Effects of maternal immune activation on offspring GABA circuitry and behavior

 描述(由申请人提供)：我的职业目标是利用动物系统进行独立的翻译研究，以了解与精神病理学相关的行为异常背后的神经生物学机制，总体目标是开发新的治疗策略。我的研究兴趣集中在了解：1)产前母体免疫激活(MIA)是多种形式精神病理学的早期环境风险因素，如何改变前额叶皮质(PFC)、腹侧海马(VHipp)和基底外侧杏仁核(BLA)中离散的GABA能中间神经元亚群的功能；2)这些中间神经元亚群中的活动如何调节认知和情感行为。通过完善我们对不同类别的中间神经元在电生理和行为水平上对前额叶、海马体和杏仁核功能的贡献的理解，我希望能产生更准确的想法，如何纠正有认知和情感症状的患者的GABA能失衡。K01职业发展奖将为我提供受保护的时间，以获得我所需的技术和智力培训 解决上述问题，促进我向建立独立研究项目的过渡。我的主要专长是翻译小鼠模型，以及用于表征它们的分子、细胞、生理和行为分析。我的职业发展计划在此背景下展开，提出了光遗传技术的基本培训，认知和情感行为领域的智力培训，以及进一步的 专业发展技能，如拨款撰写和实验室管理。研究项目。前额叶GABA能中间神经元的异常被认为是几种精神疾病的病理生理学的组成部分。然而，受到功能影响的GABA能中间神经元的特定群体，以及它们与行为异常的关系，还不是很清楚。精神疾病的环境或遗传风险因素的动物模型为直接分析与精神障碍相关的特定群体的PFC GABA能中间神经元的功能变化提供了机会。我在母体免疫激活的小鼠模型中的初步研究发现，在成年MIA后代中，PFC GABA能传递显著减少。在这项提议中，我将使用光遗传学和切片电生理学来揭示PFC中间神经元的哪些群体导致了这种缺陷。接下来，我将使用活体光遗传学来探索这些改变对认知和情感行为的影响。最后，我将通过检测vHipp和BLA中的GABA能传递，以及不同群体的vHipp和BLA中间神经元在认知和情感行为中的作用，来研究成年MIA后代的GABA能缺陷是否是PFC特有的。

 DESCRIPTION (provided by applicant): My career goal is to conduct independent translational research using animal systems to understand neurobiological mechanisms that underlie behavioral abnormalities relevant to psychopathology, with the overall goal of developing new therapeutic strategies. My research interests center on understanding: 1) How prenatal maternal immune activation (MIA), an early environmental risk factor for multiple forms of psychopathology, alters the function of discrete GABAergic interneuron sub-populations in the prefrontal cortex (PFC), ventral hippocampus (vHipp) and basolateral amygdala (BLA) and 2) How activity in these same interneuron populations modulates cognitive and affective behaviors. By refining our understanding of the contribution of different categories of interneurons to prefrontal, hippocampal and amygdalar function at both an electrophysiological and behavioral level I hope to generate more precise ideas of how to correct GABAergic imbalances in patients with cognitive and affective symptoms. This K01 career development award would provide the protected time to gain the technical and intellectual training I require to address the above questions, facilitating my transition towards establishing an independent research program. My primary expertise is in translational mouse models, and the molecular, cellular, physiological and behavioral assays used to characterize them. My career development plan expands on this background, and proposes essential training in optogenetic techniques, intellectual training in the field of cognitive and affective behaviors, and further instruction in professional development skills such as grant writing and laboratory management. Research Project. Abnormalities in PFC GABAergic interneurons are hypothesized to be integral to the pathophysiology of several psychiatric disorders. However, the specific populations of GABAergic interneurons that are functionally affected, and their relationship to behavioral abnormalities, are not well- understood. Animal models of environmental or genetic risk factors for psychiatric disease provide an opportunity to directly assay functional changes in specific populations of PFC GABAergic interneurons that are relevant to mental disorders. My preliminary studies in a murine model of maternal immune activation uncovered a profound reduction in PFC GABAergic transmission in adult MIA offspring. In this proposal I will use optogenetics with slice electrophysiology to uncover which populations of PFC interneurons contribute to this deficit. Next, I will explore the consequences of these alterations for cognitiv and affective behaviors using in vivo optogenetics. Finally, I will investigate whether GABAergic deficits in adult MIA offspring are specific to the PFC by examining GABAergic transmission in the vHipp and BLA, as well as the role of different populations of vHipp and BLA interneurons in cognitive and affective behaviors.