Role of dorsal raphe serotonergic neurons in L-dopa induced dyskinesias

 描述(申请人提供)：治疗帕金森氏病(PD)的一个主要限制因素是L-多巴诱发的运动障碍(LID)。眼睑是破坏性的不自主运动，会导致帕金森病患者的生活质量下降。到目前为止，这种令人衰弱的副作用背后的神经机制还知之甚少。因此，这一建议结合了神经生理学、光遗传学和自动运动跟踪来探索涉及的机制。先前的工作表明，在帕金森病大鼠模型中，5-羟色胺能神经元消融后LIDs减少。在拟议的研究中，我们将讨论5-羟色胺能系统的参与，首先确定5-羟色胺能神经元是否对LIDs的发育是必需的(目标1)，然后确定是否有特定的5-羟色胺能投射到纹状体中调节LIDs的D1神经元(目标2)。为了确定5-羟色胺能系统在LID发生发展中的一般作用，我们将给中枢神经系统缺乏5-羟色胺能神经元的偏侧帕金森病Lmx1bf/f/p小鼠注射L-多巴，并记录异常的不自主运动。下一步，我们建议将光遗传学靶向中缝背核(DRN)作为参与LIDs的主要核，因为它大量投射到纹状体。为了研究LID期间纹状体5-羟色胺能系统和多巴胺能系统之间的相互作用，我们首先将纹状体神经元集合记录与药物操作相结合。在清醒行为的动物中，纹状体的活动(神经元放电率和局部场电位)将与盖子配对。其次，我们在药物抑制5-羟色胺能神经元的同时测量LID，并用光遗传学技术瞬时刺激D1神经元。阐明LIDs的机制可能会导致开发出抑制运动障碍的治疗方法，增强L-多巴的运动益处，并有可能避免更具侵入性的手术治疗，显著提高这些患者的生活质量。

 DESCRIPTION (provided by applicant): A major limitation in treating Parkinson's disease (PD) is the development of L-Dopa induced dyskinesias (LIDs). LIDs are disruptive involuntary movements that lead to a decreased quality of life in PD patients. To date, the neural mechanism underlying this debilitating side effect is poorly understood. Thus, this proposal combines neurophysiology, optogenetics, and automated motion tracking to explore the mechanism involved. Prior work demonstrates a reduction in LIDs following serotonergic neuron ablation in a rat model of PD. In the proposed study, we will address the involvement of the serotonergic system by first determining if serotonergic neurons are necessary for the development of LIDs (Aim 1) and then determining if it is specifically serotonergic projections to D1 neurons in the striatum that modulate LIDs (Aim 2). To identify the general role of serotonergic system in the development of LIDs, we will inject hemiparkinsonian Lmx1bf/f/p mice, lacking serotonergic neurons in the central nervous system, with L-dopa and document abnormal involuntary movements. Next, we propose to optogenetically target the dorsal raphe nucleus (DRN) as the main nucleus involved in LIDs, as it heavily projects to the striatum. To study the interaction between the serotonergic and dopaminergic systems in the striatum during LIDs, we first combine striatal neuronal ensemble recordings with pharmacological manipulations. Striatal activity (neuronal firing rate and local field potential) will be paired wih LIDs in awake-behaving animals. Secondly, we measure LIDs while pharmacologically inhibiting serotonergic neurons and transiently stimulating D1 neurons with optogenetics techniques. Elucidating the mechanism of LIDs may lead to the development of therapies that will inhibit dyskinesias, enhance motor benefits from L-dopa, and potentially avoid the need for more invasive surgical treatment, significantly increasing the quality of life in these patients.