Influence of the Basal Ganglia on Cerebellar Action

基底神经节对小脑活动的影响

• 批准号: 6837688
• 负责人: ALAN R GIBSON
• 金额: $ 48.5万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837688
• 关键词: basal ganglia; brain mapping; cats; cerebellum; disease /disorder model; electromyography; glutamate receptor; inhibitor /antagonist; limb movement; model design /development; neural transmission; neuromuscular disorder; neuroregulation; red nucleus

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.

描述（由申请人提供）：影响基底神经节的疾病产生各种运动缺陷，这些缺陷通常是完全致残的。帕金森病影响了大约150万美国人，是一种基底神经节疾病，导致震颤，自发运动减少和随意运动缓慢。用左旋多巴对帕金森病的药物治疗在缓解疾病的运动症状方面仅部分有效，并且延长的药物治疗导致严重的副作用，例如不可控制的不自主运动。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。药物治疗和脑深部电刺激都不能恢复基底神经节中受损的神经回路。因此，这些疗法可能防止异常基底节输出干扰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，但小脑和基底神经节之间没有直接联系。我们已经发现，扰乱猫红核（连接小脑输出和脊髓）的活动，可以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的结构的处理的途径介导的。具体来说，我们假设，基底神经节输出从猫脚内核影响的活动，在红核中的细胞，从而影响细胞的活动。我们的实验将：1。识别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影响运动。3.建立猫基底节疾病的急性和慢性模型来检验假说的关键方面。4.确定额外的脑干通路，使基底节输出影响小脑电路。这些结果将使我们更深入地了解基底神经节和小脑如何相互作用来控制肢体运动，并将为治疗运动障碍提供新的方法。