Influence of the Basal Ganglia on Cerebellar Action

基底神经节对小脑活动的影响

基本信息

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
项目类别：
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

项目摘要

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会导致各种运动缺陷，这些缺陷通常完全残疾。帕金森氏病影响约150万美国人，是一种基础神经节疾病，导致震颤，自发运动的自发运动减少和自愿运动的缓慢。用L-DOPA对帕金森氏病的药物治疗仅在缓解该病的运动症状方面有效，并且长时间的药物治疗导致严重的副作用，例如无法控制的非自愿运动。基底神经节中特定部位的深脑刺激可以有效缓解帕金森症状。药物治疗和深脑刺激均未恢复基底神经节中受损的神经回路。因此，这些疗法可能会阻止异常的基底神经节输出破坏与运动控制有关的其他结构中的处理。小脑与运动控制有关的一个主要神经结构是小脑，但是小脑和基底神经节之间没有直接的连接。我们发现，将小脑输出与脊髓连接的猫红核中的活动破坏了活动，可以产生与帕金森氏病非常相似的运动症状。该提案的基础上的一般假设是，基底神经节疾病产生的运动缺陷是由途径介导的，这些途径使基底神经节产量干扰与小脑有关的结构中的处理。具体而言，我们假设来自猫肠核的基础神经节输出会影响Zona Incerta细胞的活性，这会影响红色核中细胞的活性。我们的实验将：1。确定相关核中包含与前肢运动相关的细胞的区域。 2。确定这些前肢区域如何通过注射受体拮抗剂而通过激活和失活而影响运动。 3。开发一种基底神经节疾病的急性和慢性CAT模型，以检验假设的关键方面。 4。确定允许基底神经节产量影响小脑电路的其他脑干途径。结果将对基底神经节和小脑如何相互作用以控制肢体运动有更深入的了解，并为治疗运动障碍的新方法。