The Role of a Cerebello-Thalamo-Basal Ganglia Pathway in Dystonia

描述（由申请人提供）：肌张力障碍是一种运动障碍，其特征是激动剂和拮抗剂肌肉同时和长时间的共同收缩，导致患者采取痛苦的扭曲姿势。肌张力障碍的病因是不同的，其中很少被很好地理解。肌张力障碍可由基底神经节病变引起，许多遗传性和继发性肌张力障碍与基底神经节活动改变有关，表明基底神经节在这种疾病中起作用。某些肌张力障碍是在小脑损伤后出现的，而另一些则是由于小脑输出核的损伤而减轻的，这表明某些肌张力障碍病例可能与小脑有关。在啮齿类动物中，向小脑灌注选择性Na/K atp酶（钠泵）阻滞剂瓦巴因会导致肌张力障碍。我们实验室的研究表明，这种肌张力障碍的产生机制可能在特定的遗传性肌张力障碍，DYT12或快速发作的肌张力障碍-帕金森病中很重要。我们认为，在这个模型中，小脑的异常活动转移到基底节区并介导观察到的肌张力障碍。在啮齿类动物和灵长类动物中发现了小脑输出核和基底神经节输入核之间的非突触连接。这一途径的生理作用目前尚不清楚。在这一建议中，我们评估了这一突触通路，特别是它的中间核之一，丘脑中央外侧核（CL），在小脑给药沃巴因引起的肌张力障碍中的作用。初步研究表明，在沃巴因灌注前损伤CL可防止肌张力障碍的产生。在这个建议中，我们将测试这种预防是否长期有效，是否伴有其他运动异常。我们还将探讨CL作为动物已经有肌张力障碍后的潜在干预部位。最后，我们将确定如何CL神经元放电变化的反应，以沃巴因灌注到小脑。这将使我们深入了解通过病变动物CL的突触通路的作用，并有助于开发新的干预措施，包括药物治疗和深部脑刺激，以测试劳巴因灌注的小鼠肌张力障碍。这些实验将有助于确定肌张力障碍诱导的一种机制，并提出缓解某些人类病例肌张力障碍的新方法。

DESCRIPTION (provided by applicant): Dystonia is a movement disorder characterized by simultaneous and prolonged co-contraction of agonist and antagonist muscles, causing patients to adopt painful twisting postures. The dystonias are heterogeneous in their etiologies and few of these are well understood. Dystonia can be generated by lesions in the basal ganglia and many genetic and secondary dystonias are associated with altered basal ganglia activity suggesting the basal ganglia plays a role in this disorder. Certain dystonias present after cerebellar insult and others are relieved by lesion of the cerebellar output nuclei suggesting that the cerebellum may be involved in certain cases of dystonia. In rodents, perfusing a selective Na/K ATPase (sodium pump) blocker ouabain into the cerebellum results in dystonia. Studies in our lab suggest this mechanism of dystonia generation may be important in a particular genetic dystonia, DYT12 or Rapid-Onset Dystonia- Parkinsonism. We suggest that in this model, aberrant activity in the cerebellum is transferred to the basal ganglia and mediates the observed dystonia. A disynaptic connection between the cerebellar output nuclei and basal ganglia input nuclei has been identified in rodents and primates. The physiologic role of this pathway is currently unknown. In this proposal we evaluate the role of this disynaptic pathway and specifically one of its intermediate nuclei, the centrolateral nucleus of the thalamus (CL), in dystonia induced by ouabain administration to the cerebellum. Preliminary studies suggest that lesioning of CL prior to ouabain perfusion prevents the generation of dystonia. In this proposal we will test if this prevention is long term and if it is accompanied by other motor abnormalities. We will also explore CL as a potential site of intervention after animals already have dystonia. Finally we will determine how CL neuron firing changes in response to ouabain perfusion onto the cerebellum. This should give us insight into the role of the disynaptic pathway through CL in diseased animals and help up develop new interventions to test on dystonic ouabain perfused mice including pharmacologic treatments and deep brain stimulation. These experiments together will help define one mechanism of dystonia induction and suggest new methods to alleviate dystonia in certain human cases.