Neural Mechanisms of Compensating for Brain Damage

描述（由申请人提供）：单侧脑损伤后，整体功能结果的主要影响因素是涉及同侧、受影响较小的身体侧的代偿行为改变的发展。虽然人们通常认为行为补偿只是学习的一个例子，但这种学习可能是动物成年生活中最重要的行为变化之一，必须在主要病变引起的大脑变化中完成。了解这种行为改变的神经基础以及它如何与病变诱导的退行性事件相互作用是上一个项目期间的重点。我们确定，大鼠同侧前肢的技能习得通过感觉运动皮层（SMC）的单侧损伤而增强，至少部分是由于去神经支配诱导的对侧损伤运动皮层中学习诱导的神经元结构变化的增强。我们最近还发现，影响较小的前肢的行为体验会使受损前肢的表现恶化，这种情况在完整的动物身上是无法复制的。本项目的重点是成年大鼠单侧缺血性SMC病变后受损肢体功能的经验依赖性恶化的性质和神经基础。该建议的中心假设是，对影响较小的前肢进行过多的行为体验会抑制梗死皮质剩余区域的神经可塑性过程，否则这些区域可能用于介导受损前肢功能的恢复。这将通过结合敏感的行为测量和操作，以及对梗死周围皮层神经元结构变化和运动表征可塑性的严格分析来进行测试。目的是测试：(1)轻影响前肢行为体验的不对称性和模态对残肢功能的影响；(2)轻影响前肢行为体验抑制病变周围皮层驱动功能相关神经元可塑性的假设；(3)这些影响对侧皮层活动和经胼胝体连接的依赖性；(4)前肢损伤后行为经验的时间依赖性；(5)这些影响可以通过一段时间的早期康复训练来克服的可能性。这些研究的翻译意义在于，行为功能和半球间相互作用的不对称是单侧脑损伤的突出结果。了解它们如何促进功能恢复可以指导单侧脑卒中和其他偏侧脑损伤后的康复工作和干预措施。

DESCRIPTION (provided by applicant): After unilateral cerebral damage, a major contributor to overall functional outcome is the development of compensatory behavioral changes involving the ipsilesional, less-affected, body side. While it is often assumed that behavioral compensation is merely an example of learning, this learning may be among the most significant behavioral changes of an animal's adult life and must be accomplished in the presence of major lesion-induced brain changes. Understanding the neural basis for this behavioral change and how it interacts with lesion-induced degenerative events was the focus of the last project period. We determined that skill acquisition in the ipsilesional forelimb in rats is enhanced by unilateral damage to the sensorimotor cortex (SMC), at least in part as a result of a denervation-induced enhancement of learning-induced neuronal structural changes in the motor cortex contralateral to the lesion. We have also recently discovered that behavioral experiences with the less affected forelimb can worsen performance in the impaired forelimb in a manner that cannot be duplicated in intact animals. The focus of the present project is the nature and neural basis of this experience-dependent worsening of function of the impaired limb after unilateral ischemic SMC lesions in adult rats. The central hypothesis of the proposal is that excessive behavioral experience with the less- affected forelimb suppresses neuroplastic processes in remaining regions of infarcted cortex that could otherwise be used to mediate recovery of function in the impaired forelimb. This will be tested using a combination of sensitive behavioral measures and manipulations and rigorous assays of neuronal structural changes and plasticity of movement representations in the peri-infarct cortex. The aims are to test: (1) the contribution of asymmetry and modality of behavioral experience with the less-affected forelimb on function of the impaired limb, (2) the hypothesis that experiences with the less affected forelimb suppress the ability to drive functionally relevant neuronal plasticity in peri-lesion cortex, (3) the dependency of these effects on activity of the contralesional cortex and transcallosal connections, (4) the post-lesion time- dependency of behavioral experiences with the less-affected forelimb and (5) the possibility that these effects can be overcome by a period of early rehabilitative training focused on the impaired limb. The translational relevance of these studies is that asymmetries in behavioral function and interhemispheric interactions are a prominent result of unilateral brain damage. Understanding how they contribute to functional recovery may guide rehabilitation efforts and interventions after unilateral cerebral stroke and other lateralized brain damage.