Neural mechanisms of extinction-resistant avoidance behavior

抗灭绝回避行为的神经机制

• 批准号: 7931236
• 负责人: Kevin D. Beck
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931236
• 关键词: Amygdaloid structure; Animal Model; Animals; Anterior; Anxiety Disorders; Area; Arousal; Association Learning; Attention; Aversive Stimulus; Avoidance Learning; Basic Science; Behavior; Behavioral; Cells; Characteristics; Cognitive; Cues; Development; Disinhibition; Environment; Epigenetic Process; Excision; Exhibits; Exposure to; Extinction (Psychology); Fright; Genetic; Hippocampus (Brain); Immunohistochemistry; Inbred WKY Rats; Inbreeding; Individual; Label; Learning; Light; Limbic System; Localized Lesion; Measures; Medial; Memory; Mental Health; Military Personnel; Neurobiology; Neurons; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Rattus; Reaction; Regulation; Research; Resistance; Risk; Role; Safety; Services; Shock; Signal Transduction; Source; Sprague-Dawley Rats; Stimulus; Stress; Symptoms; Techniques; Temperament; Testing; Thalamic structure; Training; Veterans; Visual; avoidance behavior; cell type; cingulate cortex; combat; coping; design; emotional adjustment; environmental stressor; inhibitor/antagonist; meetings; neuromechanism; programs; relating to nervous system; response; stressor

DESCRIPTION (provided by applicant): Veterans are at increased risk for developing anxiety disorders - particularly posttraumatic stress disorder (PTSD) -- in the aftermath of combat and service. Risk is conceptualized as genetic and epigenetic factors influencing vulnerability interacting with environmental stressors, coping strategies and availability of support. Avoidance, acquired behavioral and emotional adjustments in the face of aversive stimuli, concepts and memories, traces the course of anxiety disorders and is a critical component of PTSD. Our basic science research program is developing an animal model for understanding the role of vulnerability in avoidance learning. Inbred Wistar-Kyoto rats are stress sensitive and acquire active avoidance response faster and to a higher degree than outbred Sprague-Dawley rats. We have identified a critical feature that may explain one source of faster acquisition in WKY rats; the presence of an explicit cue during periods of non-threat, which may be encoded as an explicit signal safety signal or perceived as an additional aversive stimulus. Accordingly, AIM 1 will determine why the explicit visual cue presented during the non-threat inter-trial interval facilitates avoidance acquisition in WKY rats. AIM 2 will expose the neurobiological source of the vulnerability focusing on aspects of the medial prefrontal cortex (infralimbic, prelimbic, and anterior cingulate cortices), areas known to assess threat versus safety and avoidance learning. Consequently, this area is also implicated in causing anxiety disorders. Thus, our program is designed to expose one source of risk for the development of anxiety disorders and PTSD in particular. For the vulnerable, the processing of safety versus threat escalates normal avoidance and coping to a pathological level which is resistant to extinction and treatment. Counteracting the neurobiological processes sub-serving enhanced processing of threat and safety in the medial prefrontal cortex will reduce avoidance to tolerable levels. PUBLIC HEALTH RELEVANCE: Narrative Anxiety disorders, including post-traumatic stress disorder, are a significant mental health issue for a significant proportion of military service veterans. Individuals with behaviorally-inhibited temperaments are especially vulnerable to developing these anxiety disorders following exposure to stressors. Avoidance, whether cognitive or behavioral, is a common symptom across all anxiety disorders. Our hypothesis is that the behaviorally inhibited are vulnerable to developing anxiety disorders because they are more akin to learning avoidance behaviors, while also being more resistant to extinguishing those behaviors once acquired. This program is focused on identifying the neural processes that facilitate avoidance learning in those with a behaviorally-inhibited temperament; specifically as they pertain to the role perceived threatening stimuli and safety signals in the environment have in influencing this acquisition process.

描述（由申请人提供）： 退伍军人在战斗和服役后患焦虑症的风险增加，尤其是创伤后应激障碍（PTSD）。风险被概念化为影响脆弱性的遗传和表观遗传因素与环境压力源、应对策略和支持可用性的相互作用。回避，即面对厌恶刺激、概念和记忆时获得的行为和情绪调整，可以追踪焦虑症的病程，也是创伤后应激障碍的重要组成部分。我们的基础科学研究计划正在开发一种动物模型，以了解脆弱性在回避学习中的作用。近交 Wistar-Kyoto 大鼠对压力敏感，比远交 Sprague-Dawley 大鼠更快、更高程度地获得主动回避反应。我们已经确定了一个关键特征，可以解释 WKY 大鼠更快获取的一个来源；在非威胁期间存在明确的提示，该提示可以被编码为明确的信号安全信号或被视为额外的厌恶刺激。因此，AIM 1 将确定为什么在非威胁试验间隔期间呈现的明确视觉提示有助于 WKY 大鼠的回避习得。 AIM 2 将揭示脆弱性的神经生物学根源，重点关注内侧前额叶皮层（边缘下皮层、前边缘皮层和前扣带皮层）的各个方面，这些区域已知用于评估威胁与安全和回避学习。因此，该区域也与引起焦虑症有关。因此，我们的计划旨在揭露焦虑症和创伤后应激障碍（PTSD）发展的风险来源之一。对于弱势群体来说，安全与威胁的处理将正常的回避和应对升级到无法消除和治疗的病理水平。抵消神经生物学过程，增强内侧前额叶皮层对威胁和安全的处理，将把回避行为降低到可容忍的水平。 公共卫生相关性： 叙事焦虑症，包括创伤后应激障碍，对于很大一部分退伍军人来说是一个重要的心理健康问题。具有行为抑制气质的人在暴露于压力源后特别容易患上这些焦虑症。回避，无论是认知还是行为，是所有焦虑症的常见症状。我们的假设是，行为抑制者很容易患上焦虑症，因为他们更类似于学习回避行为，同时也更难以消除这些行为一旦获得。该项目的重点是识别促进行为抑制气质人群回避学习的神经过程；特别是因为它们涉及环境中感知到的威胁刺激和安全信号在影响这一获取过程中的作用。