Modulation of Fear Memory by Corticotropin-Releasing Factor in the Amygdala

描述（由申请人提供）：越来越多的人认识到，患有焦虑症的人类受试者在如何获得和/或消除条件性恐惧反应方面表现出异常。因此，理解焦虑和条件性恐惧如何在神经元水平上相互作用具有直接的临床意义。神经肽促肾上腺皮质激素释放因子（CRF）在压力和焦虑的条件下在整个大脑中释放。杏仁核含有特别密集的CRF受体，其激活导致焦虑行为。然而，这种神经肽对恐惧学习的调节以及焦虑和恐惧学习之间的相互作用还没有得到全面的研究。我们建议使用多种互补的方法来研究这个问题。我们将首先分析杏仁核（BLA）基底外侧核内CRF受体的解剖分布，确定这些受体是否位于BLA的主要兴奋性神经元和/或抑制性中间神经元的子集上。接下来，我们将从行为学角度研究CRF如何调节恐惧学习和表达。最后，利用离体电生理学方法，我们将研究CRF如何影响BLA神经元的电生理特性和突触可塑性。总之，这个提议中的实验代表了理解CRF如何调节巴甫洛夫恐惧条件反射的重要一步。因此，该项目的结果可能会对焦虑症的原因产生根本性的见解，并为临床研究和药物开发提供基础。 公共卫生相关性：许多焦虑症的特征是获得或消除条件性恐惧的异常。这个项目将探讨与焦虑相关的关键神经肽与学习和表达条件恐惧反应的能力之间的关系。

DESCRIPTION (provided by applicant): There is a growing realization that human subjects with anxiety disorders exhibit abnormalities in how they acquire and/or extinguish conditioned fear responses. Thus, understanding how anxiety and conditioned fear interact at the neuronal level has direct clinical relevance. The neuropeptide corticotropin-releasing factor (CRF) is released throughout the brain under conditions of stress and anxiety. The amygdala contains particularly dense concentrations of CRF receptors whose activation leads to anxious behaviors. Yet the modulation of fear learning by this neuropeptide and indeed the interaction between anxiety and fear learning has not been comprehensively explored. We propose to examine this question by using multiple complementary methods. We will first analyze the anatomical distribution of CRF receptors within the basolateral nucleus of the amygdala (BLA), determining whether these receptors are located on the principal excitatory neurons of the BLA and/or on subsets of inhibitory interneurons. We will next examine behaviorally how CRF modulates fear learning and expression. Finally, using in vitro electrophysiology, we will study how CRF affects electrophysiological properties of BLA neurons and synaptic plasticity. Together, the experiments in this proposal represent an important step in understanding how CRF modulates Pavlovian fear conditioning. Thus, the results of this project may yield fundamental insights into the causes of anxiety disorders and provide a foundation for clinical investigation and pharmaceutical development. PUBLIC HEALTH RELEVANCE: Many anxiety disorders can be characterized by abnormalities in acquiring or extinguishing conditioned fear. This project will explore the relationship between a key neuropeptide associated with anxiety and the ability to learn and express conditioned fear responses.