MOTOR FUNCTIONS OF THE BASAL GANGLIA

基底神经节的运动功能

• 批准号: 3396229
• 负责人: MAHLON R DELONG
• 金额: $ 23.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-07-01 至 1995-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3396229
• 关键词: Macaca mulatta; Parkinson's disease; apomorphine; basal ganglia; disease /disorder model; dopamine agonists; dopamine receptor; electromyography; experimental brain lesion; haloperidol; lenticular nucleus; motor neurons; muscle disorders; muscle rigidity; neural information processing; neuroanatomy; neuromuscular disorder diagnosis; neuromuscular transmission; neurotoxins; putamen; stereotaxic techniques; subthalamus; tremor

The overall aim of these studies is to obtain further insight into the role of the basal ganglia in motor control and the pathophysiology of movement disorders. Key aspects of current models of both hypokinetic (parkinsonism) and hyperkinetic (drug induced dyskinesias) disorders will be studied in the primate MPTP model of parkinsonism. In a first set of experiments, we will test the hypothesis that the major parkinsonian signs (akinesia, bradykinesia, tremor, rigidity) result from increased activity in the internal segment of the globus pallidus (GPi), the major output structure of the basal ganglia. Motor behavior will be examined in normal and parkinsonian monkeys, before and after reversible or permanent inactivation of GPi with intracerebral injections with the GABAreceptor agonist muscimol or the neurotoxin ibotenic acid. To test the hypothesis that the increased GPi output in parkinsonian monkeys is the result of increased excitatory drive from the subthalamic nucleus (STN) on GPi, we will also study the long-term effects of STN lesions in such animals. Comparison of the effects of STN and GPi lesions will provide information about the relative effects of such lesions on different parkinsonian motor signs. In additional studies, two hypotheses regarding the effects of DAergic agonists on parkinsonian animals will be tested: 1) that dopamine receptor agonists reverse parkinsonian signs by normalizing GPi output and 2) that drug-induced dyskinesias in parkinsonian animals result from subnormal neural activity in GPi. To this end, we will directly record GPi activity in parkinsonian animals treated with dopaminergic agonists in the Presence and absence of dyskinesias. To explore which pathways are involved in the development of drug-induced dyskinesias, the dyskinesia producing capabilities of DA receptor agonists win also be studied in parkinsonian monkeys with and without GPi or STN lesions. In a final set of studies, we will test the cardinal parkinsonian signs result from dopamine deficiency in the putamen, by reversibly blocking dopaminergic transmission in different locations within the basal ganglia in normal monkeys with direct injections of haloperidol. In a companion study, dopamine receptor agonists will be injected in parkinsonian monkeys into various basal ganglia nuclei in order to determine the most effective site(s) of local dopaminergic repletion for the reversal of parkinsonian signs. Taken together, these studies will help to clarify the pathophysiologic basis of parkinsonian signs and drug-related dyskinesias, will directly test the therapeutic benefits of specific lesioning and drug-treatment strategies, and may lead to important new-treatment strategies.

这些研究的总体目的是进一步了解该角色 运动控制中的基底神经节和运动的病理生理学 疾病。 当前模型的主要方面 （帕金森氏症）和运动型（药物诱发运动障碍）疾病将 在灵长类动物MPTP的帕金森主义模型中进行了研究。 在第一组 实验，我们将测试主要帕金森氏症标志的假设 （Akinesia，Bradykinesia，Tremor，刚性）是由于活动增加而导致的 在Globus Pallidus（GPI）的内部段中，主要输出 基底神经节的结构。 运动行为将在正常情况下检查 和帕金森尼猴，可逆或永久性之前和之后 对GPI的灭活室内注射GPI 激动剂麝香酚或神经毒素伊替酸。检验假设 帕金森猴的GPI产量增加是由 GPI上丘脑下核（STN）的兴奋性驱动器增加，我们 还将研究此类动物中STN病变的长期影响。 STN和GPI病变影响的比较将提供信息 关于此类病变对不同帕金森电机的相对影响 标志。 在其他研究中，关于DAERGIC的影响的两个假设 将测试帕金森氏症动物的激动剂：1）多巴胺受体 激动剂通过标准化GPI输出来反向帕金森氏症标志，2） 帕金森氏动物中药物诱导的运动障碍是由亚正常引起的 GPI中的神经活动。 为此，我们将直接记录GPI活动 在帕金森氏症动物中，在存在的情况下用多巴胺能激动剂治疗 和缺乏运动障碍。探索涉及哪些途径 药物引起的运动障碍的发展，产生运动障碍 DA受体激动剂的能力也在帕金森氏症中研究 有和没有GPI或STN病变的猴子。 在最后一组研究中，我们将测试红衣主教帕金森氏症标志 壳虫中多巴胺缺乏症导致，通过可逆地阻塞 基底神经节内不同位置的多巴胺能传播 在正常猴子中直接注射氟哌啶醇。 在同伴中 研究，多巴胺受体激动剂将被注入帕金森猴 进入各种基底神经节核，以确定最有效的 帕金森氏症逆转的当地多巴胺能的地点 标志。 综上所述，这些研究将有助于阐明病理生理 帕金森氏症的基础和与毒品相关的运动障碍的基础，将直接直接 测试特定病变和药物治疗的治疗益处 策略，并可能导致重要的新处理策略。