DOPAMINERGIC CONTROL OF SPINAL CORD AND RESTLESS LEGS

多巴胺能控制脊髓和不宁腿

• 批准号: 6924593
• 负责人: SHAWN HOCHMAN
• 金额: $ 28.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924593
• 关键词: afferent nerve; central nervous system disorders; circadian rhythms; dopamine; dopamine receptor; dorsal root; electrocardiography; electroencephalography; electromyography; genetically modified animals; hypothalamus; in situ hybridization; laboratory mouse; leg; neuromuscular transmission; spinal cord; ventral roots

DESCRIPTION (provided by applicant): Restless legs syndrome (RLS) is a CNS disorder involving abnormal muscle sensations that are reduced during motor activity, worsen at rest, and have a marked circadian pattern. Primary treatment involves providing drugs that increase CNS dopaminergic activity, particularly activation of D2-1ike receptors. The hypothalamus controls autonomic function and circadian rhythmicity. The dorso-posterior (A11) region contains the only dopaminergic (DA) projections to spinal cord. DA fibers terminate largely in the intermediolateral column (IML) housing preganglionic sympathetic neurons and in dorsal horn regions related to muscle afferent processing. We hypothesize: (i) That a deficit in hypothalamo-spinal DA activity results in an aberrant activation of muscle afferents; directly, by reducing tonic inhibition of afferent input, and; indirectly, via a disinhibition-induced increase in sympathetic drive to skeletal muscle afferents. (ii) That low-threshold afferent activity (e.g. during movement) presynaptically depresses high-threshold muscle afferents. (iii) That DA disinhibitory actions should peak at night, the nadir of hypothalamic circadian dopamine release. As the A11 region provides the only DA input, all spinal modulatory actions can be ascribed to its function. Hence, studies of DA modulatory actions in the in vitro spinal cord will characterize the complex cellular and network actions of hypothalamo-spinal dopamine function. First, we plan to characterize the dopamine receptor distribution in spinal cord using immunostaining and in situ hybridization techniques. We will then study 5-HT and dopamine modulation of IML neuronal excitability and whether increases in sympathetic drive facilitate muscle afferent activity and input to spinal neurons. Lastly, we will use A11 neurochemical lesioning and D3 receptor knockout mice to examine their effects on alterations in spinal cord function and relate these changes to changes in several movement-related behavioral parameters concomitant with recordings of EEG, neck & limb EMG, and EKG. The uniqueness of our proposal is the development of novel and testable hypotheses on putative spinal mechanisms causing RLS. It involves the first detailed study of DA modulation of spinal cord function and it is undertaken at behavioral, network, and cellular levels, including an attempt to develop an animal model of RLS.

描述（由申请人提供）：不宁腿综合症（RLS）是一种中枢神经系统疾病，涉及异常的肌肉感觉，在运动过程中减弱，在休息时恶化，并具有明显的昼夜节律模式。主要治疗包括提供增加 CNS 多巴胺能活性的药物，特别是 D2-1 样受体的激活。 下丘脑控制自主功能和昼夜节律。背后 (A11) 区域包含唯一的脊髓多巴胺能 (DA) 投射。 DA 纤维主要终止于容纳节前交感神经元的中外侧柱 (IML) 以及与肌肉传入处理相关的背角区域。我们假设：（i）下丘脑-脊髓 DA 活性的缺陷会导致肌肉传入神经的异常激活；直接地，通过减少传入输入的强直抑制，以及；间接地，通过去抑制引起的骨骼肌传入交感神经驱动的增加。 (ii) 低阈值传入活动（例如运动期间）突触前抑制高阈值肌肉传入。 (iii) DA 去抑制作用应在夜间达到峰值，即下丘脑昼夜节律多巴胺释放的最低点。 由于 A11 区域提供唯一的 DA 输入，所有脊柱调节作用都可以归因于其功能。因此，体外脊髓中 DA 调节作用的研究将表征下丘脑-脊髓多巴胺功能的复杂细胞和网络作用。首先，我们计划使用免疫染色和原位杂交技术来表征脊髓中多巴胺受体的分布。然后，我们将研究 5-HT 和多巴胺对 IML 神经元兴奋性的调节，以及交感神经驱动的增加是否促进肌肉传入活动和脊髓神经元的输入。最后，我们将使用 A11 神经化学损伤和 D3 受体敲除小鼠来检查它们对脊髓功能改变的影响，并将这些变化与伴随脑电图、颈肢肌电图和心电图记录的几个运动相关行为参数的变化联系起来。 我们提案的独特之处在于，对引起不宁腿综合征的假定脊柱机制提出了新颖且可测试的假设。它涉及对脊髓功能的 DA 调节的首次详细研究，并且是在行为、网络和细胞水平上进行的，包括尝试开发 RLS 动物模型。