Serotonin Modulation of Orbital Cortex GABA Interneurons

描述(由申请人提供)：眼眶前额叶皮质(OPFC)在处理与奖励相关的信息并利用这些信息指导决策方面发挥着重要作用。对人类和灵长类动物的研究表明，PFC 5-羟色胺(5HT)缺乏会导致对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输入的功能障碍是几种神经精神障碍的病理生理学因素，包括精神分裂症、抑郁症和强迫症。综上所述，这些观察结果表明，完整的5-羟色胺神经支配对oPFC的正常功能至关重要。不幸的是，5-羟色胺影响PFC神经元活动的机制仍不清楚。现有的解剖和电生理证据表明，GABA局部环路神经元是5-羟色胺信号转导的重要靶点。GABA神经元是一个不同种类的细胞群体，它们的电生理特性、轴突靶标以及钙结合蛋白和神经肽的表达都不同。由于这些差异，人们认为这些不同的种群在调节皮质网络活动方面起着非常不同的作用。这一建议的中心假设是，在oPFC内，这些不同的神经化学识别的GABA局部回路神经元群体表达不同的5HT受体亚型的补体，这种受体表达的特异性反映在这些GABA细胞群体对5HT的反应中。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GAD67-GFP标记神经元的单细胞RT-PCR图谱来确定神经化学鉴定的oPFC局部回路神经元群体中5-羟色胺受体亚型的协调表达。特殊目的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进行的神经化学鉴定，来确定不同神经化学鉴定的GABA局部回路神经元群体对5羟色胺受体刺激的反应。阐明5-羟色胺受体亚型在已确定的oPFC局部环路神经元群体中的表达，并更好地了解5-羟色胺如何影响这些细胞的活动，对于构建oPFC内信息处理的准确模型至关重要。此外，这些研究还可能为治疗精神分裂症、强迫症和抑郁障碍等神经精神疾病的新治疗目标提供重要的见解。公共卫生相关性：眼眶皮质功能障碍已在精神分裂症、抑郁症和强迫症中观察到。本申请中描述的研究可能为这些疾病的病因以及潜在的治疗新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.