Dopaminergic Modulation of Brain Development

描述（由申请人提供）：大多数精神健康障碍具有发育病因，并由特定前脑区域（包括内侧额叶皮层和纹状体）的形成和连通性的改变产生。多巴胺和其他生物胺在成熟的神经系统中作为神经递质，也是治疗神经和精神疾病的重要药物靶点。多巴胺系统在大脑发育早期，在突触形成之前表达，并多向调节与神经元分化和回路形成相关的决策。多巴胺对树突形态的影响是受体亚型特异性和脑区域特异性的。我们收集的初步数据表明，根据不同配体稳定的受体构象（功能选择性），不同信号通路的刺激可赋予额外的特异性。因此，本研究的目标是确定多巴胺受体在额叶皮层和纹状体发育过程中的细胞功能，并直接参考细胞亚群和功能选择性。我们提出了三个具体的目标来探索多巴胺受体刺激控制树突形态的机制。在目的1中，我们将研究激活不同多巴胺受体亚群对体外解离神经元树突分化和细胞信号反应的影响。我们将验证D1和D2受体对树突生长模式产生不同影响的假设，这取决于哪种G蛋白信号通路由功能不同的配体诱导。在目标2中，我们将使用最近创建的小鼠BAC报告系（D1-tdTomato和D2-eGFP）来研究过程生长的自发率是否随多巴胺受体表达（和/或共表达）的变化而不同。在目标3中，我们将进入体内系统，测试D1和D2受体的遗传损失分别在多大程度上改变D1和D2受体表达神经元的树突形态。因此，我们的研究计划将确定细胞对一种常见的生物配体多巴胺的发育反应的特异性差异。发育过程中多巴胺能活性的改变，无论是通过遗传还是药物手段产生的，都会改变发育关键时期调节认知和情感行为的回路，并可能导致生命后期的后续精神疾病。

DESCRIPTION (provided by applicant): Most mental health disorders have developmental etiologies and are produced by alterations in the formation and connectivity of specific forebrain regions including the medial frontal cortex and the striatum. Dopamine and other biogenic amines serve as neurotransmitters in the mature nervous system, and are also prominent drug targets in the treatment of neurological and psychiatric disorders. The dopamine system is expressed early in brain development, prior to the formation of synapses, and pleiotropically modulates decisions related to neuronal differentiation and circuit formation. Dopamine-dependent effects on dendritic morphology are receptor subtype-specific and brain region specific. We have gathered preliminary data suggesting that additional specificity is conferred by the stimulation of different signaling pathways depending on the receptor conformation(s) stabilized by distinct ligands (functional selectivity). The goals of this proposal are thus to identify the cellular functions of dopamine receptors during development of the frontal cortex and striatum, with direct reference to cellular subpopulations and functional selectivity. We propose three specific aims to probe the mechanisms by which dopamine receptor stimulation controls dendritic morphology. In Aim 1, we will examine the effects of activating distinct dopamine receptor subpopulations on dendritic differentiation and cell signaling responses of dissociated neurons in vitro. We will test the hypothesis that D1 and D2 receptors can produce distinct effects on dendritic growth patterns depending on which G protein signaling pathway is induced by functionally distinct ligands. In Aim 2, we will use recently created BAC reporter lines of mice (D1-tdTomato and D2-eGFP) to investigate whether spontaneous rates of process outgrowth differ as a function of dopamine receptor expression (and/or co-expression). In Aim 3, we will move into in vivo systems, testing to what degree genetic loss of the D1 and D2 receptors alters dendritic morphology in D1- and D2 receptor- expressing neurons, respectively. Our research program will thus identify cell-specific differences in developmental responsiveness to a common biological ligand, dopamine. Alterations in dopaminergic activity during development, whether produced by genetic or pharmacological means, alters circuits mediating cognitive and emotional behaviors during critical epochs of development, and may lead to subsequent psychiatric disease later in life.