Neural Mechanisms of Compensating for Brain Damage

描述（由申请人提供）：可存活脑损伤的一个可靠后果是，动物（包括人类）在功能丧失的情况下学习补偿性行为策略以恢复日常活动。这方面的一个明显的例子可以在临床中风人群中发现，上肢损伤依赖于受影响较小（非瘫痪）的手和手臂。该项目跨时期的重点是这种代偿性行为变化和损伤诱导的退行性和再生反应之间的相互作用。这是研究慢性上肢损伤和代偿性技能学习后，局部缺血性损伤运动皮层的大鼠模型。我们之前已经发现，由于其与缺血触发的再生反应的相互作用，学习依赖非瘫痪前肢促进了对侧运动皮层中的主要神经元生长反应，这种反应对瘫痪前肢没有已知的益处，但有利于非瘫痪前肢的补偿技能学习。最 在最近的项目期间，我们发现促进这种对侧损伤生长反应的相同技能学习也加剧了瘫痪手的功能障碍，并阻碍了受损半球中可以介导其功能改善的皮质结构和功能重组。这意味着，仅仅通过采取完全合理的策略来恢复日常活动，一些中风幸存者可能会无意中压制瘫痪手的功能潜力。提出的研究的目标是了解瘫痪肢体功能电位的这种中断的机制。我们在结果的模式中看到了“经验预期”可塑性的反映，这是一个大脑发育过程，它依赖于经验，利用活动依赖性突触竞争机制来塑造电路模式。本项目的目的是确定学习依赖非瘫痪前肢的适应不良效应是否是由于其在驱动缺血后重组模式的方向上与瘫痪肢体竞争的能力。我们将使用假设驱动的方法结合行为和皮质水平的操作，以测试在同侧和对侧半球的会聚投射到损伤失神经支配区域的电路重塑中的经验和活动依赖性竞争。具体目的是检验以下假设：非麻痹和麻痹前肢的技能学习和“再学习”驱动梗死周围MC（Aim 1）和离皮质投射（Aim 2）内的不同重组模式，非瘫痪肢体梗死周围重组的混乱可以通过平衡运动皮层（目标3）和行为活动（目标4）来克服。这些影响取决于受伤的具体区域 (Aim 5）。这些研究对于推进我们对中风后脑重组机制的基本理解，并最终为何时进行治疗决策提供信息具有重要意义。 促进或阻碍行为补偿。

DESCRIPTION (provided by applicant): A reliable consequence of survivable brain damage is that animals, including humans, learn compensatory behavioral strategies for resuming daily activities in the presence of lost function. An obvious example of this can be found in clinical stroke populations with upper extremity impairments in their reliance on the less- affected (nonparetic) hand and arm. The focus of this project across periods has been on the interactions between such compensatory behavioral changes and injury-induced degenerative and regenerative responses. This is investigated in a rat model of chronic upper extremity impairments and compensatory skill learning after focal ischemic damage to motor cortex. We've previously found that, as a result of its interaction with ischemia-triggered regenerative responses, learning to rely on the nonparetic forelimb promotes a major neuronal growth response in the contralesional motor cortex, a response that has no known benefit for the paretic forelimb, but facilitates compensatory skill learning with the nonparetic limb. In the most recent project period, we discovered that the same skill learning that promotes this contralesional growth response also exacerbates dysfunction in the paretic hand, and blocks the cortical structural and functional reorganization in the injured hemisphere that can mediate its functional improvements. The implication is that, simply by adopting perfectly reasonable strategies for resuming everyday activities, some stroke survivors could inadvertently squelch the paretic hand's potential for functionality. The goal for the proposed studies is to understand the mechanisms of this disruption of the functional potential of the paretic limb. We see in the pattern of our results reflections of "experience-expectant" plasticity, a brain developmental process that relies on experiences to sculpt circuitry patterns using mechanisms of activity-dependent synaptic competition. The purpose of this project is to determine whether the maladaptive effects of learning to rely on the nonparetic forelimb are due to its ability to outcompete with the paretic limb in driving the direction of post-ischemic reorganizational patterns. We will use a hypothesis-driven approach in combination with behavioral- and cortical-level manipulations to test for experience- and activity-dependent competition in circuitry remodeling of the converging projections of the ipsi and contralesional hemispheres to regions denervated by the injury. The specific aims are to test the hypotheses that skill learning and "re-learning" with the nonparetic and paretic forelimbs drive different reorganizational patterns within peri-infarct MC (Aim 1) and of corticofugal projections (Aim2), that the nonparetic limb's disarray of peri-infarct reorganization can be overcome by balancing motor cortical (Aim 3) and behavioral activity (Aim 4) and that these effects depend on the specific territory of the injuries (Aim 5). These studies are significant for advancing our basic understanding of the mechanisms of brain reorganization after stroke and, ultimately, for informing therapeutic decision on when to promote or discourage behavioral compensation.