Influence of the Basal Ganglia on Cerebellar Action

描述（由申请人提供）：影响基底神经节的疾病产生各种各样的运动缺陷，这些缺陷通常是完全残疾的。帕金森氏症是一种基底神经节疾病，会导致震颤、自发运动减少和自主运动缓慢，约影响150万美国人。用左旋多巴治疗帕金森病的药物治疗仅能部分缓解该疾病的运动症状，而且长期的药物治疗会导致严重的副作用，如无法控制的不自主运动。在基底神经节的特定部位进行深部脑刺激可以有效缓解帕金森症状。药物治疗和深部脑刺激都不能恢复基底神经节中受损的神经回路。因此，这些疗法很可能防止异常基底神经节输出干扰与运动控制相关的其他结构的加工。与运动控制有关的一个主要神经结构是小脑，但小脑和基底神经节之间没有直接联系。我们发现，破坏猫红核（连接小脑输出和脊髓）的活动，会产生与帕金森病惊人相似的运动症状。这一提议的一般假设是，基底神经节疾病产生的运动缺陷是由允许基底神经节输出干扰小脑相关结构加工的通路介导的。具体地说，我们假设基底神经节从猫核内的输出影响了乱带细胞的活性，而乱带又影响了红核细胞的活性。我们的实验将：识别相关核中包含与前肢运动有关的细胞的区域。2. 确定这些前肢区域如何通过注射受体拮抗剂激活和失活来影响运动。3. 发展急性和慢性基底神经节疾病猫模型，以测试该假设的关键方面。4. 确定允许基底神经节输出影响小脑回路的其他脑干通路。这一结果将对基底神经节和小脑如何相互作用来控制肢体运动提供更深入的了解，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.