CORTICAL MECHANISMS IN SCHIZOPHRENIA

该中心由五个项目组成，涉及四名调查人员 所有机构都致力于了解神经化学基础 精神分裂症患者的正常认知及其消解。解开 调节大脑的复杂认知功能的皮质机制 前额叶皮质被认为是实现这一目标的关键步骤。 理解。这个中心是由假设统一的，即 神经递质失调可能导致皮质受损 结构(“减少的神经纤维”)，是皮质的一个主要特征 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研究了多巴胺能(和5-羟色胺能)对NMDA的调节作用 以及体内工作记忆回路中的非NMDA受体。项目2 介绍了一种潜在的强大的神经病理学新方法，即 树突状细胞形态和皮质的固定切片制备研究 死后脑中涉及多巴胺(和5-羟色胺)的回路和 “先活后固定”测试多巴胺假说的准备 非人灵长类前额叶区域树突形态的改变 项目3中制作的DA失调模型。项目3涉及 慢性(急性)PCP和PCP所致非人灵长类动物模型的研究 我们的研究结果表明慢性琥珀酸致敏化会导致DA 失调；工作记忆，顺畅的追踪眼球和 将调查慢性治疗的神经化学影响。项目 4通过测量DA来检查精神分裂症患者DA失调的程度 大鼠大脑皮质和纹状体D2受体密度和周转率 精神分裂症患者使用SPECT成像来检验低 基础水平的DA易诱发高时相反应。项目5是一个 在正常猴子、正常人和糖尿病患者中的协调研究 精神分裂症旨在测试这一新假设，即 谷氨酸能神经传递在治疗中具有治疗潜力 精神分裂症的症状。这些项目的总体成果将 阐明我们对DA和ITS之间相互作用的理解 前额叶皮质的细胞和亚细胞靶点并建立 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.