GABAergic and glucocorticoid regulation of CRH neurons and extinction of fear

描述（由申请人提供）：巴甫洛夫恐惧条件反射是在一个新的线索和引起恐惧的刺激之间获得联系的过程。恐惧消退是指当新的线索不再与恐惧刺激一起出现时，反应的下降。大量证据表明，恐惧条件反射的消失会导致新的联想的形成，这种联想与原始联想竞争，甚至可能抑制对原始联想的记忆（Myers和Davis， 2007）。这种消失观点的证据来自于这样的发现：在消失后，恐惧反应可以通过提醒性休克、时间的流逝（自发恢复）或环境的改变（更新）来恢复。大量数据强调了杏仁核在恐惧获得和消除中的核心作用。伽马氨基丁酸（GABA）是大脑中的主要抑制系统，因此杏仁核和其他大脑结构中的GABA能机制可能在调节消退学习中发挥关键作用。GABA抑制促肾上腺皮质激素释放激素（CRH），这是一种在压力下参与的神经肽。由于GABA和CRH在杏仁核内强烈地共定位，两者可能相互作用以调节灭绝。我们将研究CRH在恐惧学习中的作用，通过结合分子、药理学和病毒载体的方法来操纵CRH神经元的功能，特异性地改变含有CRH的神经元的放电和CRH肽的表达。综上所述，这些目标将进一步加深我们对CRH神经元的抑制调节以及这种调节在消除恐惧行为中的作用的理解。这些研究也将提供潜在的新操作，可能挽救灭绝的情况下，与压力有关的精神病理。

DESCRIPTION (provided by applicant): Pavlovian fear conditioning is the process of acquiring an association between a novel cue and a fear eliciting stimulus. Fear extinction is the decline in responding seen when the novel cue is no longer presented with the fearful stimulus. A great deal of evidence indicates extinction of fear conditioning results in the formation of a new association that competes with, and perhaps inhibits, memory for the original association (Myers and Davis, 2007). Evidence for this view of extinction comes from the findings that after extinction fear responding can be reinstated with a reminder shock, passage of time (spontaneous recovery) or a change in context (renewal). A large amount of data highlights the central role of the amygdala in fear acquisition and extinction. Gamma amino butyric acid (GABA) is the primary inhibitory system in the brain, therefore GABAergic mechanisms within the amygdala and perhaps other brain structures may play a critical role in modulating extinction learning. GABA inhibits corticotropin releasing hormone (CRH), a well characterized neuropeptide engaged during stress. The two may interact to modulate extinction, as GABA and CRH strongly colocalize within the amygdala. We will examine the role of CRH in fear learning by manipulating CRH neuronal function through a combination of molecular, pharmacological, and viral-vector approaches to specifically alter firing of CRH containing neurons and CRH peptide expression. Together these aims will further our understanding of inhibitory regulation of CRH neurons and the role of this regulation in extinction of fear behavior. These studies will also provide for potential novel manipulations that may rescue extinction in cases of stress-related psychopathology.