Neural Mechanisms of Compensating for Brain Damage

描述(申请人提供)：在单侧脑损伤后，影响整体功能结果的一个主要因素是发生代偿性行为改变，涉及患侧，受影响较小的身体一侧。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，必须在存在重大病变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，单侧损伤感觉运动皮质(SMC)可增强大鼠一侧前肢感觉运动皮质(SMC)的技能习得，至少部分原因是失神经导致损伤对侧运动皮质学习诱导的神经元结构变化增强。我们最近还发现，受影响较小的前肢的行为体验会使受损的前肢表现恶化，这种情况在完好的动物身上是无法复制的。本研究的重点是成年大鼠单侧SMC损伤后受损肢体功能的经验依赖性恶化的本质和神经基础。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会抑制梗塞皮质剩余区域的神经可塑性进程，否则这些进程可能会被用来调节受损前肢的功能恢复。这将通过结合敏感的行为测量和操作，以及对梗死区周围皮质神经元结构变化和运动表现的可塑性的严格分析来进行测试。其目的是检验：(1)不对称性和前肢行为体验的形式对受损肢体功能的贡献，(2)受影响较轻的前肢经历抑制病变周围皮质功能相关神经元可塑性的能力的假说，(3)这些影响对对侧皮质和跨痂连接活动的依赖性，(4)损伤后与受影响较小的前肢的行为体验的时间依赖性，以及(5)这些影响可以通过一段时间的以受损肢体为重点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，行为功能和大脑半球间相互作用的不对称是单侧脑损伤的显著结果。了解它们如何有助于功能恢复，可能会指导单侧脑中风和其他偏侧性脑损伤后的康复努力和干预。

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.