Dopamine Dysfunction in Schizophrenia

精神分裂症的多巴胺功能障碍

• 批准号: 8249495
• 负责人: Anissa Abi-Dargham
• 金额: $ 188.94万
• 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/8249495
• 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. 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.

描述（由申请人提供）：“精神分裂症多巴胺功能障碍”的中心将检验以下假设，即发育过程中纹状体多巴胺能过度活跃导致额叶皮质多巴胺（DA）功能障碍在精神分裂症（SCZ）中（SCZ）和认知缺陷的疾病表征该疾病。因此，发育过程中纹状体中DA传播的失调及其对前额叶皮质（PFC）DA传播和PFC电路功能的最终影响有助于正症状，阴性症状和认知缺陷。 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情感和认知过程的整合，3）纹状体DA 小鼠发育过程中的D2受体过表达导致额叶多巴胺改变，PFC功能障碍，这是不可逆转的学习缺陷以及启动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通过关联纹状体中的过度D2信号传导改变，从而损害了跨皮质 - 纹状体 - 甲状腺 - 甲状腺thalamo - 皮层环路的皮质流动，并改变了中脑DA的功能。我们组织了4个核心支持的五个项目以检验这一假设。与健康对照相比，我们将在SCZ患者中测试纹状体DA病理学是否预测：1）通过正电子发射断层扫描（PET）（P1）和2）PFC介导的认知功能测量的皮质DA病理学，如工作记忆任务评估，并通过PFC活性在功能上的磁共振效果（FMRI）（FMRI）（P2）（P2）（P2）。我们将创建具有纹状体中D2受体早期发育过度表达的转基因小鼠（P4）或中脑DA发射模式和纹状体DA释放（P5）的改变。这些小鼠模型将用于了解异常额叶皮质DA传播以及SCZ中PFC-纹状体回路介导的认知和行为异常。我们还将确定介导这些作用的纹状体转导的临界变化（P4），猴子和啮齿动物中的基础电路（P3）（P3），以及与SCZ相关的DA成像内表型的神经化学介体（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功能障碍的发病机理中的作用，并且通过这样做将成为中断这种病原机制的新型治疗方法的关键第一步。 公共卫生相关性：无序认知会导致精神分裂症的严重功能障碍。我们对这种疾病的关键改变的新观点，即功能障碍，以及我们提出的一系列机械研究以进行测试，这将导致对疾病的新，更好地理解。反过来，这可能会导致基于这种新理解可以开发的预防或治疗策略。