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）：不安的腿综合征（RLS）是一种中枢神经系统疾病，涉及异常的肌肉感觉，在运动活动期间降低，静止状况恶化，并具有明显的昼夜节律模式。初级治疗涉及提供增加CNS多巴胺能活性的药物，尤其是D2-1-型受体的激活。 下丘脑控制自主功能和昼夜节律。 Dorso-Posterior（A11）区域包含唯一对脊髓的多巴胺能（DA）投影。 DA纤维主要终止在中间外侧柱（IML）外壳前的交感神经神经元和与肌肉传入加工有关的背角区域。我们假设：（i）下丘脑脊柱DA活性的缺陷导致肌肉传入异常激活；直接，通过减少滋补传入输入的抑制作用，并且；间接地，通过抑制作用引起的交感神经驱动力增加到骨骼肌传入。 （ii）低阈值传入活动（例如在运动期间）会降低高阈值的肌肉传入。 （iii）DA DID抑制性行动应在晚上达到顶峰，这是下丘脑昼夜节律多巴胺的释放的最低点。 由于A11区域提供了唯一的DA输入，因此所有脊柱调节作用都可以归因于其功能。因此，对体外脊髓中DA调节作用的研究将表征下丘脑脊髓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分布。然后，我们将研究IML神经元兴奋性的5-HT和多巴胺调节，以及交感神经驱动的增加是否促进了肌肉传入活性和对脊柱神经元的输入。最后，我们将使用A11神经化学病变和D3受体基因敲除小鼠来检查它们对脊髓功能改变的影响，并将这些变化与几种与运动相关的行为参数的变化相关联，以及与脑电，颈部和肢体和肢体和肢体EMG和EKG的记录相关的。 我们提案的独特性是开发有关导致RLS的假定脊柱机制的新颖和可检验的假设。它涉及对脊髓功能的DA调制的首次详细研究，并在行为，网络和细胞水平上进行，包括尝试开发RLS动物模型的尝试。