NEURAL CORRELATES OF EXERCISE THERAPY IN PD MODEL

PD 模型中运动治疗的神经相关性

• 批准号: 6785032
• 负责人: DONALD JAY WOODWARD
• 金额: $ 28.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6785032
• 关键词: Parkinson's disease; apomorphine; behavior test; behavioral /social science research tag; corpus striatum; disease /disorder model; dopamine; electrodes; electrophysiology; exercise; functional ability; laboratory rat; limb movement; nervous system disorder therapy; neuromuscular system; neurons; neurophysiology; physical therapy; sensorimotor system; single cell analysis; substantia nigra

The goal of this project is to characterize the neurophysiological changes induced during the recovery of function in awake behaving rat by the depletion of dopamine in striatum by the unilateral administration of 6-hydroxydopamine as a model for Parkinson's disease. Preliminary studies have shown that depletion of dopamine results in an elevation of resting firing rates of neurons in the neostriatum. This effect is maximum of the depleted side but is nearly equally apparent on the intact side with no depletion of DA. Activation of rotation activates reciprocal changes in neighboring neurons on both sides with no net changes in means rates, thus indicating the presence of an effective synaptic input to both intact and DA depleted striatum. An interpretation is that absence of dopamine induces a motor dysfunction directly on the affected side. This in turn activates a widespread motor recovery adaptive mechanism that engages both sides of the cortical striatal nigral thalamic system. Forced use of the limb on the DA depleted side by application of a cast to restrict use of the unaffected limb, specifically in the first 7 days after 6-OHDA, has recently been found to offer neuroprotection against 6-OHDA, and thus raised the possibility that the widespread bilateral elevation of activity may play both a neuroprotective as well as a compensatory role. An aim of this project is to record activity of populations of neurons recorded simultaneously from 64 microwires implanted bilaterally in striatum, substantia nigra reticulata/compacta, and forelimb sensorimotor cortex. These advanced recording procedures developed in this laboratory will determine activity of populations over the two weeks after 6-OHDA administration. Casting to restrict limb use will be done on both the DA depleted and intact side to compare effects of restriction of movement and to determine the neural signals during movements during tests of motor impairment. Casting will be done prior to 6-OHDA to test whether elevation of activity appears during the early period of motor reorganization and may serve to activate neuroprotection. Recordings made from dopamine neurons will test the emerging concept of a role in motor learning and reorganization. A prediction is that the novel movement patterns during forced use will produce many signals in striatum and cortex correlated with movement that are not present in over-trained circuits.

本研究的目的是通过单侧给予6-羟基多巴胺（6-hydroxydopamine）作为帕金森病模型，观察清醒行为大鼠纹状体多巴胺耗竭后功能恢复过程中的神经生理学变化。初步研究表明，多巴胺的消耗导致新纹状体神经元静息放电率的升高。这种效果是最大的耗尽的一面，但几乎同样明显的完整的一面，没有耗尽DA。激活旋转激活互惠的变化，在两侧的相邻神经元的平均速率没有净变化，从而表明存在一个有效的突触输入完整和DA耗尽纹状体。一个 解释是多巴胺的缺乏直接在受影响的一侧引起运动功能障碍。这反过来又激活了广泛的运动恢复适应机制，参与皮质纹状体黑质丘脑系统的两侧。最近发现，通过施加石膏来限制未受影响的肢体的使用，特别是在6-OHDA后的前7天内，强迫使用DA耗尽侧的肢体，可以提供针对6-OHDA的神经保护，因此提出了广泛的双侧活动升高可能起到神经保护作用以及补偿作用的可能性。该项目的目的是记录神经元群体的活动，这些神经元群体同时从64根植入双侧的微导线记录。 纹状体、网状黑质/黑质和前肢感觉运动皮质。本实验室开发的这些先进的记录程序将确定6-OHDA给药后两周内的种群活动。将在DA耗竭侧和完整侧进行限制肢体使用的铸造，以比较运动限制的影响，并确定运动障碍测试期间运动期间的神经信号。在6-OHDA之前进行铸造，以测试活动的升高是否出现在运动重组的早期阶段，并可能用于激活神经保护。多巴胺神经元的记录将测试在运动学习和重组中的作用这一新兴概念。一个预测是，在强迫使用过程中，新的运动模式将在纹状体和皮层中产生许多与运动相关的信号，这些信号在过度训练的回路中不存在。