Dopamine Dysfunction in Schizophrenia

精神分裂症的多巴胺功能障碍

• 批准号: 8448257
• 负责人: Anissa Abi-Dargham
• 金额: $ 177.26万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448257
• 关键词: Affective; Anterior; Behavioral; Cognition Disorders; Cognitive; Cognitive deficits; Corpus striatum structure; Development; Disease; Dopamine; Dopamine D2 Receptor; Functional Magnetic Resonance Imaging; Functional disorder; Human; Hyperactive behavior; Image; Lead; Learning; Measures; Mediating; Mediator of activation protein; Midbrain structure; Monkeys; Mus; Pathogenesis; Pathology; Patients; Pattern; Positron-Emission Tomography; Prefrontal Cortex; Preventive; Process; Research Personnel; Rodent; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Symptoms; Testing; Therapeutic; Transgenic Mice; base; cingulate cortex; cognitive function; endophenotype; functional disability; mouse model; neurochemistry; novel strategies; overexpression; public health relevance; social; transmission process

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.

描述（由申请人提供）：“精神分裂症中的多巴胺功能障碍”中心将测试一个中心假设，即发育过程中纹状体多巴胺能过度活跃会导致精神分裂症（SCZ）中的前额皮质多巴胺（DA）功能障碍以及该疾病的认知缺陷。因此，发育过程中纹状体中 DA 传输的失调及其对前额皮质 (PFC) DA 传输和 PFC 回路功能的最终影响会导致阳性症状、阴性症状和认知缺陷。这一假设基于中心研究人员最近的研究结果：1) 精神分裂症患者的纹状体 DAergic 过量在联想纹状体 (AST) 中最大，2) AST 接收来自背外侧前额皮质 (DLPFC) 的汇聚输入，扣带皮层 (ACC) 和边缘额叶皮层区域，使其对于情感和认知过程的整合至关重要，3) 纹状体DA 小鼠发育过程中 D2 受体过度表达会导致额叶皮质多巴胺改变、PFC 功能障碍（表现为不可逆的学习缺陷以及运动和社交缺陷）。因此，联合纹状体中过多的 D2 信号传导可能会改变来自 PFC 的传入信息的整合，从而损害跨皮质-纹状体-苍白球-丘脑-皮质环路的皮质信息流并改变中脑 DA 功能。我们组织了由 4 个核心支持的五个项目来检验这一假设。我们将测试 SCZ 患者与健康对照相比，纹状体 DA 病理学是否预测：1) 使用正电子发射断层扫描 (PET) (P1) 测量的皮质 DA 病理学和 2) 通过工作记忆任务和通过功能磁共振成像 (fMRI) 测量的 PFC 活性的相关变化 (P2)。我们将创建在纹状体 (P4) 中早期发育过度表达 D2 受体或中脑 DA 放电模式和纹状体 DA 释放 (P5) 改变的转基因小鼠。这些小鼠模型将用于了解额叶皮层 DA 传输异常以及 SCZ 中 PFC 纹状体回路介导的认知和行为异常的可能机制。我们还将确定介导这些效应的纹状体信号转导的关键改变（P4）、猴子和啮齿动物的潜在电路（P3）以及与 SCZ 相关的 DA 成像内表型的可能神经化学介质（P5）。这一套 对人类、猴子和小鼠的研究将确定纹状体 DA 失调在 SCZ PFC 功能障碍发病机制中的作用，并且通过这样做将成为中断这种致病机制的新治疗方法的关键第一步。