A11 Diencephalospinal Dopamine Neurons and Restless Legs Syndrome

描述（由申请人提供）：不宁腿综合征（RLS）是一种常见的神经系统疾病，包括极度渴望移动腿部，并伴有疼痛感，在休息和睡眠期间恶化。这种疾病的患病率在女性中较高，并且随着年龄的增长而增加，这导致了RLS本质上是神经退行性疾病的假设。大多数RLS患者患有昼夜周期性肢体运动（PLM），这是一种与几种神经异常相关的症状，在女性中也更为普遍。RLS的发病机制可能与脊髓多巴胺（DA）抗痛觉作用和神经调节运动作用的丧失有关，D2/3受体是对症治疗的治疗靶点。这些研究的总体目标是建立一种新的小鼠RLS模型，利用A11双脑脊髓DA神经元的神经毒素病变和铁状态的改变，并结合损伤动物在清醒和睡眠时的PLM测量。选择性地破坏投射到腰椎脊髓的A11神经元，同时保留投射到脊髓其他水平的神经元，可能会导致后肢运动抑制调节的缺陷，这与RLS的症状一致。此外，A11神经元特征的性别差异和铁状态的影响将被研究作为女性RLS患病率较高的可能解释。在三个特定目标中描述的拟议研究将采用双标记免疫组织化学、体视学、药理学和神经化学方法来确定雄性和雌性小鼠腰脊髓A11双脑脊髓DA神经元的位置、分布、活动和调节。此外，我们还将研究选择性1-甲基-4-苯基吡啶（MPP+）诱导的腰椎脊髓突出A11神经元病变对脊髓DA浓度和行为的影响。与现有的基于病变的方法相比，该模型具有许多优势，将增强对性别、铁状态和A11 DA功能障碍在RLS发病机制中的作用的理解，并将利用一种新的行为终点来测量小鼠PLM。随着该模型的发展，这种新颖的、可重复的小鼠模型将用于筛选da调节药物，以开发新的治疗RLS的药物。

DESCRIPTION (provided by applicant): Restless legs syndrome (RLS) is a common neurological disorder involving an extreme urge to move the legs accompanied by painful sensations that worsen during periods of rest and sleep. Prevalence of the disorder is higher in females, and increases with age, leading to the hypothesis that RLS is neurodegenerative in nature. The majority of RLS patients suffer from circadian periodic limb movements (PLM), a symptom associated with several neurological abnormalities, which is also more prevalent in females. The pathogenesis of RLS likely involves the loss of spinal cord dopamine (DA) antinociceptive and neuromodulatory motor effects via action at D2/3 receptors, representing a therapeutic target for symptomatic treatment. The overall goal of these studies is to develop a novel mouse model of RLS utilizing neurotoxin-based lesions of A11 diencephalospinal DA neurons and alterations in iron status, combined with measurement of PLM in lesioned animals while awake and during sleep. Selective destruction of A11 neurons projecting to the lumbar spinal cord, while sparing the neurons that project to other levels of the spinal cord should cause deficits in inhibitory regulation of hindlimb movements consistent with symptoms of RLS. Additionally, gender differences in the characteristics of A11 neurons and the effects of iron status will be examined as possible explanations for the higher prevalence of RLS in females. Proposed studies described in three Specific Aims will employ dual label immunohistochemical, stereological, pharmacological, and neurochemical methods to determine the location, distribution, activity, and regulation of A11 diencephalospinal DA neurons projecting to the lumbar spinal cord in male and female mice. Additionally, the effects of selective 1-methyl-4-phenylpyridinium (MPP+) induced lesion of lumbar spinal cord-projecting A11 neurons on DA concentrations in the spinal cord and behavior will be examined. The proposed model has many advantages over currently available lesion-based methods, will enhance the understanding of the roles of gender, iron status, and A11 DA dysfunction in the pathogenesis of RLS, and will utilize a novel behavioral endpoint for the measurement of PLM in mice. Following its development, this novel, reproducible murine model will be used for the screening of DA-modulating pharmacological agents for the development of new treatments for RLS.