组胺受体对星形胶质细胞线粒体动力学的调控及其在糖尿病低血糖相关认知障碍中的作用

反复低血糖可导致糖尿病患者出现认知障碍，是困扰临床的难题。糖尿病反复低血糖后引起的星形胶质细胞（AS）功能改变，是导致神经功能缺失的重要原因。有研究报道应激后AS线粒体动力学的平衡对于维持自身功能及神经元活动至关重要，而其具体调控机制仍未明确。我们预实验发现模型小鼠AS功能改变，伴随组胺受体表达下降。他人研究表明组胺受体与AS能量代谢及信号转导密切相关。故我们假设：组胺受体通过调控AS线粒体动力学参与糖尿病低血糖相关认知障碍的发生发展。本课题拟用小鼠糖尿病反复非严重低血糖模型，激活脑内组胺受体，观察其调控AS功能在改善糖尿病低血糖相关认知障碍中的作用；在体外建立AS高糖后反复低糖模型，干预不同组胺受体亚型及动力相关蛋白DRP1的表达，探讨AS组胺受体调控线粒体动力学的神经保护机制。本课题将为糖尿病低血糖相关认知障碍的机制研究开拓新的思路，并为探索组胺受体作为治疗靶点提供实验基础。

Repeated hypoglycemia can lead to cognitive impairment in diabetic patients, which is a difficult problem in clinical practice. The functional change of astrocytes (As) caused by repeated hypoglycemia in diabetes mellitus is an important reason for the loss of neurological function. It has been reported that the balance of AS’s mitochondrial dynamics after stress is crucial to maintain its own function and neuronal activity, but its specific regulatory mechanism remains unclear. In our pre-experiment, we found that the function of AS in model mice was changed, accompanied by the decrease of histamine receptor expression. Other studies have shown that histamine receptor is closely related to energy metabolism and signal transduction of AS. In this study, a mouse model of recurrent non-severe diabetic hypoglycemia will be used to activate the histamine receptor and observe its role in regulating AS function in improving the cognitive impairment related to diabetic hypoglycemia; In order to explore the neuroprotective mechanism of AS histamine receptor regulating mitochondrial dynamics, high glucose combined with repeated hypoglycemia as a model is established in vitro to intervened the expression of different histamine receptor subtypes and DRP1. The study will open up new ideas for the mechanism of diabetic hypoglycemia related cognitive impairment, and provide experimental basis for exploring histamine receptor as a therapeutic target.