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，涉及移动腿的极端冲动，伴有疼痛感，在休息和睡眠期间加重。该疾病的患病率在女性中较高，并且随着年龄的增长而增加，导致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，在女性中也更普遍。RLS的发病机制可能涉及通过作用于D2/3受体的脊髓多巴胺（DA）抗伤害感受和神经调节运动效应的丧失，这代表了对症治疗的治疗靶点。这些研究的总体目标是开发一种新的RLS小鼠模型，利用A11间脑脊髓DA神经元的神经毒素为基础的病变和铁状态的改变，结合在清醒和睡眠期间测量损伤动物的PLM。选择性破坏投射到腰髓的A11神经元，同时保留投射到脊髓其他水平的神经元，应导致与RLS症状一致的后肢运动抑制调节缺陷。此外，A11神经元特征的性别差异和铁状态的影响将被检查作为女性RLS患病率较高的可能解释。三个特定目的中描述的拟定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，以确定雄性和雌性小鼠中投射至腰髓的A11间脑脊髓DA神经元的位置、分布、活性和调节。此外，将检查选择性1-甲基-4-苯基吡啶鎓（MPP+）诱导的腰脊髓投射A11神经元损伤对脊髓中DA浓度和行为的影响。所提出的模型具有许多优势，目前可用的病变为基础的方法，将提高性别，铁的状态，和A11 DA功能障碍的发病机制的RLS的角色的理解，并将利用一种新的行为终点测量PLM小鼠。在其开发之后，这种新型的、可重复的小鼠模型将用于筛选DA调节药理学药物，以开发新的RLS治疗方法。

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.