GABAergic and glucocorticoid regulation of CRH neurons and extinction of fear

描述(由申请者提供)：巴甫洛夫恐惧条件作用是在新线索和引发恐惧的刺激之间建立联系的过程。恐惧消退是指当小说线索不再呈现可怕的刺激时，反应的下降。大量证据表明，恐惧条件作用的消失会导致一种新的联想的形成，这种联想与最初联想的记忆相竞争，甚至可能会抑制这种联想(Myers and Davis，2007)。这种灭绝观点的证据来自一项发现，即在灭绝后，恐惧反应可以通过提醒震惊、时间流逝(自发恢复)或环境变化(更新)来恢复。大量数据突显了杏仁核在恐惧获得和消退过程中的中心作用。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)，CRH是一种在应激过程中参与的具有良好特性的神经肽。当GABA和CRH强烈地共存于杏仁核时，两者可能相互作用以调节消亡。我们将研究CRH在恐惧学习中的作用，通过分子、药物和病毒载体相结合的方法来操纵CRH神经元的功能，从而特异性地改变含有CRH的神经元的放电和CRH多肽的表达。这些目的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消除恐惧行为中的作用的理解。这些研究还将提供潜在的新颖操作，在与压力相关的精神病理学病例中拯救灭绝。 公共卫生相关性：我们的发现可能对焦虑症的治疗具有很大的临床相关性，例如创伤后应激障碍(PTSD)，因为一个决定性的症状是在安全条件下对恐惧的抑制中断。这项拨款中提议的工作是操纵与抑制恐惧有关的神经过程。这些发现将增强我们对焦虑症的基本理解，并有助于发现新的药理靶点作为治疗衰弱焦虑症的工具。

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. PUBLIC HEALTH RELEVANCE: Our findings could have great clinical relevance for the treatment of anxiety disorders, such as post traumatic stress disorder (PTSD), because a defining symptom is disruption of the inhibition of fear under safe conditions. Work proposed within this grant manipulates neural processes involved in the inhibition of fear. These findings will enhance our basic understanding of anxiety disorders as well as inform the discovery of novel pharmacological targets as tools to treat debilitating anxiety disorders.