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获得新线索和恐惧诱发刺激之间关联的过程。恐惧消退是当新线索不再与恐惧刺激一起呈现时，反应的下降。大量的证据表明，恐惧条件反射的消失会导致一种新的联想的形成，这种联想会与最初的联想竞争，甚至可能会抑制记忆（Myers和Davis，2007）。这种灭绝观点的证据来自于这样的发现，即在灭绝后，恐惧反应可以通过提醒休克、时间的推移（自发恢复）或环境的变化（更新）来恢复。大量的数据强调了杏仁核在恐惧获得和消除中的核心作用。γ-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起关键作用。GABA抑制促肾上腺皮质激素释放激素（CRH），一个很好的特点，神经肽从事在压力。这两者可能相互作用，以调节灭绝，因为GABA和CRH强烈共定位在杏仁核内。我们将研究CRH在恐惧学习中的作用，通过分子，药理学和病毒载体方法的组合来操纵CRH神经元功能，以特异性地改变CRH神经元和CRH肽表达的放电。这些目标将进一步加深我们对CRH神经元的抑制性调节以及这种调节在恐惧行为消退中的作用的理解。这些研究还将提供潜在的新的操作，可能挽救灭绝的情况下，与压力有关的精神病理学。

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.