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: 9521159
• 负责人: James L Abelson
• 金额: $ 77.58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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/9521159
• 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 environment; 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; 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.

项目摘要/摘要 50%到90%的美国人暴露在创伤中，这可能导致创伤后应激障碍(PTSD)。 只有少数人会患上创伤后应激障碍。识别脆弱人群并修改将风险转化为疾病的流程 可以减轻这一严重疾病的公共卫生负担。危险因素和神经生物学机制 目前正在确认身份，但仍有许多未知之处。新兴模型识别相关基因、环境、大脑 电路和行为，将我们的重点从简单的恐惧学习扩展到包括更复杂的神经 调节对威胁的反应的回路。对这些电路及其功能的研究产生了一种新的 创伤后应激障碍的病理生理学模型，关注上下文处理(CP)和海马区的缺陷- 辅助CP功能的前额叶回路。这一模型得到了越来越多的证据的支持，解释了许多 创伤后应激障碍的现象学，并整合了它的许多神经生物学。该项目的目的是进一步 开发和测试这一模型，并探索对治疗和潜在的预防的影响。 创伤后应激障碍患者即使在安全的环境中(例如， 自家后院)。难以将线索与上下文联系起来可能是他们的核心问题，破坏了访问 应该调节适应性反应的背景信息。海马体(HPC)在 在这个过程中，中介核心CP的功能类似于模式分离(PS)和模式完成(PC)。PS/PC 缺陷可能是创伤后应激障碍的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(灭绝召回)，或者当危险信号与背景相关时识别潜在危险 (恐惧更新)。HPC中的糖皮质激素(GC)信号会损害CP功能，因此GC增加的证据 创伤后应激障碍的受体敏感性符合CP模型。已知的遗传和发育因素 形状GC敏感性可能通过影响PS/PC等CP功能而导致创伤后应激障碍风险 由HPC-前额叶(PFC)回路内的活动/连通性调节。 本项目将测试CP模型，检查PS/PC等CP功能与HPC-PFC之间的链接 辅助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 和功能，以及GC改善或削弱CP功能的能力。它将通过研究120来做到这一点 健康受试者在低皮质醇，生理皮质醇， 皮质醇水平升高(中度和高度)。GC信号的“基准”水平将通过以下方式进行评估 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)。该项目 我还将在相同的范式下研究150名PTSD患者，以确定PS/PC过程是否为核心 创伤后应激障碍，通过HPC-PFC与症状严重程度和消退回忆/恐惧更新缺陷相关 通过对HPC-PFC通路的影响，测试GCs在创伤后应激障碍中“挽救”CP缺陷的能力。