A role for dopamine in brain development

本申请中提出的研究旨在检验多巴胺影响神经发生和中枢神经系统细胞结构发育的假设。多巴胺是一种神经调节剂，它在情绪、动机和注意力等复杂行为的调节中的作用是众所周知的。最近的报道表明，多巴胺受体的激活影响神经元和神经胶质细胞的分化。胎儿接触可卡因，一种针对大脑多巴胺系统的药物，会改变神经发生，导致大脑结构和功能的永久性缺陷。精神分裂症和自闭症谱系障碍被认为是由发育引起的疾病，也与多巴胺失衡有关。因此，发育中的大脑多巴胺能系统的失衡正在被认为是导致中枢神经系统结构和功能改变的潜在原因。这项拟议的研究旨在检查多巴胺对细胞周期的影响，细胞周期是驱动神经发生的分子引擎。重点将放在神经节隆起和新皮质神经上皮上，这两个胚胎前体群体接受丰富的多巴胺能输入，占前脑细胞的大多数。神经节突起是纹状-掌系统的前体，也是多个前脑区域GABA能神经元的来源。了解多巴胺在神经节隆起的神经发生中的作用具有额外的意义，因为精神分裂症和某些形式的癫痫会发生前脑范围的多巴胺和/或GABA能功能障碍。这些拟议的研究将考察多巴胺受体激活对神经上皮祖细胞细胞周期动力学的影响，以及对调节神经发生的分子机制的影响。将使用转基因小鼠模型，其中将使用四环素可调节的基因表达系统，在神经上皮祖细胞中选择性地诱导多巴胺受体转基因，并在特定的发育时期选择性地诱导转基因。在这个模型中，将研究多巴胺受体激活对胚胎期间细胞周期调节分子、细胞周期动力学、细胞死亡和细胞输出的影响，以及成熟时大脑的细胞结构。多巴胺受体转基因基因在特定细胞类型中的可诱导表达为实验建模和分析药物滥用、注意力/活动障碍和精神分裂症的病理生理学提供了前所未有的优势，所有这些都与发育中的大脑多巴胺能系统的失衡有关。它也是一个很好的模型，可以模拟中枢神经系统中的多巴胺失衡，这种失衡可以由有意或无意针对发育中大脑的多巴胺能系统的治疗药物产生。

The studies proposed in this application are designed to test the hypothesis that dopamine influences neurogenesis and the development of cellular architecture of the CNS. Dopamine is a neuromodulator whose actions in the regulation of complex behaviors such as mood, motivation and attention are well known. Recent reports indicate that dopamine receptor activation influences neuronal and glial cell differentiation. Fetal exposure to cocaine, a drug that targets dopaminergic systems of the brain, alters neurogenesis and causes permanent deficits in brain structure and function. Schizophrenia and autism spectrum disorder, diseases considered to have developmental origins, also are associated with dopamine imbalance. Thus, imbalances in the dopaminergic system of the developing brain are gaining recognition as potential causes of altered CNS structure and function. The proposed studies are designed to examine the effects of dopamine on cell cycle, the molecular engine that drives neurogenesis. The focus will be on the ganglionic eminence and the neocortical neuroepithelium, two embryonic precursor populations that receive rich dopaminergic inputs and that account for the majority of forebrain cells. The ganglionic eminence is the precursor of the striato-paltidal system and also a source of GABAergic neurons of multiple forebrain regions. Understanding dopamine's role in neurogenesis in the ganglionic eminence acquires added significance as forebrain-wide dopaminergic and/or GABAergic dysfunction occurs in schizophrenia and some forms of epilepsy. The proposed studies will examine the effects of dopamine receptor activation on cell cycle kinetics of neuroepithelial progenitor cells and on the molecular machinery that regulates neurogenesis. A transgenic mouse model will be used in which dopamine receptor transgenes will be induced selectively in neuroepithelial progenitor cells and electively at specified developmental periods, using a tetracycline regulatable gene expression system. The effects of dopamine receptor activation will be examined in this model on cell cycle regulatory molecules, cell cycle kinetics, cell death and cell output during the embryonic period and the cellular architecture of the brain at maturity. The inducible expression of dopamine receptor transgenes in specific cell types offers unprecedented advantages to experimentally model and analyze the pathophysiology of drug abuse, attention/activity disorders and schizophrenia, all of which are associated with imbalances in the dopaminergic system of the developing brain. It is also an excellent model to mimic dopamine imbalance in the CNS that can be produced by therapeutic drugs that intentionally or unintentionally target the dopaminergic system of the developing brain.