Rehabilitative Training Effects on Corticofugal Plasticity after Cortical Damage

描述（由申请人提供）：中风仍然是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。在遭受皮层损伤后的几周到几个月内，会发生一定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损伤同侧半球的剩余回路的可塑性。这种神经重塑可能因损伤部位而异，但尚未对这种可能性进行直接调查。这个建议的中心假设是，自发的和训练诱导的可塑性离皮质的预测不同的皮质损伤的解剖位点。这将使用运动皮质不同区域缺血性皮质病变后上肢损伤的啮齿动物模型进行研究。尾侧运动皮层（CMC）已被发现的能力，以促进快速恢复熟练的前肢功能后，吻侧运动皮层（RMC）的损害，但相反的损害后的CMC并不成立。这是否是由于来自CMC的离皮质纤维的轴突可塑性增加的能力尚未确定。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（目标1）病变后皮质脊髓和皮质红核的投射模式，并确定功能有益（目标2）和功能适应不良（目标3）的行为操作如何改变这种投射模式。对于目标1，大鼠将接受RMC或CMC的单侧缺血性损伤，并进行为期一个月的麻痹前肢功能的定期行为评估。同侧至病变皮质的皮质内微刺激（ICMS）映射将指导生物素化葡聚糖胺（BDA）注射到备用RMC或CMC中，具体取决于原始病变。将荧光金（FG）同时双侧注射到C8脊髓中。光镜和电子显微镜将用于检查备用同侧病变离皮质纤维及其突触接触的发芽。熟练的运动训练可以进一步促进功能恢复。然而，目前的研究还没有集中在了解可塑性备用下行离皮质纤维起源于同侧病变半球。这些轴突对于控制正常动物的熟练伸手是最重要的，并且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相同的病变模型，增加接受麻痹前肢康复运动训练（熟练伸展）的动物。最后，目标3将探讨非麻痹前肢的经验如何影响离皮质发芽。训练非麻痹性前肢可以改善麻痹性前肢的功能，并有助于学会不使用。我们将调查是否异常可塑性的下行运动纤维起源于对侧和/或同侧运动皮层的非麻痹性前肢训练的不利影响。这项研究将有助于阐明单侧皮质梗死后促进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.