Dopamine Dysfunction in Schizophrenia

描述（由申请人提供）：“精神分裂症中的多巴胺功能障碍”研究中心将检验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）功能障碍和该疾病特征的认知缺陷的中心假设。因此，纹状体发育过程中DA传递的失调及其对前额皮质（PFC） DA传递和PFC回路功能的最终影响导致了阳性症状、阴性症状和认知缺陷。这一假设是基于中心研究人员最近的发现：1)精神分裂症患者的纹状体DAergic过剩在联想纹状体（AST）中最大，2)AST接收来自背外侧前额叶皮层（DLPFC）、前扣带皮层（ACC）和边缘额叶皮质区域的收敛输入，使得它对情感和认知过程的整合至关重要，3)纹状体DA

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.