低频功能性电刺激对痴呆大鼠认知功能影响的cAMP/PKA-MAPK-CREB-BDNF-LTP通路的机制研究

运动可以通过BDNF介导的信号机制改善认知。我们的基础研究发现低频功能性电刺激（LFFES）能增强脑卒中大鼠的运动功能，提高海马BDNF水平，提示其通过BDNF相关通路易化突触可塑性；临床研究显示LFFES通过增强使用依赖性可塑性改善脑卒中肢体运动功能。因此我们假设LFFES诱导产生的运动也可以通过BDNF-LTP通路提高脑梗死大鼠皮层可塑性，并通过cAMP/PKA-MAPK-CREB通路改善认知功能，为临床提供新的认知康复手段。本研究采用大鼠四血管阻断痴呆模型，给予低频电刺激，诱导肢体运动，采用电镜和体视学方法研究突触结构可塑性变化，分子生物学技术检测cAMP/PKA-CREB-BDNF -LTP通路相关核酸/蛋白的表达，电生理技术检测在体和脑片海马区LTP变化，morris水迷宫、新事物认知实验和巴恩斯迷宫检测学习记忆功能，以阐明痴呆大鼠应用此方法提高认知的效果和机制，便于临床推广应用

Exercise can improve the cognition of the healty and the patient ,such as the stroke, the Alzhiher disease, the TBI and the Parkinson disease.Our previous study on the stroke rats found that low-frenquency functional electrical stimulations (LFFES) could increase the brain-derived neurotrophic factor (BDNF) at the area of hippocampus, which indicated that LFFES facilitates synaptic plasticity through the related pathway. The randomized clinical trial on patients with stroke at either acute or chronic stage conducted by our team have demonstrated that LFFES improved the functional recovery of patients with stroke through strengthening the activity-dependent plasticity. Therefore, we hypothesis that LFFES strengthen the cortical plasticity of rat with ischemic stroke via the pathway of BDNF-LTP,and improve the cogniton. The LFFES maybe can increase the BDNF level, active the pathway of cAMP/PKA-MAPK-CREB-BDNF, and facilatate the LTP at the hippocampus, and then improve the cognition of the demetia rat. In this study, we will first establish the dementia model induced by four-vessel occlusion(4-VO) in Wistar rat. And then usethe low-frenquency functional electrical stimulation. Moreover, after the treatment with LFFES, the following was measured, including the structure of the synaptic junction, amplitude of LTP in vivo and in the hippocampus area and the changes of protein expression associated cAMP/ PKA-CREB-of BDNF-LTP signaling pathways in the maintain phase of LTP. The results of this study are expected to identify whether LFFES on the limb of rats with 4-VO can improve the cogniton of the dementia rat,the treatment of LFFES can be used to the early stage stroke and the patient without the initiative to do exercise ,enhence the effectcy of the neurorehabilitation.