Neural Mechanisms of Compensating for Brain Damage

描述(申请人提供)：可存活脑损伤的一个可靠结果是，包括人类在内的动物在丧失功能的情况下学习恢复日常活动的代偿性行为策略。一个明显的例子可以在临床中风人群中找到，他们的上肢损伤是因为他们依赖受影响较小的(非瘫痪)手和手臂。这一项目的重点一直是这种代偿性行为变化与损伤诱导的退化和再生反应之间的相互作用。这是在运动皮质局灶性缺血损伤后慢性上肢损伤和代偿性技能学习的大鼠模型中进行的研究。我们之前已经发现，由于它与缺血触发的再生反应相互作用，学习依赖非偏瘫前肢促进了对侧运动皮质中的主要神经元生长反应，这一反应对偏瘫前肢没有已知的好处，但促进了非偏瘫肢体的补偿性技能学习。在大多数情况下 在最近的项目期间，我们发现促进这种对比性生长反应的同样的技能学习也会加剧偏瘫手的功能障碍，并阻止损伤大脑半球中能够调节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。这项拟议研究的目标是了解瘫痪肢体功能潜力的这种破坏的机制。我们在研究结果的模式中看到了“经验-期待”可塑性的反映，这是一种大脑发育过程，它依靠经验来塑造回路模式，使用依赖活动的突触竞争机制。这个项目的目的是确定学习依赖非偏瘫前肢的不适应效应是否源于它在驱动缺血后重组模式的方向上与偏瘫肢体竞争的能力。我们将使用假说驱动的方法结合行为和皮质水平的操作来测试在IPSI和对侧半球到因损伤而失神经的区域的会聚投射的电路重塑中，经验和活动相关的竞争。具体目的是检验这样的假设，即非偏瘫和偏瘫前肢的技能学习和重新学习驱动梗塞周围MC(目标1)和皮质分离投影(AIM2)内不同的重组模式，非瘫痪肢体的梗塞周围重组的混乱可以通过平衡运动皮质(目标3)和行为活动(目标4)来克服，并且这些影响取决于损伤的特定区域 (目标5)。这些研究对于促进我们对中风后大脑重组机制的基本理解，并最终为治疗决策提供信息具有重要意义。 促进或阻止行为补偿。

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.