Mechanisms of Stress-Enhanced Aversive Conditioning

 描述(申请人提供)：在一些人中，创伤性的压力经历会留下持久的痛苦记忆。在另一些情况下，它们会导致分离性健忘症--无法有意识地获取创伤事件的记忆。然而，这种难以接近的记忆可能会深刻地扰乱情感和社交功能。在根本层面上，分离性健忘症被认为植根于状态依赖学习，在这种学习中，当大脑处于相同状态时，以某种情感或药物诱导的状态编码的记忆最容易被提取。对状态依赖学习的神经生物学的研究将使我们更好地理解分离性健忘症和与压力相关的精神病理的发展。利用小鼠模型，我们建议确定状态依赖恐惧条件反射的分子机制，以及它们影响社会行为的电路机制。我们将使用情境恐惧条件反射作为由海马体结构处理的情景记忆的模型。根据我们最近的发现，我们假设(1)海马区突触外GABAA受体(GABAAR)及其与催产素受体(OXTR)的性别特异性相互作用有助于状态依赖性恐惧条件反射；(2)这些机制通过干扰海马-外侧隔区回路而扰乱不同的社会行为表型。我们的具体目标是确定哪些突触外GABAAR复合体参与状态依赖性恐惧条件反射(目标1)，它们是如何受OXTR调节的(目标2)，以及它们是否通过背-海马-和腹侧海马-外侧隔回路影响社会行为(目标3)。我们期望证明OXTR对主要的GABA能效应有重要的海马区细分和性别依赖性的贡献。这些机制可能构成治疗伴随应激相关疾病的分离性症状和社会缺陷的新靶点。

 DESCRIPTION (provided by applicant): In some individuals, traumatic stressful experiences leave lasting painful memories. In others, they cause dissociative amnesia-an inability to consciously access memories of the traumatic events. Nevertheless, such inaccessible memories can profoundly disrupt affective and social functioning. At a fundamental level, dissociative amnesia is thought to be rooted in state-dependent learning, wherein memories encoded in a certain affective or drug-induced state can best be retrieved when the brain is in the same state. Research into the neurobiology of state-dependent learning will give us a better understanding of the development of dissociative amnesia and stress-related psychopathologies. Using mouse models, we propose to identify the molecular mechanisms of state-dependent fear conditioning and the circuit mechanisms by which they affect social behavior. We will use contextual fear conditioning as a model of episodic memory processed by the hippocampal formation. Based on our recent findings, we hypothesize that (1) hippocampal extrasynaptic GABAA receptors (GABAAR) and their sex-specific interactions with oxytocin receptors (Oxtr) contribute to state-dependent fear conditioning, and (2) these mechanisms disrupt distinct social behavioral phenotypes by interfering with hippocampal-lateral septal circuits. Our specific aims are designed to establish which extrasynaptic GABAAR complexes contribute to state-dependent fear conditioning (Aim 1), how they are regulated by Oxtr (Aim 2), and whether they affect social behavior through dorsohippocampal- and ventrohippocampal-lateral septal circuits (Aim 3). We expect to demonstrate important hippocampal subdivision- and sex-dependent contributions of Oxtr to the main GABAergic effects. These mechanisms could constitute new targets for the treatment of dissociative symptoms and social deficits accompanying stress-related disorders.