GC-GR信号通路调控脑海马区突触可塑性及神经元数量损害糖尿病认知功能的机制

Diabetic cognitive dysfunction is one of the most serious complications in patients with diabetes mellitus (DM), presenting gradually with cognitive impairments, poor memory or even psychological problems such as emotional frustration and depression. Diabetic cognitive decline has significantly impacts on the quality of life and health care costs. However, mechanisms underlying diabetic cognitive dysfunction remains unclear. Activation of glucocorticoids (GC)-glucocorticoids receptor (GR) signaling pathway associating with cognitive dysfunction has been well documented. We revealed that activation of GC-GR signaling pathway in diabetic hippocampus contributes to diabetic cognitive dycline by regulationg hippocampus neuronal number and by regulating synaptic plasticity in hippocampus, showing neuronal atrophy, neuronal loss, decrease in synaptic density and astrocytic reactivity. Synaptic plasticity is the foundation of learning and memory. Better and more comprehensive understandings of deterious effects of GC-GR signaling pathway on diabetic cognition are desired. We, therefore, try to elucidate these questions with methods including animal behavior testing, morphology, cytobiology, molecular biology and electrophysiology. Based on previous researches and our previous data, we seek further to explore effects of GC-GR signaling pathway on neuronal number from perspective of neurogenesis, neuronal maturation, neuronal apoptosis. Morover, we try to elucidate effects of GC-GR signaling pathway on diabetic hippocampal synaptic plasticity by investigating neuronal morphology and synaptic membrane receptor. Further investigations into the mechanisms underlying GC-GR signaling pathway impairing diabetic cognition will contribute to a novel understanding of diabetic cognitive dysfunction, and will help to discover and develop new treatment for diabetic encephalopathy.

糖尿病（DM）可导致患者学习记忆能力减退，不仅影响患者身体健康，也严重影响患者心理健康，由于DM认知功能障碍机制不清，目前仍无有效治疗手段。文献及本课题组前期研究表明，糖皮质激素（GC）-糖皮质激素受体（GR）信号通路激活是DM认知功能障碍的重要机制。我们发现，DM时GC-GR 信号通路的激活可导致脑海马区神经元缺失及突触可塑性改变，出现神经元萎缩、排列紊乱、突触密度降低及星形胶质细胞活性下降等表现，但其影响及分子机制仍待进一步阐明。因此，本课题拟通过行为学、形态学、细胞生物学、分子生物学及电生理等手段，从神经元的再生、分化、成熟及凋亡等角度探索GC-GR信号通路对DM时脑海马区神经元数量的影响及机制；从神经元形态及突触膜受体的表达、活化、细胞定位等角度探讨 GC-GR 信号通路对DM时脑海马区突触可塑性的影响及机制。本课题对于揭示 DM 认知功能障碍的机制，提供新的治疗思路具有重要意义。

糖尿病可患者损害脑功能，逐渐出现注意力不集中、语言表达能力下降、认知功能减退等表现，严重影响患者的学习记忆和工作能力，在激烈的社会竞争中产生挫败感，不仅影响患者的身体健康也严重影响患者的心理健康。但糖尿病认知功能障碍发病机制不清，目前尚无有效治疗手段。本项目研究发现，糖皮质激素长期升高，能激活糖皮质激素受体（glucocorticoids receptor，GR），是糖尿病患者认知功能障碍的主要原因之一。GR激活后，可能通过以下机制损害糖尿病学习记忆功能：1.抑制糖尿病脑海马区与学习记忆功能密切的N-甲基D-天门冬氨酸受体2B（N-methyl-D-aspartate receptor 2B，NR2B）蛋白表达，并抑制了NR2B的磷酸化；2. 抑制了微管相关蛋白2（microtubule-associated protein 2，MAP2）在脑海马区神经元内的表达，导致神经元突起数目减少、突起长度缩短，减少了神经元直接互相连接、接触部位的数量，降低了突触密度；3. 凋亡相关基因Bax及神经生长抑制因子受体NgR（Nogo Receptor）表达增加，使糖尿病脑海马区神经元凋亡增加，数目减少，出现神经元形态不规整，排列紊乱等表现。4. 抑制了糖尿病脑海马区DNA甲基化，影响了蛋白表达，其中显著抑制了ngr基因甲基化，上调NgR表达之后启动了线粒体细胞凋亡途径。