食源性肥胖影响海马学习记忆功能及其相关突触可塑性的神经化学机制

Recently, changes in food composition and availability have contributed to the dramatic increase in obesity, and it is a major risk factor in many diseases, including diabetes and hypertention. Obesity influences the cognitive function, and a growing body of animal and epidemiological study suggests that obesity is associated with the development of cognitive impairment and Alzheimer's disease (AD). Learning and memory is a basis of cognition, and hippocampus is a key structure for learning and memory. In the hippocampus, synaptic plasticity is a potential neurophysiological mechanism for learning and memory. Studies have shown that learning and memory processes carried out within the hippocampus are influenced by obesity, however, how does obesity affect synaptic plasticity in the hippocampus during learning and memory process remains unclear. In the previous studies, applicant simultaneously observed the learning and memory behavior, learning-dependent synaptic plasticity and changes of several neurotransmitters in the hippocampal dentate gyrus (DG) in freely moving rats, and explored the neurochemical mechanisms responsible for the changes of synaptic plasticity of DG during learning and memory processes in normal and Alzheimer's disease (AD) rats. Therefore, base on these results, applicant will use in vivo barin microdialysis, HPLC, behavioral assessment, electrophysiological recording, western blot, ELISA and pharmacological methods to investigate neurochemical mechanisms responsible for effects of dietary obesity on learning and memory-related synaptic plasticity and the neurotransmitter system in the DG. This study aims to clarify the mechanism of dietary obesity-induced learning and memory abnormity and to provide theoretical evidences for the prevention and treatment of metabolic disease-induced cognitive impairment.

目前，食物成分和可利用性的改变导致越来越多的肥胖，而肥胖是糖尿病、高血压等多种疾病的常见诱因。肥胖明显影响认知功能，和进行性认知障碍、阿尔兹海默病（AD）等密切相关。学习记忆是认知功能的基础，而海马是学习记忆的关键部位。虽然研究表明肥胖可影响海马的学习记忆功能，但其具体的神经化学机制尚不清楚。前期研究中，本课题组用同步观察大鼠的学习记忆行为、海马区突触效应及神经递质变化的研究平台，整体水平上阐述了海马DG区突触可塑性在正常和AD大鼠的学习记忆中的变化及其神经化学机制。本项目拟在前期工作基础上，用脑部微量透析、高效液相色谱、行为学、在体生物电记录、神经药理学、蛋白印迹、ELISA检测等方法，观察食源性肥胖对DG区学习记忆相关突触可塑性和神经递质系统的影响，并探讨其神经化学机制。本研究将为阐明食源性肥胖诱发学习记忆异常的产生机制做贡献，并为预防和治疗代谢性疾病诱发的认知功能障碍提供理论依据。

肥胖是21世纪较为严重的健康相关问题，主要与高能量饮食和久坐的生活方式等有关。肥胖不仅与心血管及代谢性疾病等密切相关，还明显影响认知功能，和阿尔兹海默病（AD）等认知障碍有关。学习记忆是认知功能的基础，而海马是学习记忆的关键部位。虽然研究表明肥胖可影响海马的学习记忆功能，但其具体的神经化学机制尚不完全清楚。前期研究中，本课题组用同步观察大鼠的学习记忆行为、海马区突触效应及神经递质变化的研究平台，整体水平上阐述了海马齿状回（DG）区突触可塑性在正常和AD大鼠的学习记忆中的变化及其神经化学机制。因此，本项目在前期工作的基础上，用脑部微量透析、高效液相色谱、行为学、神经药理学、蛋白印迹、ELISA检测等实验方法，观察食源性肥胖对学习记忆行为及DG区相关突触可塑性的影响，并进一步探讨其神经化学机制。本项目的研究结果提示：① 用高脂饲料（45%脂肪）喂养大鼠12周后，大鼠的体重、血脂、血中瘦素和胰岛素的含量均明显增加，提示食源性肥胖模型建立成功；② 食源性肥胖大鼠出现明显的学习记忆功能损伤；③ 食源性肥胖损伤大鼠的学习记忆功能与增强DG区谷氨酸（Glu）在学习过程中的反应，并过度激活其NMDA受体有关；④ 食源性肥胖模型大鼠海马DG区NMDA受体的过度激活损伤大鼠学习记忆及其相关突触可塑性与抑制CaMKII-CREB- BDNF通路活性，并增加DG区的氧化应激、内质网应激和神经炎症有关；⑤ 食源性肥胖损伤大鼠的学习和记忆功能和DG区的多巴胺（DA）-D1受体系统的活动异常，以及随之而来的PKA-CREB-BDNF通路抑制有关；⑥ 食源性肥胖模型大鼠海马DG区的DA-D1受体系统活动的异常引起兴奋性（谷氨酸）和抑制性（GABA）递质系统间的平衡失调，进而损伤学习记忆功能。本研究的研究结果将为阐明食源性肥胖诱发学习记忆异常的产生机制做贡献，并为预防和治疗代谢性疾病诱发的认知功能障碍提供理论依据。