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

中缝背侧血清素能神经元在左旋多巴诱导的运动障碍中的作用

• 批准号: 9135143
• 负责人: Stephanie Lorraine Alberico
• 金额: $ 3.2万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135143
• 关键词: Ablation; Address; Adverse effects; Affect; Animals; Aromatic-L-Amino-Acid Decarboxylases; Attenuated; Cell Nucleus; Corpus striatum structure; Data; Development; Dopamine; Dopamine D1 Receptor; Dorsal; Dyskinetic syndrome; Exhibits; Goals; Involuntary Movements; Lead; Levodopa; Link; Maps; Measures; Midbrain structure; Modeling; Motion; Motor; Movement; Movement Disorders; Mus; Neuraxis; Neurodegenerative Disorders; Neurons; Neurotransmitters; Operative Surgical Procedures; Parkinson Disease; Patients; Pharmacotherapy; Population; Quality of life; Rattus; Role; Serotonergic System; Substantia nigra structure; System; Techniques; Testing; Therapeutic Agents; Transgenic Animals; Transgenic Organisms; Treatment Efficacy; United States; Work; abnormal involuntary movement; awake; dopaminergic neuron; dorsal raphe nucleus; innovation; motor symptom; mouse model; neuromechanism; neurophysiology; novel therapeutics; optogenetics; public health relevance; raphe nuclei; receptor expression; research study; therapy development

 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.

 描述（由申请人提供）：治疗帕金森病（PD）的一个主要限制是L-多巴诱导的运动障碍（LID）的发展。LID是破坏性的不自主运动，会导致PD患者的生活质量下降。到目前为止，这种使人衰弱的副作用背后的神经机制还知之甚少。因此，该提案结合了神经生理学，光遗传学和自动运动跟踪来探索所涉及的机制。先前的工作表明，在PD大鼠模型中，多巴胺能神经元消融后LID减少。在拟议的研究中，我们将通过首先确定多巴胺能神经元是否是LID发展所必需的（目的1），然后确定是否是纹状体中调节LID的D1神经元的特异性多巴胺能投射（目的2）来解决多巴胺能系统的参与。 为了确定多巴胺能系统在LIDS发展中的一般作用，我们将向中枢神经系统中缺乏多巴胺能神经元的偏侧帕金森病Lmx 1bf/f/p小鼠注射L-多巴并记录异常不自主运动。接下来，我们提出将中缝背核（DRN）作为参与LID的主要核团进行光遗传学靶向，因为它大量投射到纹状体。 为了研究LIDS过程中纹状体中多巴胺能和多巴胺能系统之间的相互作用，我们首先将联合收割机纹状体神经元集合记录与药理学操作相结合。纹状体活动（神经元放电率和局部场电位）将与清醒动物的LID配对。其次，我们测量LIDS，同时用光遗传学技术抑制多巴胺能神经元和瞬时刺激D1神经元。阐明LID的机制可能会导致开发抑制运动障碍的治疗方法，增强左旋多巴的运动益处，并可能避免对更具侵入性的手术治疗的需要，从而显着提高这些患者的生活质量。