Rehabilitative Training Effects on Corticofugal Plasticity after Cortical Damage

描述(申请人提供)：中风仍然是导致死亡和残疾的主要原因，仅在美国每年就有数千人受到影响。在皮质损伤后的几周到几个月内，会出现某种程度的自发行为恢复，对这种恢复的一个有利的解剖学解释是同侧至病变半球剩余环路的可塑性。这种神经重塑很可能因损伤部位的不同而不同，但目前还没有对这种可能性的直接调查。这一建议的中心假设是自发的和训练诱导的皮质分离投射的可塑性随着皮质损伤的解剖位置而不同。这将使用上肢损伤的啮齿动物模型进行研究，该模型是在运动皮质的不同区域发生缺血性皮质损伤后进行的。尾侧运动皮质(CMC)在头侧运动皮质(RMC)损伤后具有促进熟练前肢功能快速恢复的能力，但在CMC损伤后则相反。这是否是由于来源于CMC的皮质分离纤维轴突可塑性增加所致，目前尚不清楚。为了研究行为结果与皮质传出神经重组之间的关系，我们将分析CMC和RMC损伤(AIM 1)后的皮质脊髓和皮质灰质投射模式，并确定功能有益(AIM2)和功能不适应(AIM 3)行为操作如何改变这一模式。目的1：损毁大鼠一侧RMC或CMC，进行为期一个月的周期性行为学评估。皮质内微刺激(ICMS)对同侧至病变皮质的标测将指导将生物素化葡聚糖胺(BDA)注射到备用RMC或CMC，具体取决于原始病变。荧光金(FG)将同时注射到C8脊髓的两侧。光镜和电子显微镜将被用来检查备用的同侧到病变的皮质分离纤维及其突触接触的萌发。熟练的运动训练可进一步促进功能恢复。然而，目前的研究还没有集中于了解起源于同侧至病变半球的备用下行皮质分离纤维的可塑性。在正常动物中，这些轴突是控制熟练伸展的最重要的，并可能有助于增强运动恢复。因此，对于目标2，将使用与目标1相同的损伤模型，并增加接受瘫痪前肢康复运动训练(熟练伸展)的动物。最后，目标3将调查非偏瘫前肢的经验如何影响皮质松质细胞的萌发。训练非偏瘫患者的前肢会恶化偏瘫患者的前肢功能，并导致习得的不使用。我们将研究起源于对侧和/或自体运动皮质的下行运动纤维的异常可塑性是否与非偏瘫前肢训练的不良影响有关。这项拟议的研究将有助于阐明促进单侧皮质梗死后运动恢复的神经解剖学基础。

DESCRIPTION (provided by applicant): Stroke remains a leading cause of mortality and disability, with several thousands of individuals being affected every year in the United States alone. Some degree of spontaneous behavioral recovery occurs during the weeks to months after suffering cortical injury, and one favorable anatomical explanation for this recovery is plasticity of remaining circuits of the ipsilateral-to-lesion hemisphere. It is likely that this neural remodeling varies depending on the locus of injury, but there has been no direct investigation of this possibility. The central hypothesis of this proposal is that spontaneous and training induced plasticity of corticofugal projections vary with the anatomical locus of cortical damage. This will be investigated using a rodent model of upper extremity impairment after ischemic cortical lesions of distinct regions of the motor cortex. The caudal motor cortex (CMC) has been found to posses the capacity to promote rapid recovery of skilled forelimb function after rostral motor cortex (RMC) lesions, but the opposite does not hold true after lesions of the CMC. Whether this is due to the increased capacity for axonal plasticity of corticofugal fibers originating from the CMC has yet to be determined. To investigate the relationship between behavioral outcome and reorganization of cortical efferents, we will assay corticospinal and corticorubral projection patterns after lesions of the CMC and RMC (Aim 1) and determine how this is altered by functionally beneficial (Aim2) and functionally maladaptive (Aim 3) behavioral manipulations. For Aim 1, rats will receive unilateral ischemic lesions of the RMC or CMC and undergo periodic behavioral assessment of paretic forelimb function for one month. Intracortical microstimulation (ICMS) mapping of the ipsilateral-to-lesion cortex will guide injections of biotinylated dextran- amine (BDA), into the spared RMC or CMC depending on the original lesion. Fluorogold (FG) will be injected bilaterally into the C8 spinal cord at the same time. Light and electron microscopy will be used to examine sprouting of spared ipsilateral-to-lesion corticofugal fibers and their synaptic contacts. Skilled motor training can further enhance functional recovery. However, current research has not focused on understanding plasticity of spared descending corticofugal fibers originating in the ipsilateral-to-lesion hemisphere. These axons are the most important for the control of skilled reaching in the normal animal and are likely to contribute to the enhanced motor recovery. Therefore, for Aim 2, the same lesion model will be used as Aim 1, with the addition of animals receiving paretic forelimb rehabilitative motor training (skilled reaching). Finally, Aim 3 will investigate how experience with the non-paretic forelimb influences corticofugal sprouting. Training the non- paretic forelimb worsens paretic forelimb function and contributes to learned non-use. We will investigate whether aberrant plasticity of descending motor fibers originating in the contralateral and/or ipsilesional motor cortex contribute to the adverse affects of non-paretic forelimb training. The proposed research will help elucidate neuroanatomical substrates that promote motor recovery following unilateral cortical infarcts.