Cortical Cells Circuits Connectivity and Cognition in Schizophrenia

描述(由申请人提供)：精神分裂症和相关障碍患者的功能结果主要由某些核心认知能力的损害程度决定。例如，精神分裂症的受试者在视觉工作记忆和注意力方面表现出缺陷，在利用这些能力的任务中，大脑皮质活动的模式也发生了变化。这些活动模式依赖于分布在包括初级视觉(VI)、后顶叶(PPC)和背外侧前额叶(DLPFC)皮质的网络中的神经元的适当的临时放电。这些发现突出了一个尚未回答的关键问题：精神分裂症患者视觉工作记忆和注意力受损的大脑皮层细胞、回路和连接基础是什么？为了回答这个问题，拟议中心的补充研究旨在检验以下中央假设：新皮质第三层锥体细胞的内在分子干扰导致这些神经元的形态异常。由于第3层锥体细胞特性的正常区域差异，这种细胞病理的严重性在不同的皮质区域是适度的。这种细胞病理改变了区域内和区域之间的皮质回路，损害了跨区域的功能连接，并导致精神分裂症患者在视觉工作记忆和注意力过程中自下而上和自上而下的过程都受到干扰。拟议中心的五个相互关联的项目(P)在死后人类大脑(P1和P2)的分子、细胞、板层和局部电路水平上提供了这一假说的汇聚测试，并通过从未服用药物的首发精神病患者(P5)的成像和神经生理学研究在区域和分布电路水平上提供了这一假说的汇聚测试；这些研究既提供了信息，也受到猴子(P3和P4)平行研究的限制。这种方法的一个关键创新是整合了从分子到行为的多层次分辨率的研究，这些研究为自下而上和自上而下对精神分裂症皮质功能障碍的解释提供了翻译评估。相关性(参见说明书)：拟议的研究具有很高的临床相关性，因为分子-细胞-电路水平分析与体内脑功能指数的结合为随后识别新的、基于病理的治疗干预靶点提供了一个平台，这些靶标伴随着可用于预测和监测此类干预效果的病理生理学信息的生物标志物。

DESCRIPTION (provided by applicant): Functional outcome in individuals with schizophrenia and related disorders is primarily determined by the degree of impairment in certain core cognitive abilities. For example, subjects with schizophrenia exhibit deficits in visual working memory and attention, and altered patterns of cortical activity during tasks that tap these abilities. These patterns of activity depend on the proper temporal firing of neurons distributed across a network that includes primary visual (VI), posterior parietal (PPC) and dorsolateral prefrontal DLPFC) cortices. These findings highlight an unanswered critical question: What are the cortical cellular, circuitry and connectivity bases for the impairments in visual working memory and attention in schizophrenia? To answer this question, the complementary studies in the proposed Center are designed to test the following Central Hypothesis: Intrinsic molecular disturbances in layer 3 pyramidal cells of the neocortex give rise to morphological abnormalities in these neurons. The severity of this cellular pathology is moderated across cortical regions as a function of normal regional differences in the properties of layer 3 pyramidal cells. This cellulr pathology alters cortical circuitry within and between regions, impairs functional connectivity across regions, and results in disturbances in both bottom up and top down processes during visual working memory and attention in individuals with schizophrenia. The five inter-related projects (P) of the proposed Center provide convergent tests of this hypothesis at the molecular, cellular, laminar and local circuitry levels in postmortem human brain (P1&P2), and at the regional and distributed circuitry levels through imaging and neurophysiological studies in never-medicated subjects with a first-episode of psychosis (P5); these studies are both informed and constrained by parallel studies in monkeys (P3&P4). A key innovation of this approach is the integration of studies with multiple levels of resolution, from molecules to behavior, that provide a translational assessment of both bottom up and top down explanations of cortical dysfunction in schizophrenia. RELEVANCE (See instructions): The proposed studies have high clinical relevance as the combination of molecular-cellular-circuit level analyses with in vivo indices of brain function offers a platform for subsequent identification of novel, pathologically-based targets for therapeutic interventions that are accompanied by pathophysiologically informed biomarkers that can be used to predict and monitor the efficacy of such interventions.