Serotonin Modulation of Orbital Cortex GABA Interneurons

描述（由申请人提供）：眶前额叶皮层（oPFC）在处理奖励相关信息以及使用该信息指导决策方面起着重要作用。对人类和灵长类动物的研究表明，PFC 5-羟色胺（5-HT）耗竭会导致对oPFC完整性敏感的认知任务出现缺陷。此外，汇聚线的证据表明功能障碍的前额叶皮层和其5羟色胺输入的病理生理学的几种神经精神疾病，包括精神分裂症，抑郁症和强迫症的贡献因素。两者合计，这些观察结果表明，一个完整的5 HT神经支配是至关重要的正常运作的前额叶皮层。不幸的是，5 HT影响oPFC神经元活动的机制仍然知之甚少。现有的解剖学和电生理学证据表明，GABA局部回路神经元是5-HT信号传导的重要靶点。GABA神经元是一种异质性细胞群体，其在电生理特性、轴突靶点以及钙结合蛋白和神经肽的表达方面不同。由于这些区别，人们认为这些不同的人群在调节皮层网络的活动中起着非常不同的作用。该建议的中心假设是，这些不同的神经化学鉴定的GABA局部回路神经元的oPFC内的人口表达不同的5-HT受体亚型的补充，这种特异性的受体表达是反映在这些群体的GABA细胞如何响应5-HT。为了验证这一假设，我们建议使用电生理和分子方法的组合来解决两个特定的目标。具体目标1将使用急性分离的GAD 67-GFP标记神经元的单细胞RT-PCR分析，以确定神经化学鉴定的oPFC局部回路神经元群体内5 HT受体亚型的协调表达。具体目标2将利用GFP标记的GABA局部回路神经元的全细胞体外膜片钳，结合随后使用单细胞RT-PCR的神经化学鉴定，以确定不同神经化学鉴定的GABA局部回路神经元群体如何响应5 HT受体刺激。阐明5 HT受体亚型的表达内确定的人口oPFC局部回路神经元，结合更好地了解5 HT如何影响这些细胞的活动，是至关重要的，在构建准确的模型oPFC内的信息处理。此外，这些研究还可能为治疗精神分裂症、强迫症和抑郁症等神经精神疾病的新治疗靶点提供重要见解。公共卫生相关性：在精神分裂症、抑郁症和强迫症中观察到眶皮层功能障碍。本申请中描述的研究可能为这些疾病的病因学及其治疗的潜在新治疗靶点提供重要的新见解。

DESCRIPTION (provided by applicant): The orbital prefrontal cortex (oPFC) plays important roles in the processing of reward related information and the use of that information to guide decision making. Studies in humans and primates have shown that PFC serotonin (5HT) depletion produces deficits in cognitive tasks that are sensitive to the integrity of the oPFC. Furthermore, converging lines of evidence suggest dysfunction of the oPFC and its 5HT input as contributing factors in the pathophysiology of several neuropsychiatric disorders, including schizophrenia, depression, and obsessive-compulsive disorder. Taken together, these observations suggest that an intact 5HT innervation is vital to the proper functioning of the oPFC. Unfortunately, the mechanisms through which 5HT influences oPFC neuronal activity are still poorly understood. The available anatomical and electrophysiological evidence indicates that GABA local circuit neurons are an important target of 5HT signaling. GABA neurons are a heterogeneous population of cells that differ in their electrophysiological properties, axonal targets and expression of calcium binding proteins and neuropeptides. Because of these distinctions, it is thought that these different populations mediate very distinct roles in regulating the activity of cortical networks. The central hypothesis of this proposal is that these different neurochemically identified populations of GABA local circuit neurons within the oPFC express distinct complements of 5HT receptor subtypes and that this specificity in receptor expression is reflected in how these populations of GABA cells respond to 5HT. To test this hypothesis, we propose to use a combination of electrophysiological and molecular methods to address two specific aims. Specific Aim 1 will use single cell RT-PCR profiling of acutely dissociated GAD67-GFP labeled neurons to determine the coordinated expression of 5HT receptor subtypes within neurochemically identified populations of oPFC local circuit neurons. Specific Aim 2 will utilize whole cell in vitro patch clamp of GFP labeled GABA local circuit neurons, coupled with subsequent neurochemical identification using single cell RT-PCR, to determine how different neurochemically identified populations of GABA local circuit neurons respond to 5HT receptor stimulation. Elucidating the expression of 5HT receptor subtypes within identified populations of oPFC local circuit neurons, combined with a better understanding of how 5HT influences the activity of these cells, is vital in constructing accurate models of information processing within the oPFC. Moreover, these studies may also provide important insights into new therapeutic targets for treating neuropsychiatric disorders such as schizophrenia, OCD and depressive disorders. PUBLIC HEALTH RELEVANCE: Dysfunction within the orbital cortex has been observed in schizophrenia, depression, and obsessive- compulsive disorder. The studies described in this application may provide vital new insights into both the etiology of these disorders as well as potential new therapeutic targets for their treatment.