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

糖皮质激素对情境处理及其神经回路的调节：测试 PTSD 病理生理学的新模型

• 批准号: 10358975
• 负责人: James L Abelson
• 金额: $ 56.56万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358975
• 关键词: Acute; American; Amygdaloid structure; Behavior; Behavioral; Biological Markers; Brain; Characteristics; Cognitive remediation; Complex; Cues; Development; Disease; Disease model; Environment; Episodic memory; Extinction (Psychology); Failure; Fostering; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Hair; Health; Hippocampus (Brain); Home; Hormonal; Hormones; Human; Hydrocortisone; Impairment; In Vitro; Individual; Intervention; Lead; Learning; Link; Loudness; Mediating; Memory; Modeling; Molecular; Muramidase; Neural Pathways; Neurobiology; Neurosecretory Systems; Noise; Outcome; Pathogenicity; Pathway interactions; Patients; Pattern; Performance; Physiological; Play; Post-Traumatic Stress Disorders; Prevention; Preventive; Primary Prevention; Process; Public Health; Retrieval; Risk; Risk Factors; Rodent; Role; Secondary Prevention; Severities; Shapes; Signal Transduction; Stress; Symptoms; System; Testing; Translating; Trauma; Up-Regulation; base; brain pathway; classical conditioning; disorder risk; hypothalamic-pituitary-adrenal axis; improved; learning extinction; neural circuit; neurobiological mechanism; neurophysiology; novel; phenomenological models; prevent; receptor; receptor sensitivity; relating to nervous system; response; trait; trauma exposure

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.

项目概要/摘要 50% 到 90% 的美国人遭受过可能导致创伤后应激障碍 (PTSD) 的创伤。 只有少数人会患上创伤后应激障碍（PTSD） 识别弱势群体并修改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。 正在被识别，但许多新兴模型仍然未知。 电路和行为，将我们的注意力扩展到简单的恐惧学习之外，以纳入更复杂的神经 调节对威胁的反应的电路研究这些电路及其功能已经产生了一种新颖的方法。 PTSD 病理生理学模型，重点关注情境处理（CP）和海马的缺陷 前额叶回路促进 CP 功能，这一模型得到了越来越多证据的支持，对此进行了很多解释。 该项目的目的是进一步研究 PTSD 的现象学，并整合其大部分神经生物学。 开发和测试该模型，并探索对治疗和预防的潜在影响。 即使在安全的环境中（例如， 难以将线索与环境联系起来可能是他们的核心问题，从而影响了对环境的访问。 海马体（Hpc）在调节适应性反应中发挥着关键作用。 在此过程中，调解核心 CP 功能，例如模式分离 (PS) 和模式完成 (PC)。 缺陷可能是 PTSD 中 CP 困难的基础，导致无法记住曾经发生过的事情 威胁现在是安全的（灭绝召回）或在危险信号与上下文相关时识别潜在危险 （恐惧更新）Hpc 中的糖皮质激素 (GC) 信号传导会损害 CP 功能，因此有证据表明 GC 增加。 PTSD 中的受体敏感性与已知的 CP 模型的遗传和发育因素一致。 形状 GC 敏感性可能通过影响 PS/PC 等 CP 功能而导致 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 PS/PC 和 HPC-PFC 等 CP 功能之间的联系 促进这些功能的神经通路，糖皮质激素信号在调节这些通路中的作用 第 120 章 健康受试者在低皮质醇、生理皮质醇、fMRI 中执行 PS/PC 和恐惧学习任务， GC 信号传导的升高（中度和高度）皮质醇水平将通过评估。 综合皮质醇分泌（头发皮质醇）和GC受体敏感性（体外溶菌酶抑制）该项目。 还将以相同的范式研究 150 名 PTSD 患者，以确定 PS/PC 过程是否是核心 PTSD 缺陷，通过 Hpc-PFC 与症状严重程度和消退回忆/恐惧更新缺陷相关 功能障碍，并测试 GC 通过影响 Hpc-PFC 通路“拯救”PTSD 中 CP 缺陷的能力。