Influence of the Basal Ganglia on Cerebellar Action

描述(申请人提供)：影响基底节的疾病会产生各种运动缺陷，这些缺陷通常是完全丧失能力的。帕金森氏症影响着大约150万美国人，是一种基底节疾病，会导致震颤、自发活动减少和自主活动缓慢。L多巴药物治疗帕金森病在缓解该病运动症状方面仅有部分疗效，且药物治疗时间长会导致无法控制的不自主运动等严重副作用。在基底节的特定部位进行脑深部刺激可以有效地缓解帕金森症状。药物治疗和脑深部刺激都不能恢复基底节受损的神经回路。因此，这些疗法可能会阻止异常的基底节输出扰乱与运动控制相关的其他结构的处理。与运动控制相关的一个主要神经结构是小脑，但小脑和基底节之间没有直接联系。我们已经发现，连接小脑输出和脊髓的猫红核的活动中断，可以产生与帕金森氏症惊人相似的运动症状。支持这一建议的一般假设是，由基底节疾病产生的运动缺陷是由允许基底节输出干扰与小脑相关结构的处理的通路所介导的。具体地说，我们假设猫内侧双侧核的基底节输出影响未定带细胞的活动，而未定带细胞又影响红核细胞的活动。我们的实验将：1.确定相关核团中包含与前肢运动相关的细胞的区域。2.通过注射受体拮抗剂，确定这些前肢区域如何通过激活和失活来影响运动。3.建立一个急性和慢性的猫基底节疾病模型，以检验该假说的关键方面。4.确定允许基底节输出影响小脑回路的其他脑干通路。这一结果将使我们更深入地了解基底节和小脑如何相互作用来控制肢体运动，并将为运动障碍的治疗提供新的方法。

DESCRIPTION (provided by applicant): Diseases affecting the basal ganglia produce a variety of movement deficits, and these deficits are often totally disabling. Parkinson's disease, which affects about 1.5 million Americans, is a basal gangliar disease that leads to tremor, decreased spontaneous movement and slowness of voluntary movement. Drug treatment of Parkinson's disease with L-DOPA is only partially effective in relieving the motor symptoms of the disease, and prolonged drug treatment leads to severe side effects such as uncontrollable involuntary movements. Deep brain stimulation at specific sites in the basal ganglia can provide effective relief of Parkinson symptoms. Neither drug treatment nor deep brain stimulation restores damaged neural circuitry in the basal ganglia. Therefore, it is likely that these therapies prevent abnormal basal gangliar output from disrupting processing in other structures related to movement control. One major neural structure related to movement control is the cerebellum, but there are no direct connections between the cerebellum and the basal ganglia. We have discovered that disrupting activity in the cat red nucleus, which connects cerebellar output to the spinal cord, can produce motor symptoms that are strikingly similar to those of Parkinson's disease. The general hypothesis underlying this proposal is that motor deficits produced by basal gangliar disease are mediated by pathways that allow basal gangliar output to disturb processing in structures related to the cerebellum. Specifically, we hypothesize that basal gangliar output from the cat entopeduncular nucleus affects activity of cells in zona incerta, which affects activity of cells in the red nucleus. Our experiments will: 1. Identify regions in the related nuclei that contain cells related to forelimb movement. 2. Determine how these forelimb regions affect movement with activation and inactivation by injection of receptor antagonists. 3. Develop an acute and chronic cat model of basal gangliar disease to test critical aspects of the hypothesis. 4. Identify additional brainstem pathways that allow basal gangliar output to influence cerebellar circuits. The results will provide a deeper understanding of how the basal ganglia and cerebellum interact to control limb movements and will lead to new approaches for the treatment of movement disorders.