Spinal cord injury: plasticity and recovery of function

描述(申请人提供)：脊髓损伤导致中枢神经系统的广泛变化。然而，脊髓损伤后发生的解剖重组的确切性质和范围以及它是如何被调控的，还不是很清楚。单侧中枢神经系统损伤后，损伤通路的再生和未损伤区域的解剖重组都可能发生，并有助于功能的恢复。我们推测，在成年大鼠脊髓损伤后，经过促进轴突生长的治疗后，功能的恢复不仅是由于脊髓上轴突的再生，也是由于脊髓损伤上方神经元回路的重组。我们还假设，增加固有神经元生长能力的药物干预和增加活性的特定康复策略协同作用，增加神经解剖可塑性和功能恢复。建议的研究将使用C3/C4(CHX)处的颈髓过半切。这一损伤使我们能够比较直接和完全受损的通路的可塑性与未受损的通路的重塑。我们的研究表明，直接损伤通路的再生和备用通路的重组都有助于功能的恢复。该模型还允许我们检查熟练的前肢功能的恢复以及运动能力。这些研究将考察特定的药物干预以增加神经元内cAMP的效果，以及康复策略以增加神经解剖可塑性和功能恢复的活性。干预措施将在受伤(急性)、延迟2周(亚急性)和延迟3个月(慢性)后立即实施。我们将使用定量神经解剖学和行为学技术以及最先进的功能成像方法，纵向跟踪损伤后的神经解剖和功能重组，并确定特定的重构对所观察到的功能恢复的贡献。我们将定义在具有代表性的脊柱上和脊柱区域内发生的解剖学重组。我们还将确定运动功能恢复的时间进程和程度。本文概述的实验将有助于更好地了解受损中枢神经系统内发生的变化以及这些变化是如何调节的，并将在脊髓损伤后增加神经可塑性和功能恢复的康复策略中发挥重要作用。

DESCRIPTION (provided by applicant): Spinal cord injury results in widespread changes in the central nervous system. The precise nature and extent of the anatomical reorganization that occurs after spinal cord injury and how it is regulated, however, are not well understood. After unilateral CNS injury, it is likely that both regeneration of damaged pathways and anatomical reorganization of undamaged regions occur and contribute to recovery of function. We hypothesize that recovery of function after treatments to increase axonal growth following spinal cord injuries in adult rats is not only due to supraspinal axon regeneration but is also due to reorganization of the neuronal circuitry above the SCI. We also hypothesize that pharmacological interventions to increase the intrinsic neuronal capacity for growth and specific rehabilitative strategies to increase activity act synergistically to increase both neuroanatomical plasticity and functional recovery. Studies proposed will use cervical spinal cord over-hemisection at C3/C4 (CHX). This lesion allows us to compare plasticity in pathways damaged directly and completely with remodeling in undamaged pathways. Our studies indicate that both regeneration of pathways damaged directly and reorganization in spared pathways contribute to the recovery of function. This model also allows us to examine recovery of skilled forelimb function as well as locomotion. The studies proposed will examine the effects of specific pharmacological intervention to increase intraneuronal cAMP and rehabilitation strategies to increase activity on neuroanatomical plasticity and recovery of function. Interventions will be applied immediately after injury (acute), after a 2 week delay (sub-acute) and after a 3 month delay (chronic). We will use quantitative neuroanatomical and behavioral techniques and state-of-the-art functional imaging methods to follow neuroanatomical and functional reorganization longitudinally after injury and to define the contribution of specific remodeling to the recovery of function observed. We will define the anatomical reorganization that occurs within representative supraspinal and spinal regions. We will also define the time course and extent of recovery of motor function that occurs. The experiments outlined here will lead to a better understanding of the changes that take place within the injured CNS and how they are regulated and will be important in rehabilitation strategies to increase neuroplasticity and functional recovery after spinal cord injury.