Adaptive rewiring of the mature brain after injury

描述（由申请人提供）：中风或创伤性脑损伤的恢复部分受到成熟神经元无法显著重组其连接的限制。这种重组可能既需要激活神经元内在生长状态的积极刺激，也需要克服通常抑制生长的抑制信号的方法。肌苷，一种嘌呤核苷，激活细胞信号通路，调节轴突生长重要基因的表达。在成熟大鼠中，肌苷在横断特定纤维束或单侧中风后刺激主要皮质通路的重组。这种重组允许来自完整半球的投射部分地再神经支配失去正常输入的脑干和脊髓区域，并导致行为结果的改善。目的1将研究帮助克服轴突生长抑制影响的药物是否可以增强肌苷对神经重组和行为结果的影响。目的2将研究单侧脑损伤后的强化训练本身是否会促进轴突重组，以及这种训练是否会增强肌苷治疗的效果。最后，脑损伤后有一个有限的时间窗口，肌苷治疗必须开始，以获得持久的好处。Aim 3将尝试鉴定在这一“机会之窗”期间，其表达使神经元能够对肌苷做出反应的基因，以及在此期间因肌苷处理而表达的基因。这将使用激光捕获显微解剖来分离皮质锥体细胞和微阵列来鉴定表达被选择性改变的基因。Aim 3的第二部分将使用基因治疗方法来研究改变皮层锥体细胞轴突生长相关基因表达的影响。这些研究将增加我们对成熟大脑可塑性的理解，并有可能使我们改善损伤后的功能结果。

DESCRIPTION (provided by applicant): Recovery from stroke or traumatic brain injury is limited in part by the inability of mature neurons to reorganize their connections significantly. Such reorganization may require both positive stimuli to activate neurons' intrinsic growth state and methods to overcome inhibitory signals that normally suppress growth. Inosine, a purine nucleoside, activates a cellular signaling pathway that regulates the expression of genes important for axon outgrowth. In mature rats, inosine stimulates the reorganization of major cortical pathways after transecting a specific fiber tract or after a unilateral stroke. This reorganization allows projections from the intact hemisphere to partially reinnervate brainstem and spinal cord areas that have lost their normal inputs, and results in improved behavioral outcome. Aim 1 will investigate whether agents that help overcome inhibitory influences on axon growth can enhance the effects of inosine on neural reorganization and behavioral outcome. Aim 2 will investigate whether intensive training after unilateral brain damage itself promotes axonal reorganization, and whether such training will augment the effects of inosine treatment. Finally, there is a limited time window after brain injury in which inosine treatment must begin in order to achieve long-lasting benefits. Aim 3 will attempt to identify genes whose expression enables neurons to respond to inosine during this "window of opportunity", as well as genes that are expressed as a result of inosine treatment during this period. This will be done using laser-capture microdissection to isolate cortical pyramidal cells and microarrays to identify genes whose expression is selectively altered. The second part of Aim 3 will use a gene therapy approach to investigate the effects of altering the expression of genes related to axon growth in cortical pyramidal cells. These studies will increase our understanding of plasticity in the mature brain and potentially enable us to improve functional outcome after injury.