Mechanisms of Stress-Enhanced Aversive Conditioning

压力增强厌恶性条件反射的机制

• 批准号: 10250615
• 负责人: Jelena Radulovic
• 金额: $ 23.58万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250615
• 关键词: Affect; Affective; Alcohols; Anxiety; Area; Arousal; Barbiturates; Benzodiazepines; Brain; Cognitive; Complex; Conscious; Data; Development; Dissociative Amnesias; Dissociative disorder; Distress; Dorsal; Episodic memory; Foundations; Fright; Glutamates; Hippocampal Formation; Hippocampus (Brain); Impairment; Individual; Interneurons; Lateral; Learning; Link; Mediating; Memory; Modeling; Molecular; Mood Disorders; Mus; Neurobiology; Neurons; Oxytocin Receptor; Pain; Parvalbumins; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Plant Roots; Post-Traumatic Stress Disorders; Process; Psychopathology; Publishing; Reporter; Research; Role; Schizophrenia; Sex Differences; Social Behavior; Social Functioning; Stress; Symptoms; System; Testing; Trauma; Unconscious State; Venus; aversive conditioning; base; behavioral phenotyping; conditioned fear; delta opioid receptor; dentate gyrus; design; effective therapy; emotional functioning; experience; memory encoding; memory process; mouse model; novel; programs; public health relevance; receptor; receptor expression; receptor function; response; sex; social; social deficits; stress related disorder; therapy design; traumatic event; traumatic stress

 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.

 描述（由申请人提供）：在一些人中，创伤性压力经历会留下持久的痛苦记忆。在其他情况下，它们会导致分离性失忆症--无法有意识地访问创伤事件的记忆。然而，这种难以接近的记忆会严重破坏情感和社会功能。从根本上说，解离性遗忘症被认为植根于状态依赖性学习，其中当大脑处于相同状态时，以某种情感或药物诱导状态编码的记忆可以最好地恢复。对状态依赖学习的神经生物学研究将使我们更好地理解分离性遗忘症和压力相关精神病理学的发展。 使用小鼠模型，我们建议确定状态依赖性恐惧条件反射的分子机制和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海马结构处理情景记忆的模型。基于我们最近的研究结果，我们假设：（1）海马突触外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-外侧隔回路破坏了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复合体有助于状态依赖性恐惧条件反射（目标1），它们如何受到Oxtr的调节（目标2），以及它们是否通过背海马和腹侧海马Campal-lateral septal回路影响社会行为（目标3）。我们希望证明重要的海马细分和性别依赖性贡献的Oxtr的主要GABA能的影响。这些机制可能构成新的目标，治疗解离症状和社会赤字伴随着压力相关的障碍。