Effects of maternal immune activation on offspring GABA circuitry and behavior

母体免疫激活对后代 GABA 回路和行为的影响

• 批准号: 9230437
• 负责人: SARAH E CANETTA
• 金额: $ 18.38万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230437
• 关键词: Address; Adult; Affect; Affective; Affective Symptoms; Amygdaloid structure; Anatomy; Animal Model; Animals; Anxiety; Anxiety Disorders; Attention; Behavior; Behavioral; Behavioral Assay; Biological Assay; Bipolar Disorder; Brain region; Categories; Cells; Characteristics; Cognition; Cognitive; Cognitive deficits; Data; Development Plans; Disease; Electrophysiology (science); Environmental Risk Factor; Functional disorder; Goals; Grant; Hippocampus (Brain); Impaired cognition; Impairment; In Vitro; Instruction; Interneurons; K-Series Research Career Programs; Laboratories; Light; Link; Literature; Measures; Mental Depression; Mental disorders; Molecular; Mus; Neurobehavioral Manifestations; Neurons; Parvalbumins; Patients; Physiological; Population; Prefrontal Cortex; Probability; Psychopathology; Public Health; Pyramidal Cells; Research; Research Project Grants; Role; Schizophrenia; Short-Term Memory; Slice; Somatostatin; Structure; Synapses; System; Techniques; Testing; Time; Training; Translational Research; Viral; Writing; base; behavioral impairment; calretinin; career; career development; cognitive process; economic cost; functional disability; gamma-Aminobutyric Acid; genetic risk factor; hippocampal pyramidal neuron; immune activation; in vivo; interest; molecular marker; mouse model; neural circuit; neurobiological mechanism; new therapeutic target; novel therapeutic intervention; offspring; optogenetics; prenatal; programs; public health relevance; skill acquisition; symptom treatment; tool; transmission process

 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.

 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转化研究，以了解与精神病理学相关的行为异常的神经生物学机制，总体目标是开发新的治疗策略。我的研究兴趣集中于理解：1) 产前母体免疫激活 (MIA)（多种形式的精神病理学的早期环境危险因素）如何改变前额皮质 (PFC)、腹侧海马 (vHipp) 和基底外侧杏仁核 (BLA) 中离散 GABA 能中间神经元亚群的功能，以及 2) 这些相同中间神经元群体的活动如何 调节认知和情感行为。通过在电生理和行为水平上完善我们对不同类别的中间神经元对前额叶、海马和杏仁核功能的贡献的理解，我希望能够就如何纠正患有认知和情感症状的患者的 GABA 能失衡产生更精确的想法。 K01 职业发展奖将提供受保护的时间来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计划的过渡。我的主要专业知识是转化小鼠模型，以及用于表征它们的分子、细胞、生理和行为测定。我的职业发展计划在此背景下进行了扩展，并提出了光遗传学技术的基本培训、认知和情感行为领域的智力培训以及进一步的指导 专业发展技能，例如资助写作和实验室管理。研究项目。据推测，PFC GABA 能中间神经元的异常是多种精神疾病病理生理学的组成部分。然而，功能受影响的 GABA 能中间神经元的特定群体及其与行为异常的关系尚不清楚。精神疾病的环境或遗传危险因素的动物模型提供了直接分析与精神障碍相关的特定 PFC GABA 能中间神经元群体的功能变化的机会。我对母体免疫激活小鼠模型的初步研究发现，成年 MIA 后代中 PFC GABA 能传递显着减少。在本提案中，我将使用光遗传学和切片电生理学来揭示哪些 PFC 中间神经元群体导致了这种缺陷。接下来，我将利用体内光遗传学探讨这些改变对认知和情感行为的影响。最后，我将通过检查 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，研究成年 MIA 后代的 GABA 能缺陷是否是 PFC 所特有的。