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

小脑-丘脑-基底神经节通路在肌张力障碍中的作用

• 批准号: 8496145
• 负责人: Rachel Fremont
• 金额: $ 2.02万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496145
• 关键词: Adopted; Agonist; Animals; Area; Basal Ganglia; Behavior; Behavior assessment; Brain; Cell Nucleus; Cerebellar Diseases; Cerebellum; Characteristics; Communication; Data; Deep Brain Stimulation; Disease; Dystonia; Dystonia 12; Etiology; Financial compensation; Functional disorder; Generations; Genetic; Goals; Human; Intervention; Intralaminar Nuclear Group; Lesion; Link; Mediating; Methods; Modeling; Motor; Movement Disorders; Mus; Muscle; Muscle Contraction; Na(+)-K(+)-Exchanging ATPase; Nature; Neurologic; Neuromodulator; Neurons; Ouabain; Output; Pain; Pathway interactions; Patients; Pattern; Perfusion; Pharmaceutical Preparations; Physiological; Play; Posture; Prevention; Primates; Purkinje Cells; Rattus; Research; Rodent; Rodent Model; Role; Secondary Dystonia; Signal Transduction; Site; Structure; Symptoms; Testing; Thalamic Nuclei; Thalamic structure; Travel; Work; awake; cerebellar lesion; extracellular; in vivo; insight; prevent; public health relevance; research study; response

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.

描述（由申请人提供）：肌张力障碍是一种运动障碍，其特征为激动肌和拮抗肌同时和长期共同收缩，导致患者采取痛苦的扭转姿势。肌张力障碍的病因是异质性的，其中很少有很好的理解。肌张力障碍可由基底神经节病变产生，许多遗传性和继发性肌张力障碍与基底神经节活动改变相关，表明基底神经节在这种疾病中起作用。某些肌张力障碍出现在小脑损伤后，而另一些则因小脑输出核团的损伤而缓解，这表明小脑可能参与了某些肌张力障碍病例。在啮齿类动物中，将选择性Na/K ATP酶（钠泵）阻断剂哇巴因灌注到小脑中会导致肌张力障碍。我们实验室的研究表明，这种肌张力障碍产生的机制可能在特定的遗传性肌张力障碍，DYT 12或快速发作的肌张力障碍-帕金森综合征中很重要。我们认为，在这个模型中，小脑的异常活动转移到基底神经节，并介导观察到的肌张力障碍。在啮齿动物和灵长类动物中，小脑输出核团和基底神经节输入核团之间存在双突触联系。该途径的生理作用目前尚不清楚。在这个建议中，我们评估的作用，这种双突触通路，特别是它的中间核，丘脑（CL）的中央外侧核，哇巴因管理引起的肌张力障碍的小脑。初步研究表明，哇巴因灌注前CL损伤可防止肌张力障碍的产生。在本建议中，我们将测试这种预防是否是长期的，以及是否伴有其他运动异常。我们还将探索CL作为动物已经患有肌张力障碍后的潜在干预部位。最后，我们将确定如何CL神经元放电的变化，以响应哇巴因灌注到小脑。这应该让我们深入了解通过CL在患病动物中的双突触通路的作用，并帮助开发新的干预措施，以测试对张力障碍的哇巴因灌注小鼠，包括药物治疗和脑深部刺激。这些实验将有助于确定肌张力障碍诱导的一种机制，并提出新的方法来缓解某些人类病例中的肌张力障碍。