Neural Mechanisms of Compensating for Brain Damage

描述（由申请人提供）：单侧脑损伤后，总体功能结局的主要贡献者是涉及同病灶、受影响较小的体侧的代偿性行为变化的发展。虽然人们通常认为行为补偿仅仅是学习的一个例子，但这种学习可能是动物成年后最重要的行为变化之一，必须在存在主要损伤诱导的大脑变化的情况下完成。了解这种行为变化的神经基础以及它如何与病变引起的退行性事件相互作用是最后一个项目期的重点。我们确定，技能收购在同侧前肢大鼠增强单侧损伤的感觉运动皮层（SMC），至少在一定程度上是由于去神经诱导的增强学习引起的神经元结构变化的运动皮层对侧的病变。我们最近还发现，受影响较小的前肢的行为体验会使受损前肢的表现恶化，其方式在完整动物中无法复制。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这种经验依赖性恶化的性质和神经基础。该提议的中心假设是，对受影响较小的前肢的过度行为体验抑制了梗死皮层剩余区域的神经可塑性过程，否则这些区域可以用于介导受损前肢的功能恢复。这将使用敏感的行为措施和操作的组合和严格的分析的神经元结构的变化和可塑性的运动表示在梗死周围皮层进行测试。目的是测试：（1）不对称性和受影响较少的前肢的行为体验模式对受损肢体功能的贡献，（2）受影响较少的前肢的体验抑制了在病变周围皮层中驱动功能相关神经元可塑性的能力的假设，（3）这些效应对侧病变皮层和跨胼胝体连接的活动的依赖性，（4）损伤后受影响较小的前肢的行为体验的时间依赖性和（5）这些影响可以通过集中于受损肢体的早期康复训练来克服的可能性。这些研究的翻译相关性是，行为功能和半球间相互作用的不对称是单侧脑损伤的一个突出结果。了解它们如何促进功能恢复可能会指导单侧脑卒中和其他侧脑损伤后的康复工作和干预。

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.