CORTICAL MECHANISMS IN SCHIZOPHRENIA

该中心由五个项目组成， 所有致力于了解神经化学基础的机构， 精神分裂症患者的正常认知功能及其消失。Unraveling the 调节大脑皮层复杂认知功能的皮质机制 前额叶皮层被认为是实现这一目标的重要一步 认识这个中心的统一假设是， 神经递质失调可能会导致受损的皮质 结构（“减少的神经元”），是皮质神经元的主要特征。 功能障碍，特别是多巴胺（DA），在调节 工作记忆回路中的兴奋性神经传递。项目 1检查NMDA的多巴胺能（和多巴胺能）调节的作用 和非NMDA受体在体内的工作记忆回路。计划2 介绍了一个潜在的强大的新方法，神经病理学， 固定切片制备以研究树突形态和皮质 死后大脑中涉及多巴胺（和5-羟色胺）的回路， “先活后定”的准备来检验多巴胺 改变非人灵长类动物前额区的树突形态 项目3中产生的DA失调模型。项目3涉及 研究慢性（和急性）五氯苯酚产生的非人类灵长类动物模型， 我们的研究结果表明，慢性AMPH致敏导致DA 工作记忆、平滑追踪眼球追踪和 将研究慢性治疗的神经化学作用。项目 4通过测量DA来检查精神分裂症中DA失调的程度 的皮质和纹状体中的D2受体密度 精神分裂症患者使用SPECT成像来检验低 基础水平的DA倾向于高阶段性反应。项目5是一个 在正常猴子、正常人和患有 精神分裂症旨在测试新的假设，减少 多巴胺能神经传递在治疗中具有治疗潜力 精神分裂症这些项目的集体成果将 阐明了我们对DA及其 细胞和亚细胞的目标，并建立 多巴胺失调在病因学、病理生理学和 精神分裂症的神经病理学

This Center is composed of five projects involving investigators at four institutions all committed to understanding the neurochemical basis of normal cognition and its dissolution in schizophrenia. Unraveling the cortical mechanisms which mediate the complex cognitive functions of the prefrontal cortex is considered an essential step in achieving this understanding. This Center is unified by the hypothesis that neurotransmitter dysregulation may produce compromised cortical architecture ("reduced neuropil") and is a primary feature of cortical functional disturbance in particularly dopamine (DA), in the regulation of excitatory neurotransmission in the circuitry of working memory. Project 1 examines the role of dopaminergic (and serotonergic) modulation of NMDA and non-NMDA receptors in working memory circuits in vivo. Project 2 introduces a potentially powerful new approach to neuropathology, the fixed-slice preparation to study dendritic morphology and cortical circuitry involving dopamine (and serotonin) in postmortem brain and a "living-then-fixed" preparation to test the hypothesis that dopamine alters dendritic morphology in prefrontal regions of non-human primate models of DA dysregulation produced in Project 3. Project 3 involves the study of non-human primate models produced by chronic (and acute)PCP and chronic AMPH sensitization which our findings indicate result in DA dysregulation; working memory, smooth pursuit eye tracking and neurochemical effects of chronic treatments will be investigated. Project 4 examines the degree of DA dysregulation in schizophrenia by measuring DA turnover and D2 receptor density in cortex and the striatum of schizophrenic patients using SPECT imaging to test the hypothesis that low basal levels of DA predispose to high phasic response. Project 5 is a coordinated study in normal monkeys, normal humans and patients with schizophrenia designed to test the novel hypothesis that reduction in glutamatergic neurotransmission has therapeutic potential in the treatment of schizophrenia. The collective results from these projects will illuminate our understanding of the interactions between DA and its cellular and subcellular targets in prefrontal cortex and establish the role of dopamine dysregulation in the etiology, pathophysiology, and neuropathology of schizophrenia.