Cortical Cells Circuits Connectivity and Cognition in Schizophrenia

描述（由申请人提供）：精神分裂症和相关疾病患者的功能结局主要取决于某些核心认知能力的受损程度。例如，患有精神分裂症的受试者表现出视觉工作记忆和注意力的缺陷，并且在利用这些能力的任务期间改变了皮质活动模式。这些活动模式取决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时间激发。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皮层细胞、电路和连接基础是什么？为了回答这个问题，在拟议的中心的补充研究旨在测试以下中心假说：内在的分子干扰层3锥体细胞的新皮层引起这些神经元的形态异常。这种细胞病理学的严重程度在皮质区域中作为第3层锥体细胞特性的正常区域差异的函数而被缓和。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受到干扰。拟议中心的五个相互关联的项目（P）在死后人脑的分子、细胞、层和局部回路水平（P1和P2），以及在区域和分布式回路水平，通过对从未接受药物治疗的首次精神病发作受试者（P5）的成像和神经生理学研究，对这一假设进行会聚测试;这些研究都受到猴子平行研究的启发和限制（P3和P4）。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研究，为精神分裂症中皮质功能障碍的自下而上和自上而下的解释提供了翻译评估。相关性（参见说明）：拟议的研究具有高度的临床相关性，因为分子-细胞-回路水平分析与脑功能的体内指标相结合，为后续识别治疗干预的新的、基于病理学的靶点提供了平台，这些靶点伴随有病理生理学信息的生物标志物，可用于预测和监测此类干预的疗效。

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.