DOPAMINE AND MUSCARINIC MEDIATED STRIATAL GENE REGULATION

多巴胺和毒蕈碱介导的纹状体基因调节

• 批准号: 6243645
• 负责人: CHARLES R GERFEN
• 金额: $ 13万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243645
• 关键词: 6 hydroxydopamine; G protein; central neural pathway /tract; cholinergic agents; cooperative study; corpus striatum; dopamine; dopamine receptor; drug administration routes; enkephalins; experimental brain lesion; gene expression; genetic regulation; in situ hybridization; laboratory rat; lenticular nucleus; messenger RNA; muscarinic receptor; neuroanatomy; neurons; neuropharmacology; pharmacogenetics; receptor expression; regulatory gene; substantia nigra

The overall goal of the proposal is to study the functional organization of the striatum. To do this, dopamine and acetylcholine muscarinic receptor mediated gene regulation of striatal neurons will be studied in rats. Administration of selective D1 and D2 dopamine and muscarinic receptor drugs will be used to examine specific receptor mediated gene regulation in connectionally and neurochemically characterized striatal neurons. Striatal neurons will be characterized by their connections using retrograde axonal tracing techniques and by the localization of D1 and D2 dopamine and m1 and m4 muscarinic receptor subtype mRNAs using in situ hybridization histochemical techniques. To assay changes in altered gene regulation, quantitative in situ hybridization histochemical techniques will be used to measure drug-induced changes in mRNAs encoding the transcription factor c-fos, and the neuropeptides enkephalin, substance P, and dynorphin, which serve as markers of specific striatal projection neurons. Results of these studies will provide insight into the molecular and cellular mechanisms through which dopamine and acetylcholine modulate gene regulation in connectionally defined subpopulations of striatal projection neurons. The segregation of the D1 and D2 dopamine receptor subtypes in striatal neurons projecting to the substantia nigra and the globus pallidus, respectively, results in opposite patterns of dopamine agonist-mediated gene regulation in these projection neurons. The goal of the proposed experiments is to study the interaction between dopamine and muscarinic receptor-mediated alterations in gene regulation. This research is relevant to understanding the cellular and molecular changes that occur in the striatum in Parkinson's disease and in helping to devise clinically relevant pharmacologic therapies for reversing these effects.

该提案的总体目标是研究职能组织 纹状体。 为此，多巴胺和乙酰胆碱毒蕈碱 受体介导的纹状体神经元基因调控将在 老鼠。 选择性给予 D1 和 D2 多巴胺和毒蕈碱 受体药物将用于检查特定受体介导的基因 连接和神经化学特征纹状体的调节 神经元。 纹状体神经元的特征在于它们的连接 使用逆行轴突追踪技术和 D1 的定位 和 D2 多巴胺以及 m1 和 m4 毒蕈碱受体亚型 mRNA 用于 原位杂交组织化学技术。 测定改变后的变化 基因调控、定量原位杂交、组织化学 技术将用于测量药物诱导的 mRNA 编码变化 转录因子 c-fos 和神经肽脑啡肽， P物质和强啡肽，作为特定纹状体的标记 投射神经元。 这些研究的结果将提供深入了解 多巴胺和细胞的分子和细胞机制 乙酰胆碱以相关定义调节基因调控 纹状体投射神经元的亚群。 的隔离 纹状体神经元中的 D1 和 D2 多巴胺受体亚型投射到 黑质和苍白球分别导致 多巴胺激动剂介导的基因调控的相反模式 投射神经元。 所提出的实验的目的是研究 多巴胺和毒蕈碱受体介导的改变之间的相互作用 在基因调控方面。 这项研究有助于理解 帕金森病患者纹状体发生的细胞和分子变化 疾病并帮助设计临床相关的药理学 逆转这些影响的疗法。