CELLULAR MECHANISMS OF NEUROPLASTICITY IN STROKE NEUROREHABILITATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。拟议的研究反映了博士实验室之间的跨学科合作。McNeill， Jones和Schallert的研究将进一步加深我们对神经可塑性和促进脑损伤后功能恢复的治疗策略之间协同作用的细胞和分子事件的理解。实验设计结合了McNeill实验室在神经可塑性细胞机制方面的研究专长，以及Jones和Schallert的研究专长，他们研究了行为经验对缺血性脑损伤后神经可塑性和功能恢复的影响。本研究的目的是确定康复训练是否可以促进神经突生长和参与反应性突触发生的候选分子的基因表达，并确定关键分子，这些分子可以作为卒中康复新方法开发的重点。这项研究的基本原理是基于先前研究人员实验室的研究，以及其他人的研究，他们报告说：1)神经可塑性在缺血性脑损伤后的功能恢复中起关键作用；2)康复训练可增强脑卒中后的功能恢复；3)脑损伤后皮层重组和突触替代涉及病变特异性的特定组生长相关蛋白、神经递质和神经营养因子的差异调节；4)黑质纹状体神经元同时含有多巴胺和脑源性神经营养因子（BDNF）。脑损伤后纹状体靶神经元皮质纹状体突触的维持是神经元存活和突触功能所必需的分子。需要验证的主要假设是：1)辅助使用康复训练增强了已知调节皮层和纹状体神经元中神经突生长和脊柱密度的分子的上调；2)这些干预措施集中在与单胺激活和BDNF上调相关的细胞内信号通路上，以达到其治疗效果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed study reflects the interdisciplinary collaboration between the laboratories of Drs. McNeill, Jones and Schallert that will further our understanding of the cellular and molecular events underlying the synergism between neural plasticity and treatment strategies that promote the recovery of function after brain damage. The experimental design integrates the research expertise on the cellular mechanism of neural plasticity from McNeill''s laboratory with that of Jones and Schallert, who have examined the influence of behavioral experience on neural plasticity and recovery of function after ischemic brain injury. The goal of the study is to determine whether rehabilitative training can enhance neurite outgrowth and gene expression of candidate molecules involved in reactive synaptogenesis and identify key molecules that can serve as the focus for the development of new and innovative approaches in stroke rehabilitation. The rationale for the study is based on previous studies from the investigators'' laboratories, as well as those of others, who have reported that: 1) neural plasticity plays a critical role in the recovery of function after ischemic brain injury, 2) rehabilitative training can enhance the recovery of function after stroke, 3) cortical reorganization and synapse replacement after brain injury involves the differential regulation of specific sets of growth-associated proteins, neurotransmitters and neurotrophins that are lesion-specific, and 4) nigrostriatal neurons that contain both dopamine and brain-derived neurotrophic factor (BDNF), a molecule essential to neuron survival and synapse function, are essential for the maintenance of corticostriatal synapses on striatal target neurons after brain injury. The overarching hypotheses to be tested are: 1) that adjunctive use of rehabilitative training enhances the upregulation of molecules known to modulate neurite outgrowth and spine density in neurons of the cortex and striatum; and 2), that these interventions converge on intracellular siqnaling pathways associated with monoamine activation and BDNF upregulation for their therapeutic effect.