Hippocampal Mechanisms of Fear Extinction

描述（由申请人提供）：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。大多数形式的焦虑都伴随着普遍性的痛苦，这是对威胁环境的反应，可以通过情境依赖恐惧条件反射来模拟。人类和啮齿动物通过经典条件反射程序快速获得对环境背景的恐惧反应。将一个情境与一个被认为有害的刺激单独配对，就会形成持续数年的厌恶事件的长期记忆。然而，在没有有害刺激的情况下，多次重新暴露于条件反射环境通常会导致恐惧反应的下降，这种现象被称为消退。尽管它在焦虑障碍中的重要性日益得到认可，但灭绝的分子基础，特别是情境依赖性恐惧的灭绝，还没有得到很好的理解。本研究旨在确定导致灭绝的关键分子机制，并从情境恐惧习得的机制中描述它们。啮齿类动物模型已经成功地建立了海马信号包括蛋白磷酸化和基因表达是必要的环境依赖性恐惧条件反射。我们假设这些细胞内信号通路与基因反应的改变耦合有助于灭绝。通过结合免疫组织化学和免疫印迹方法，我们希望确定camp依赖性蛋白激酶、蛋白激酶C和丝裂原激活和细胞外信号调节激酶在消失过程中的主要海马底物。这些途径在基因反应和恐惧消退的调控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情境恐惧消失的神经回路有重要贡献。已确定的信号转导通路可能作为开发新的治疗方法的潜在目标，这些治疗方法将消除在一般焦虑和创伤后应激障碍中观察到的对威胁环境的持续恐惧。

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.