Hippocampal Mechanisms of Fear Extinction

描述(申请人提供)：焦虑症被认为是由与厌恶事件的记忆相关的异常情绪反应引起的。大多数形式的焦虑伴随着对威胁环境的普遍痛苦，这可以通过上下文依赖的恐惧条件反射来模拟。人类和啮齿动物通过经典的条件反射程序迅速获得对环境背景的恐惧反应。一种背景与一种被认为有害的刺激的单一配对会导致对持续多年的厌恶事件的长期记忆。然而，在没有有害刺激的情况下，几次重新暴露在条件反射环境中，通常会导致恐惧反应的下降，这一现象被称为消亡。尽管它在焦虑症中的重要性得到了越来越多的认识，但消亡的分子基础，特别是上下文相关恐惧的消退，还没有被很好地理解。这项拟议的研究旨在识别导致物种灭绝的关键分子机制，并将它们与背景恐惧获得的潜在机制区分开来。啮齿动物模型已经成功地被用来证实，包括蛋白质磷酸化和基因表达在内的海马区信号对于上下文相关的恐惧条件反射是必不可少的。我们假设，这些细胞内信号通路与基因反应的耦合改变导致了物种灭绝。通过结合免疫组织化学和免疫印迹方法，我们期望在灭绝过程中确定海马cAMP依赖的蛋白激酶、蛋白激酶C和丝裂原激活的和细胞外信号调节的激酶的主要底物。这些途径在调节基因反应和恐惧消退中的作用将通过结合药理学方法和遗传小鼠模型来确定。我们希望证明，海马体对调节背景恐惧消退的神经回路起着重要作用。已识别的信号转导通路可作为开发新的治疗方法的潜在靶点，以消除对环境背景威胁的持续恐惧，如在一般焦虑和创伤后应激障碍中观察到的。

DESCRIPTION (provided by applicant): Anxiety disorders are thought to result from abnormal emotional responses associated with memories of aversive events. Most forms of anxiety are accompanied by generalized distress in response to threatening environments that can be modeled by context-dependent fear conditioning. Humans and rodents rapidly acquire fear responses to environmental contexts by classical conditioning procedures. A single pairing of a context with a stimulus perceived as harmful leads to the formation of long-term memory of the aversive episode persisting for years. Nevertheless, several re-exposures to the conditioning context without the harmful stimulus commonly lead to a decline of the fear response, a phenomenon termed extinction. In spite of its increasingly recognized significance in anxiety disorders, the molecular basis of extinction, in particular extinction of context-dependent fear is not well understood. The proposed research is designed to identify the key molecular mechanisms leading to extinction and delineate them from mechanisms underlying acquisition of contextual fear. Rodent models have been successfully employed to establish that hippocampal signaling encompassing protein phosphorylation and gene expression is essential for context- dependent fear conditioning. We hypothesize that altered coupling of these intracellular signaling pathways to gene responses contributes to extinction. By combining immunohistochemical and immunoblot approaches we expect to identify the main hippocampal substrates of the cAMP-dependent protein kinase, protein kinase C and mitogen-activated and extracellular signal regulated kinase during extinction. The role of these pathways in the regulation of gene responses and fear extinction of will be determined by combining pharmacological approaches with genetic mouse models. We expect to demonstrate that the hippocampus significantly contributes to the neuronal circuitry regulating extinction of contextual fear. The identified signal transduction pathways may serve as potential targets for the development of new therapeutic approaches that would eliminate persistent fear of threatening environmental contexts as observed in general anxiety and post-traumatic stress disorder.