PATHOPHYSIOLOGICAL MECHANISMS OF MOVEMENT DISORDERS

运动障碍的病理生理机制

• 批准号: 2714382
• 负责人: MARK Stephen BARON
• 金额: $ 11万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2714382
• 关键词: Macaca mulatta; Parkinson's disease; abnormal involuntary movement; antiparkinson drugs; apomorphine; basal ganglia; behavior test; brain mapping; disease /disorder model; dosage; experimental brain lesion; histopathology; lenticular nucleus; mental disorder chemotherapy; motor cortex; muscimol; neurons; neuropharmacology; nonhuman therapy evaluation; psychomotor function; sensorimotor system; sign /symptom; stimulus /response; subthalamus

The major aim of this study is to better define the contribution of the basal ganglia "motor" circuits to the development of hypokinetic and hyperkinetic movement disorders. The basal ganglia nuclei appear to influence motor control through multiple reentrant cortico-subcortical pathways. Lesioning and reversible inactivation studies in parkinsonian monkeys have demonstrated that the "motor", and not the "associative", circuits directly influence parkinsonian motor signs. Based upon the demonstration of site specific inactivation effects in the "motor" territory of the internal portion of the globus pallidus (GPi), we hypothesize that the recently identified anatomically segregated cortico- subcortical "motor" subcircuits differentially influence specific parkinsonian motor signs. We have recently shown that electrolytic lesioning of the sensorimotor territory of GPi is an effective means for ameliorating all parkinsonian signs, as well as drug-induced dyskinesias, in patients with idiopathic Parkinson's disease (PD). After surgery, however, patients continue to require comparable medication dosages for adequate control of their symptoms. Experimental lesions placed in the subthalamic nucleus (STN) of parkinsonian monkeys have similarly been shown to cause dramatic improvement of parkinsonian signs, with mainly transient lesion-induced dyskinesias. Because STN projects not only to GPi, but also to such structures as the substantia nigra (SN), lesioning of STN could potentially provide better amelioration of parkinsonian symptoms, while reducing patients' dependencies on dopamine therapy. The proposed studies will address these issues related to the specific pathways influencing normal and abnormal motor control. Specifically, we will 1) determine whether the primary motor cortex (MC) and supplementary motor area (SMA) subcircuits contribute differentially to the production Of parkinsonian motor signs, in the PD animal model, 2) investigate whether in the parkinsonian state, these subcircuits converge at the level of single neurons in the basal ganglia, 3) assess the contribution of SN pars reticulata to the expression of parkinsonian motor signs, 4) examine the role of STN pathways in the development of parkinsonian symptoms and drug- related dyskinesias and compare the results of GPi and STN lesions in parkinsonian animals, and 5) determine the patterns of basal ganglia neural activity associated with drug-induced dyskinesias.

这项研究的主要目的是更好地定义 基底神经节“电动机”电路，发展不足和发育 超动运动障碍。基底神经节核似乎 通过多个再入皮质皮质来影响运动控制 途径。 帕金森尼的病变和可逆失活研究 猴子已经证明了“马达”，而不是“关联”， 电路直接影响帕金森氏电动标志。 基于 演示“电动机”中现场特异性失活效应 Globus Pallidus（GPI）内部的领土，我们 假设最近确定的解剖分离的皮质 皮层“运动”亚电路差异影响特定 帕金森式汽车标志。 我们最近表明，感觉运动的电解病变 GPI领土是改善所有帕金森氏症的有效手段 特发性患者的体征以及药物诱导的运动障碍 帕金森氏病（PD）。但是，手术后，患者继续 需要可比较的药物剂量以充分控制其 症状。放置在丘脑下核（STN）的实验病变 帕金森尼猴子同样被证明会引起戏剧性 改善帕金森氏症标志，主要是短暂病变引起的 运动障碍。 因为STN不仅向GPI进行项目，而且还针对此类 结构作为黑质（SN），STN的病变可能有可能 减轻帕金森氏症状的更好缓解 患者对多巴胺治疗的依赖性。 拟议的研究将解决与特定有关的这些问题 影响正常和异常运动控制的途径。具体来说，我们 1）确定主要运动皮层（MC）和补充是否 电机区域（SMA）子电路对生产有不同的贡献 PD动物模型中的帕金森汽车标志，2）调查是否是否 在帕金森州，这些子电路在 基底神经节中的单个神经元，3）评估SN PAR的贡献 网状表达帕金森氏电动标志的表达，4）检查 STN途径在帕金森氏症状和药物发展中的作用 - 相关的运动障碍并比较GPI和STN病变的结果 帕金森氏动物，5）确定基底神经神经的模式 与药物诱导的运动障碍有关的活性。