Dopamine Dysfunction in Schizophrenia

描述（由申请人提供）：“精神分裂症多巴胺功能障碍”中心将测试中心假设，即发育过程中纹状体多巴胺能亢进导致精神分裂症（SCZ）的前额叶皮质多巴胺（DA）功能障碍和认知缺陷。因此，发育过程中纹状体中DA传递的失调及其对前额叶皮质（PFC）DA传递和PFC回路功能的最终影响导致阳性症状、阴性症状和认知缺陷。这一假说是基于中心研究人员最近的研究结果：1）精神分裂症患者纹状体DA能过度在联合纹状体（AST）中最大，2）AST接受来自背外侧-前额叶皮层（DLPFC），前扣带皮层（ACC）和边缘额叶皮层区域的会聚输入，使其对情感和认知过程的整合至关重要，3）纹状体DA能 D2受体在小鼠发育过程中的过度表达导致额叶皮质多巴胺改变、PFC功能障碍，如不可逆的学习缺陷以及动机和社会缺陷所证明的。因此，来自PFC的传入信息的整合可能会被联合纹状体中过量的D2信号传导所改变，这会损害皮质-纹状体-苍白球-丘脑-皮质环路之间的皮质信息流，并改变中脑DA功能。我们组织了由4个核心支持的5个项目来验证这一假设。我们将在SCZ患者与健康对照组中测试纹状体DA病理学是否预测：1）用正电子发射断层扫描（PET）（P1）测量的皮质DA病理学和2）PFC介导的认知功能（用工作记忆任务评估）和PFC活性的相关变化（用功能性磁共振成像（fMRI）测量）（P2）。我们将创建纹状体中D2受体早期发育过度表达（P4）或中脑DA放电模式和纹状体DA释放（P5）改变的转基因小鼠。这些小鼠模型将被用来了解潜在的机制异常额叶皮质DA传输以及认知和行为异常介导的PFC纹状体电路在SCZ。我们还将确定纹状体中介导这些效应的信号转导的关键改变（P4），猴子和啮齿动物中的潜在回路（P3），以及与SCZ相关的DA成像内表型的可能神经化学介质（P5）。这套 在人类、猴子和小鼠中的研究将确定纹状体DA失调在SCZ中PFC功能障碍的发病机制中的作用，并且通过这样做将作为中断这种致病机制的新治疗方法的关键的第一步。 公共卫生相关性：精神分裂症患者认知障碍导致严重的功能障碍。我们对这种疾病的一个关键变化的新观点，即DA功能障碍，以及我们为了测试它而提出的一系列机制研究，将导致对这种疾病的新的更好的理解。这反过来又可能导致预防或治疗策略，可以根据这一新的理解。

DESCRIPTION (provided by applicant): The Center on "Dopamine Dysfunction in Schizophrenia" will test the central hypothesis that striatal dopaminergic hyperactivity during development leads to prefrontal cortical dopamine (DA) dysfunction in schizophrenia (SCZ) and the cognitive deficits that characterize the disorder. Thus, dysregulation of DA transmission in the striatum during development and its ultimate effect on prefrontal cortical (PFC) DA transmission and PFC circuit function contribute to positive symptoms, negative symptoms and cognitive deficits. This hypothesis is based on a convergence of recent findings from Center investigators: 1) the striatal DAergic excess in schizophrenia is greatest in the associative striatum (AST), 2) the AST receives convergent input from dorsolateral-prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC) and limbic frontal cortical regions, rendering it crucial for integration of affective and cognitive processes, 3) striatal DA D2 receptor overexpression during development in mice results in frontal cortical dopamine alterations, PFC dysfunction, as evidenced by irreversible learning deficits, as well as rnotivational and social deficits. Thus,integration of incoming information from the PFC may be altered by excessive D2 signaling in the associative striatum, which impairs cortical flow of information across cortico-striato-pallido-thalamo-cortical loops and alters midbrain DA function. Our five Projects supported by 4 Cores are organized to test this hypothesis. We will test in patients with SCZ compared to healthy controls whether the striatal DA pathology predicts: 1) cortical DA pathology measured with Positron Emission Tomography (PET) (P1) and 2) PFC-mediated cognitive functioning as assessed with working memory tasks and the associated changes in PFC activity as measured with Functional Magnetic Resonance Imaging (fMRI) (P2). We will create transgenic mice with early developmental overexpression of D2 receptors in striatum (P4) or alterations in midbrain DA firing patterns and striatal DA release (P5). These mouse models will be used to understand possible mechanisms underlying abnormal frontal cortical DA transmission as well as cognitive and behavioral abnormalities mediated by PFC-striatal circuits in SCZ. We will also determine the critical alterations in signal transduction in the striatum mediating these effects (P4), the underlying circuitry both in monkeys and in rodents (P3), and possible neurochemical mediators of DA imaging endophenotypes associated with SCZ (P5). This set of studies in humans, monkeys and mice will establish the role of striatal DA dysregulation in the pathogenesis of PFC dysfunction in SCZ, and by doing so will serve as a critical first step to novel approaches to treatment that interrupt this pathogenic mechanism. PUBLIC HEALTH RELEVANCE: Disordered cognition leads to severe functional impairment in schizophrenia. Our new perspective on a key alteration in this illness, which is DA dysfunction, and the set of mechanistic studies we propose in order to test it, will lead to new and better understanding of the disorder. This in turn may lead to preventive or therapeutic strategies that can be developed based on this new understanding.