Cortical Cells Circuits Connectivity and Cognition in Schizophrenia

精神分裂症的皮层细胞回路连接和认知

• 批准号: 8666277
• 负责人: David A Lewis
• 金额: $ 215万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666277
• 关键词: Accounting; Attention; Autopsy; Behavior; Biological Markers; Brain; Cells; Cognition; Cognitive; Cognitive deficits; Communication; Dendrites; Dendritic Spines; Detection; Disease; Exhibits; Functional disorder; Future; Gene Expression; Human; Image; Impaired cognition; Impairment; Individual; Instruction; Intervention; Measures; Molecular; Molecular Abnormality; Monitor; Monkeys; Morphology; Neocortex; Neurons; Parietal; Parietal Lobe; Pathology; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Primates; Process; Property; Pyramidal Cells; Resolution; Sampling; Schizoaffective Disorders; Schizophrenia; Severities; Short-Term Memory; Specificity; Testing; Therapeutic Intervention; Visual; Visual Cortex; Visual attention; area V1; area striata; base; cell type; cellular pathology; clinically relevant; density; design; first episode psychosis; functional outcomes; gray matter; in vivo; indexing; innovation; neuronal cell body; neurophysiology; novel; regional difference; visual information

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.

描述（由申请人提供）：精神分裂症和相关疾病患者的功能结果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缺陷，并且在利用这些能力的任务中皮质活动模式发生改变。这些活动模式取决于分布在网络中的神经元的正确时间放电，该网络包括初级视觉（VI）、后顶叶（PPC）和背外侧前额叶皮层（DLPFC）。这些发现凸显了一个尚未解答的关键问题：精神分裂症患者视觉工作记忆和注意力受损的皮质细胞、电路和连接基础是什么？为了回答这个问题，该中心的补充研究旨在测试以下中心假设：新皮质第 3 层锥体细胞的内在分子扰动导致这些神经元的形态异常。这种细胞病理学的严重程度在整个皮质区域中受到调节，作为第 3 层锥体细胞特性的正常区域差异的函数。这种细胞病理学改变了区域内和区域之间的皮质回路，损害了区域之间的功能连接，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（P1＆P2）的分子、细胞、层流和局部电路水平以及通过成像和神经生理学在区域和分布式电路水平上提供对这一假设的聚合测试对从未接受过药物治疗的首发精神病受试者进行的研究（P5）；这些研究既受到猴子平行研究的启发又受到限制（P3&P4）。这种方法的一个关键创新是将研究与从分子到行为的多个分辨率水平相结合，为精神分裂症皮质功能障碍的自下而上和自上而下的解释提供转化评估。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体内脑功能指数的结合为随后识别新的、基于病理学的治疗干预目标提供了一个平台。通过病理生理学的生物标志物，可用于预测和监测此类干预措施的功效。