Serotonin Modulation of Orbital Cortex GABA Interneurons

描述（由申请人提供）：眼眶前额叶皮层（oPFC）在处理与奖励相关的信息和使用这些信息来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血清素（5HT）耗竭会导致对oPFC完整性敏感的认知任务出现缺陷。此外，越来越多的证据表明，oPFC及其5HT输入功能障碍是多种神经精神疾病（包括精神分裂症、抑郁症和强迫症）的病理生理因素。综上所述，这些观察结果表明，完整的5HT神经支配对oPFC的正常功能至关重要。不幸的是，5HT影响oPFC神经元活动的机制仍然知之甚少。现有的解剖和电生理证据表明，GABA局部回路神经元是5HT信号的重要靶点。GABA神经元是一种异质细胞群，它们在电生理特性、轴突靶点和钙结合蛋白和神经肽的表达方面存在差异。由于这些区别，人们认为这些不同的群体在调节皮层网络活动方面起着非常不同的作用。该建议的中心假设是，oPFC内这些不同的经神经化学鉴定的GABA局部回路神经元群表达不同的5HT受体亚型补体，并且受体表达的这种特异性反映在这些GABA细胞群对5HT的反应中。为了验证这一假设，我们建议使用电生理学和分子方法的结合来解决两个特定的目标。特异性目的1将使用急性解离GAD67-GFP标记神经元的单细胞RT-PCR分析，以确定在神经化学鉴定的oPFC局部回路神经元群体中5HT受体亚型的协调表达。Specific Aim 2将利用全细胞体外膜片钳对GFP标记的GABA局部回路神经元进行膜片钳，再加上随后使用单细胞RT-PCR进行神经化学鉴定，以确定不同神经化学鉴定的GABA局部回路神经元群体如何对5HT受体刺激做出反应。阐明5HT受体亚型在确定的oPFC局部回路神经元群体中的表达，结合更好地了解5HT如何影响这些细胞的活性，对于构建oPFC内信息处理的准确模型至关重要。此外，这些研究还可能为精神分裂症、强迫症和抑郁症等神经精神疾病的治疗提供新的治疗靶点。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质功能障碍。本应用程序中描述的研究可能为这些疾病的病因学以及潜在的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.