFC dysfunction, and to test the ability of GCs to “rescue” CP deficits in PTSD, via impact on Hpc-PFC pathways.