Role of the hippocampal GABA system in the development of post-traumatic stress

遗传倾向和儿童虐待和虐待已被确定为创伤后应激障碍和重度抑郁症发展的主要决定因素。我们最近开发了一种新的焦虑和情感障碍的动物模型，在该模型中，幼年大鼠暴露于压力下，会诱发成年期情绪创伤后出现焦虑或抑郁症状的倾向。我们建议使用该模型系统来探索抑制性gaba能神经元在成年期情绪应激和创伤后应激和创伤后抑郁易感性中的作用。我们关注GABA能机制，因为我们中的一个人（OS）先前的工作表明，GABA合成酶GAD65的缺乏会导致恐惧和焦虑的增加。此外，我们最近发现恐惧条件反射或幼年应激可以降低杏仁核中GAD65的表达。我们组建了一个由四个研究小组组成的团队，他们的专业知识从行为分析到系统分析，再到分子水平，目的是：1。幼鼠应激后海马突触后gaba能功能变化的表征。表征特定gaba能神经元的特性变化涉及应激后海马不同区域节律性活动的产生和可塑性。该项目提出了一种新的、综合的转化研究方法，以解决当今生物精神病学中最紧迫的问题之一——改善压力相关疾病的治疗，特别是创伤后应激障碍的治疗。在这里聚集的独特的整合团队确保了项目的原创和有效的进展，这将产生对创伤后应激障碍神经生物学的重要理解，这在今天显然是缺乏的。

Both genetic disposition and child maltreatment and abuse have been identified as majordeterminants in the development of posttraumatic stress disorder and major depression.We have recently developed a novel animal model of anxiety and affective disorders, in which theexposure of juvenile rats to stress induces a predisposition for the development of anxiety ordepressive symptoms following an emotional trauma in adulthood. We propose to use this modelsystem to explore the role of inhibitory GABAergic neurons in emotional stress in adulthood and inthe predisposition to the development of post-traumatic stress and post-traumatic depression.We focus on GABAergic mechanisms as previous work by one of us (OS) has shown that adeficiency in the GABA synthesizing enzyme, GAD65 results in increased fear and anxiety. Inaddition, we have recently shown that fear conditioning or juvenile stress can reduce the expressionof GAD65 in the amygdala. We have formed a team of four research groups with expertise ranging from behavioral analysis, to system analysis, to the molecular level with the aim of:1. Characterizing changes in postsynaptic GABAergic function in the hippocampusfollowing juvenile stress.2. Characterizing changes in properties of defined GABAergic neurons involved ingeneration of rhythmic activities and plasticity in different fields of the hippocampusfollowing stress.3. Developing strategies for intervention in the emergence of stress/depressionThe proposed project puts forward a novel, integrative approach for translational researchaddressing one of the most urgent issues in biological psychiatry today - improving treatment ofstress-related disorders, and in particular of post-traumatic stress disorder. The uniquely integratedteam assembled here ensures original and yet effective progression of the project that will yield avital understanding of the neurobiology of PTSD that is clearly lacking today.