A11 Diencephalospinal Dopamine Neurons and Restless Legs Syndrome

描述(申请人提供)：不宁腿综合症(RLS)是一种常见的神经系统疾病，涉及极端的腿部运动冲动，并伴随着在休息和睡眠期间恶化的疼痛感觉。这种疾病在女性中的患病率更高，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，在女性中也更常见。RLS的发病机制可能涉及通过作用于D2/3受体失去脊髓多巴胺(DA)的抗伤害性和神经调制运动效应，代表了对症治疗的治疗靶点。这些研究的总体目标是利用基于神经毒素的11个间脑脊髓DA神经元的损伤和铁状态的变化，结合在清醒和睡眠中对受损动物的PLM进行测量，建立一种新型的RLS小鼠模型。选择性地破坏投射到腰髓的A11神经元，而保留投射到脊髓其他水平的神经元，应该会导致与RLS症状一致的后肢运动抑制调节的缺陷。此外，A11神经元特征的性别差异和铁状态的影响将被视为女性RLS患病率较高的可能解释。拟在三个特定目标中描述的研究将使用双重标记免疫组织化学、体视学、药理学和神经化学方法来确定投射到雄性和雌性小鼠腰髓的11个间脑脊髓DA神经元的位置、分布、活性和调节。此外，还将检测选择性1-甲基-4-苯基吡啶(MPP+)诱导的腰髓投射A11神经元对脊髓中DA浓度和行为的影响。与现有的基于病变的方法相比，该模型具有许多优点，将增强对性别、铁状态和A11 DA功能障碍在RLS发病机制中作用的理解，并将利用一种新的行为终点来测量小鼠的PLM。随着它的发展，这一新颖的、可重复性的小鼠模型将被用于筛选DA调节的药理学药物，以开发治疗RLS的新方法。

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.