Neural mechanisms of extinction-resistant avoidance behavior

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，特别是创伤后应激障碍（PTSD）。风险的概念是影响脆弱性的遗传和表观遗传因素，与环境压力、应对策略和支持的可用性相互作用。回避，在面对厌恶性刺激，概念和记忆时获得的行为和情绪调整，追溯了焦虑症的过程，是PTSD的关键组成部分。我们的基础科学研究项目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。近交系Wistar-Kyoto大鼠是应激敏感的，并且比远交系Sprague-Dawley大鼠更快地获得主动回避反应，并且获得的程度更高。我们已经确定了一个关键的功能，可以解释一个来源的更快的收购WKY大鼠;在非威胁期间，这可能是编码为一个明确的信号安全信号或感知为一个额外的厌恶刺激的一个明确的线索的存在。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大鼠的回避获取。AIM 2将揭示脆弱性的神经生物学来源，重点关注内侧前额叶皮层（边缘下、边缘前和前扣带皮层），这些区域已知用于评估威胁与安全和回避学习。因此，这个区域也与引起焦虑症有关。因此，我们的计划旨在揭示焦虑症和创伤后应激障碍的风险来源之一。对于脆弱者来说，安全与威胁的处理将正常的回避和应对升级到一个病理水平，这个水平抵抗灭绝和治疗。在内侧前额叶皮层中，抵消辅助增强威胁和安全处理的神经生物学过程将使回避减少到可容忍的水平。 公共卫生相关性： 叙事焦虑症，包括创伤后应激障碍，是一个重要的心理健康问题，为一个显着比例的退伍军人。具有行为抑制气质的个体在暴露于压力源后特别容易发展这些焦虑症。回避，无论是认知还是行为，都是所有焦虑症的共同症状。我们的假设是，行为受抑制的人容易患上焦虑症，因为他们更类似于学习回避行为，同时也更不愿意在获得这些行为后将其消除。该计划的重点是识别促进行为抑制气质的人避免学习的神经过程;特别是因为它们与环境中感知到的威胁刺激和安全信号在影响这种获取过程中的作用有关。

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.