Gsdd45b调节脑梗死后皮质脊髓束可塑性及其机制研究

Cerebral ischemia is a common disease of the central nervous system. It is a common cause of acquired disability, motor impairment caused enormous economic and emotional burden to the family and society. Cerebral ischemia survivors have motor function recovery to some degree in a few days and months after stroke. This shows that plasticity exists in corticospinal tract (CST). Emegring studies showed that Gadd45b can promote long-term neural brain plasticity. Our previous research discovered electrical stimulation promoted the expression of Gadd45b and motor function recovery after focal cerebral ischemia in rats. So we hypothesis Gadd45b may play an critical role in linking rehabilitation and electrical stimulation to CST plasticity. This study plan to adobt rat MACO and cultured cortical neurons cell models, studies the impact of regulation and control of Gadd45b expression (inhibited by RNAi, promoted by enriched environment and electrical stimulation ) on CST plasticity and affected forelimb motor function recovery after cerebral ischemia from the whole, tissue, cell and molecular levels. In this research, we explore the role of proliferation and migration of SVZ endogenous neural stem cells, new neurons formating, axonal regeneration and RhoA-ROCK signaling pathway in the mechanism of Gadd45b regulating CST plasticity. We hope to find a theoretical basis for the rehabilitation of patients with cerebral ischemia by this study.

脑梗死是神经系统的常见病，其高致残率给家庭和社会造成巨大的经济和精神负担。脑梗死幸存者病后数天到数月肢体运动功能障碍有一定程度恢复，说明脑梗死后恢复期损伤皮质脊髓束（CST）存在可塑性。最新研究表明Gadd45b可促进大脑长期神经可塑性。我们前期发现电刺激可促进脑缺血后Gadd45b表达与运动功能恢复,所以我们推测Gadd45b可能是将康复训练和电刺激等与CST可塑性联系起来的关键环节。本研究采用大鼠MCAO模型结合大脑皮质神经元培养的细胞模型，从整体、组织、细胞和分子水平研究脑梗死后恢复期Gadd45b表达及其调控（用RNAi技术进行抑制，丰富环境刺激和电刺激进行促进）对CST可塑性和前肢运动功能的影响，探讨内源性神经干细胞增殖和迁移、新神经元形成、轴突再生及RhoA-ROCK信号通路活动调控机制在Gadd45b调控CST可塑性中的作用，藉此为脑梗死患恢复期补充治疗方式研究提供理论依据。

幸存脑梗死患者常遗留有明显的运动功能障碍，脑梗死后Gadd45b表达变化影响皮质脊髓束（CST）可塑性可能在其运动功能康复中发挥重要作用。我们应用右侧大脑中动脉阻塞（MCAO）大鼠脑梗死模型和大脑皮层神经元细胞缺血细胞模型对脑缺血后调控Gadd45b表达变化影响CST可塑性及其病理生理机制进行了研究，发现：（1）脑梗死可以上调Gadd45b的表达，丰富环境和电刺激小脑顶核可进一步上调Gadd45b的表达；（2）Gadd45b表达变化与脑缺血后CST可塑性和运动功能恢复密切相关，利用RNAi干扰Gadd45b表达消除丰富环境和电刺激小脑顶核对脑梗死后运动功能恢复的促进作用；（3）Gadd45b可通过影响BDNF的甲基化，进而调节cAMP/PKA-CREB信号通路和RhoA-ROCK信号通路活动，对脑缺血后的轴突可塑性和运动功能恢复发挥影响；（4）丰富环境刺激可以上调Gadd45b和BDNF的表达，并促进侧脑室下区的神经发生； RNAi抑制Gadd45b表达后丰富环境刺的这种作用消失；（5）Gadd45b表达上调通过JNK信号通路活动抑制神经细胞凋亡。研究发现丰富了脑梗死恢复期肢体运动功能康复病理生理机制的认识。丰富环境和电刺激小脑顶核可通过上调Gadd45b表达促进皮质脊髓束可塑性和运动功能恢复，为其临床应用研究提供了理论依据。