海马内胰岛素受体在晕动症空间学习记忆损伤中的作用及机制研究

Long-term acceleration can cause motion sickness, even affect the function of the hippocampus, and induce spatial learning and memory impairment, however its mechanism is still unclear. Insulin receptor plays an important role in learning and memory function in the hippocampus. Spatial learning and memory function can be significantly improved by intrahippocampal insulin microinjection via insulin receptor signaling pathway. Our previous experiments showed that during acceleration-induced motion sickness, spatial learning and memory function, and the activity of insulin receptor and proteins related to learning and memory were decreased in the hippocampus. However, after the intrahippocampal insulin microinjection, the activity of insulin receptor and proteins related to learning and memory were increased and the spatial learning and memory impairment was relieved during motion sickness. Therefore, we intend to investigate the effect and its mechanism of insulin receptor on the activity of proteins related to learning and memory in the hippocampus and spatial learning and memory function during motion sickness, which contains various methods including molecular biology, behavioral science, immunohistochemistry and so on, and by analyzing the effect of changes in insulin receptor signaling pathway on relieved spatial learning and memory impairment by hippocampal microinjection of insulin during motion sickness, the mechanism of of insulin in improving spatial learning and memory function during motion sickness is further clarified, providing a scientific basis for using insulin to prevent from spatial learning and memory impairment during motion sickness.

长时加速度刺激可以引起晕动症，严重的甚至会影响到海马的功能，引起空间学习记忆损伤，但其具体机制还不清楚。胰岛素受体在海马学习记忆功能中起着非常重要的作用，海马内微注射胰岛素可以通过胰岛素受体信号通路改善学习记忆功能。我们的前期实验发现加速度刺激诱发晕动症后，空间学习记忆功能降低，海马内胰岛素受体和学习记忆相关蛋白活性降低，而海马内微注射胰岛素可以上调胰岛素受体和学习记忆相关蛋白活性，减轻晕动症的空间学习记忆损伤。因此，本项目拟采用动物实验和细胞实验相结合的方法，以分子生物学，行为学、免疫组化等多种技术手段，研究胰岛素受体对海马内学习记忆相关蛋白活性和晕动症空间学习记忆功能的影响及其机制，并通过分析胰岛素受体及下游信号通路活性变化对海马内微注射胰岛素改善晕动症空间学习记忆损伤作用的影响，进一步明确胰岛素改善晕动症学习记忆功能的机制，为胰岛素用于防治晕动症的空间学习记忆损伤提供更好的科学依据。

晕动症不仅会引起恶心呕吐等症状，严重的甚至会影响到海马的功能，引起空间学习记忆损伤。胰岛素受体在海马学习记忆功能中起着非常重要的作用，但其在晕动症空间学习记忆损伤中的作用和机制还未系统阐明。我们拟从分子、细胞和整体动物水平，利用分子生物学、行为学等多种技术手段，观察胰岛素受体对晕动症空间学习记忆功能的影响，探索其发挥作用的下游信号通路和关键学习记忆相关蛋白，进一步明确胰岛素改善晕动症学习记忆功能的机制。具体取得如下结果：（1）实验开展了多次人群调查，进一步明确晕动症与疲劳呈正相关。晕动症及伴随的疲劳均可能引起学习记忆损伤；（2）大鼠加速度暴露后，晕反应指数升高，学习记忆能力下降；海马内PSD95表达降低，胰岛素受体信号通路关键分子IRβ、IRS1、AKT、mTOR磷酸化水平降低，GluA1磷酸化水平没有明显差异，尼氏染色显示神经元数量没有明显差异；（3）大鼠海马内过表达PSD95可以有效缓解晕动症空间学习记忆损伤；（4）给予大鼠海马内微注射胰岛素可以激活IRβ及其下游信号通路和PSD95表达，改善晕动症空间学习记忆损伤，而单独给予胰岛素受体抑制剂S961会抑制上述通路，加重晕动症空间学习记忆损伤；（5）胰岛素通过胰岛素受体及下游信号分子和PSD95改善晕动症空间学习记忆损伤。本研究分析了胰岛素受体信号通路在晕动症空间学习记忆损伤及胰岛素防护作用中的机制，为胰岛素用于防治晕动症的空间记忆损伤提供更好的科学依据。