Rehabilitative Training Effects on Corticofugal Plasticity after Cortical Damage

描述（由申请人提供）：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。在遭受皮质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同侧到病变半球的剩余回路的可塑性。这种神经重塑很可能因损伤部位而异，但尚未对这种可能性进行直接调查。该建议的中心假设是，自发和训练诱导的皮质投射的可塑性随皮质损伤的解剖位置而变化。这将被调查使用上肢损伤的啮齿动物模型后的不同区域的运动皮质缺血性损伤。研究发现，尾侧运动皮层（CMC）具有促进吻侧运动皮层（RMC）损伤后熟练前肢功能快速恢复的能力，而尾侧运动皮层（CMC）损伤后则相反。这是否由于源自CMC的皮质纤维轴突可塑性的能力增加，还有待确定。为了研究行为结果与皮层传出神经重组之间的关系，我们将分析CMC和RMC病变后的皮质脊髓和皮质投影模式（目的1），并确定功能有益（目的2）和功能不良（目的3）的行为操作如何改变这一模式。在Aim 1中，大鼠将接受RMC或CMC单侧缺血性病变，并定期进行一个月的麻痹性前肢功能行为评估。皮质内微刺激（ICMS）映射同侧到病变皮层将引导生物素化右旋糖酐胺（BDA）注射到根据原始病变而保留的RMC或CMC。同时向C8脊髓双侧注射氟金（FG）。光镜和电子显微镜将用于检查未受损伤的同侧皮质纤维的发芽及其突触接触。熟练的运动训练可以进一步增强功能恢复。然而，目前的研究尚未集中在了解起源于同侧到病变半球的备用下行皮质纤维的可塑性。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Aim 2，将使用与Aim 1相同的病变模型，并增加接受麻痹性前肢康复运动训练（熟练伸展）的动物。最后，目的3将探讨如何经验与非麻痹的前肢影响皮质发芽。训练非麻痹性前肢会使麻痹性前肢功能恶化，导致习得性不使用。我们将研究源自对侧和/或同侧运动皮层的下行运动纤维的异常可塑性是否有助于非麻痹性前肢训练的不利影响。提出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. PUBLIC HEALTH RELEVANCE: The goal of this series of experiments is to understand how neural plasticity of descending motor systems influences functional recovery after brain injury and how behavioral experience further shapes this re-wiring. These studies specifically address how injury-induced plasticity and behavioral manipulations restructure connectivity of existing neural networks to drive functional motor output. This work is pursued to obtain a basal understanding of the anatomical and behavioral substrates that may be targeted in order to facilitate behavioral recovery after brain damage.