Neurobiology of Dopamine in Schizophrenia

描述（由申请人提供）：这是精神疾病神经科学中心（CCNMD）提交的第二篇题为“精神分裂症中多巴胺的神经生物学”的论文。精神分裂症可能由涉及多个皮质-皮质下和皮质内网络的神经发育中断引起。虽然这些改变的精确定位尚不清楚，但多项证据表明，前额叶皮层（PFC）在精神分裂症病理生理学基础上的神经回路中起着至关重要的作用。在这些回路中，DA （DA）和谷氨酸（GLU）传递的失调密切相关。该中心的统一假设是精神分裂症与DA （DA）系统的失衡有关，其特征是前额皮质DA功能的持续缺陷（导致在这些患者中观察到的认知障碍）和皮质下DA功能的间歇性过剩（导致精神病状态的出现）。这种DA失衡可能源于涉及GLU传输的PFC连接改变以及PFC无法适当调节DA功能。该中心的总体目标是将临床成像与正电子发射断层扫描（PET）以及小鼠和恒河猴的表观遗传和转基因动物模型相结合，以验证这一假设。提出了一系列相关的临床和临床前研究，以1)更好地表征精神分裂症中DA失衡的存在；2)探索可能解释这种DA表型的潜在生物学机制；3)了解这种不平衡对脑功能、临床症状和治疗的后果。提出了六个高度整合的项目，包括两个精神分裂症患者的临床成像项目（Abi-Dargham和Laruelle的项目）四个临床前项目，在恒河猴（Haber和Javitt的项目）和小鼠（Kandel和Rayport的项目）中进行。这些项目将用最先进的方法调查这一假设。六个核心将为这些项目提供共享资源和支持（行政、生物统计和数据管理、临床、脑成像、分子和细胞以及神经化学核心）。来自三个机构（哥伦比亚大学、罗切斯特大学和内森克莱恩研究所）的杰出研究人员将带来具体的研究技能，并在这一转化调查中密切合作。通过以独特的方式整合基础和临床研究，该中心将在理解精神分裂症的神经基质、这种表型的发育病因学以及这些发现对新治疗方式发展的影响方面提供根本性的进展。

DESCRIPTION (provided by applicant): This is the second submission of this Conte Center for the Neuroscience of Mental Disorders (CCNMD) entitled "The Neurobiology of Dopamine in Schizophrenia. Schizophrenia might result from neurodevelopmental disruptions involving multiple cortico-subcortical and intracortical networks. While the precise mapping of these alterations remains unclear, multiple lines of evidence suggest that prefrontal cortex (PFC) is critically involved in the neurocircuitry underlying the pathophysiology of schizophrenia. Within these circuits, dysregulations of DA (DA) and glutamate (GLU) transmission have been strongly implicated. The unifying hypothesis of the Center is that schizophrenia is associated with an imbalance of DA (DA) systems, characterized by a persistent deficit in prefrontal cortical DA function (contributing to the cognitive impairment observed in these patients) and an intermittent excess of subcortical DA function (contributing to the emergence of psychotic states). This DA imbalance might stem from altered PFC connectivity involving GLU transmission and from a failure of PFC to appropriately modulate DA function. The overall goal of the Center is to combine clinical imaging with Positron Emission Tomography (PET) and epigenetic and transgenic animal models in mice and rhesus monkeys to test this hypothesis. A set of interrelated clinical and preclinical investigations are proposed to 1) better characterize the existence of such a DA imbalance in schizophrenia; 2) explore the underlying biological mechanisms that might account for such a DA phenotype; 3) understand the consequence of this imbalance for brain functions, clinical symptoms and treatment. Six highly integrated projects are proposed, including two clinical imaging projects in patients with schizophrenia (Projects by Abi-Dargham and Laruelle) four preclinical projects, performed in rhesus monkeys (Projects by Haber and Javitt) and mice (Projects by Kandel and Rayport). These projects will investigate this single hypothesis with state-of-the art methodologies. Six cores will provide shared resources and support for these projects (Administrative, Biostatistics and Data management, Clinical, Brain Imaging, Molecular and Cellular, and Neurochemistry Cores). Prominent investigators from three Institutions (Columbia University, University of Rochester and Nathan Kline Research Institute) will bring specific research skills and collaborate closely in this translational investigation. By integrating basic and clinical research in a unique way, this Center will provide a fundamental advance in understanding the neural substrates underlying schizophrenia, the developmental etiology of this phenotype, and the implications of these findings for the development of new treatment modalities.