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学，并且是由特定前脑区域（包括内侧额叶皮质和纹状体）的形成和连接改变引起的。多巴胺和其他生物胺在成熟的神经系统中充当神经递质，并且也是治疗神经和精神疾病的突出药物靶标。多巴胺系统在脑发育的早期，在突触形成之前表达，并且多效性地调节与神经元分化和回路形成相关的决定。多巴胺对树突形态的依赖性作用具有受体亚型特异性和脑区特异性。我们收集的初步数据表明，额外的特异性是由不同的信号传导途径的刺激，取决于受体构象（S）稳定的不同的配体（功能选择性）。因此，本提案的目标是确定额叶皮层和纹状体发育过程中多巴胺受体的细胞功能，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，探讨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的多巴胺受体亚群对树突状细胞分化和细胞信号转导反应的影响在体外分离的神经元。我们将测试的假设，D1和D2受体可以产生不同的影响树突状细胞的生长模式取决于G蛋白信号通路诱导的功能不同的配体。在目标2中，我们将使用最近创建的小鼠BAC报告细胞系（D1-tdTomato和D2-eGFP）来研究过程生长的自发速率是否作为多巴胺受体表达（和/或共表达）的函数而不同。在目标3中，我们将进入体内系统，测试D1和D2受体的遗传缺失分别在多大程度上改变了D1和D2受体表达神经元中的树突形态。因此，我们的研究计划将确定细胞特异性差异的发育反应，一个共同的生物配体，多巴胺。发育过程中多巴胺能活性的改变，无论是通过遗传还是药理学手段产生的，都会改变发育关键时期介导认知和情感行为的回路，并可能导致以后生活中的精神疾病。 公共卫生相关性：脑儿茶酚胺系统功能障碍与精神疾病的发展和表现有关。这项研究将有助于阐明配体特异性多巴胺受体调节如何有助于建立适当的大脑结构。

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. PUBLIC HEALTH RELEVANCE: Dysfunctions in brain catecholamine systems have been linked to both the development and expression of mental illness. The studies contained in this proposal will help elucidate how ligand- specific dopamine receptor modulation contributes to the establishment of proper brain architecture.