Dopaminergic Modulation of Brain Development

大脑发育的多巴胺能调节

• 批准号: 8101969
• 负责人: GREGG D STANWOOD
• 金额: $ 37.97万
• 依托单位: VANDERBILT UNIVERSITY
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101969
• 关键词: Adult; Affect; Agonist; Architecture; Area; Behavior; Biogenic Amines; Biological; Biological Assay; Brain; Brain region; Catecholamines; Cell physiology; Cells; Chemicals; Co-Immunoprecipitations; Cognitive; Complex; Corpus striatum structure; Coupling; Data; Dendrites; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Drug Delivery Systems; Emotional; Etiology; Event; Exhibits; Functional disorder; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; Genetic; Goals; Growth; Heterogeneity; In Vitro; Joints; Knock-out; Knockout Mice; Lead; Life; Ligands; Link; Medial; Mediating; Mental disorders; Molecular; Molecular Conformation; Morphology; Mus; Nervous system structure; Neurites; Neuroglia; Neuronal Differentiation; Neurons; Neurotransmitters; Pathway interactions; Pattern; Phenotype; Phospho-Specific Antibodies; Prefrontal Cortex; Process; Prosencephalon; Proteins; Radial; Receptor Activation; Receptor Signaling; Regulation; Reporter; Reporting; Research; Role; Signal Pathway; Signal Transduction; Specificity; Synapses; Synaptic plasticity; System; Techniques; Testing; Tomatoes; base; cell type; dopamine system; frontal lobe; in vivo; nervous system disorder; neurochemistry; offspring; programs; promoter; public health relevance; receptor; receptor expression; research study; response; synaptogenesis

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.

描述（由申请人提供）：大多数精神健康障碍都有发育性病因，是由特定前脑区域（包括内侧额叶皮层和纹状体）的形成和连接性改变引起的。多巴胺和其他生物胺作为成熟神经系统中的神经递质，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、突触形成之前表达，并多效性调节与神经元分化和回路形成相关的决策。多巴胺依赖性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，根据由不同配体稳定的受体构象（功能选择性）刺激不同的信号通路，可以赋予额外的特异性。因此，该提案的目标是直接参考细胞亚群和功能选择性，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。我们提出了三个具体目标来探讨多巴胺受体刺激控制树突形态的机制。在目标 1 中，我们将研究激活不同的多巴胺受体亚群对体外分离神经元的树突分化和细胞信号传导反应的影响。我们将测试以下假设：D1 和 D2 受体可以对树突生长模式产生不同的影响，具体取决于功能不同的配体诱导的 G 蛋白信号传导途径。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速率是否随多巴胺受体表达（和/或共表达）而变化。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表达 D1 和 D2 受体的神经元的树突形态。因此，我们的研究计划将识别细胞对常见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，并可能导致以后的精神疾病。 公共卫生相关性：大脑儿茶酚胺系统功能障碍与精神疾病的发展和表现有关。该提案中包含的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。