Microglia in obesity-induced synapse loss and cognitive decline

描述(由申请者提供)：肥胖是一个主要的公共健康问题，影响着超过30%的美国人口。除了对身体其他部位的负面影响外，肥胖还与严重的神经和认知缺陷有关。这项提案的长期目标是确定肥胖引起的认知功能障碍的细胞基础，最终目标是开发新的干预措施。神经成像研究表明，肥胖者大脑支持较高水平认知的区域体积减少，包括前额叶皮质。在饮食诱导肥胖的啮齿动物模型中，也观察到了相似的发现，以及树突棘、兴奋性突触的初级位置和突触蛋白的丢失。此外，肥胖还会增加与认知有关的大脑区域中的小胶质细胞数量。由于小胶质细胞在疾病和损伤条件下会吞噬神经元碎片，因此对这些发现的传统解释是，肥胖大脑中小胶质细胞数量的增加有助于清除退化的突触。然而，发育研究表明，小胶质细胞在塑造神经回路方面发挥着积极作用，这表明了另一种可能性：小胶质细胞吞噬突触是肥胖患者突触丧失的原因而不是结果，也是认知能力下降的原因之一。这一探索性建议的重点是检验这一假说。首先，在野生型和转基因小鼠中，饮食诱导的肥胖以及免疫标记、免疫印迹、DiI标记、电子显微镜和行为任务将被用来确定突触的小胶质细胞吞噬是否与认知能力下降有关。其次，小胶质细胞激活和小胶质细胞吞噬的阻滞剂将与上述方法结合使用，以检查小胶质细胞是否与突触丢失和认知能力下降有关。综上所述，这些实验将探索小胶质细胞和突触丢失之间的关系，并有助于阐明肥胖导致认知功能障碍的机制。

DESCRIPTION (provided by applicant): Obesity is a major public health problem affecting over 30% of the US population. In addition to its negative consequences on the rest of the body, obesity is associated with profound neural and cognitive deficits. The long-term objectives of this proposal are to determine the cellular underpinnings of obesity-induced cognitive dysfunction with the ultimate goal of developing novel interventions. Neuroimaging studies have shown that obese humans exhibit decreases in the volume of brain regions supporting higher level cognition, including the prefrontal cortex. In a rodent model of diet-induced obesity, simila findings have been observed, as well as the loss of dendritic spines, primary sites of excitatory synapses, and synaptic proteins. In addition, obesity increases the numbers of microglia in brain regions involved in cognition. Because microglia are known to phagocytose neuronal debris under conditions of disease and damage, a traditional interpretation of these findings is that the increased numbers of microglia in the obese brain facilitate clearance of degenerating synapses. However, developmental studies showing that microglia play an active role in sculpting neural circuitry suggest an alternative possibility: that microglial phagocytosis of synapses is a cause rather than an effect of synaptic loss in obesity, and a contributor to cognitive decline. The focus of this exploratory proposal is to test this hypothesis. First, diet-induced obesity in wildtype and transgenic mice along with immunolabeling, western blots, DiI labeling, electron microscopy and behavioral tasks will be used to determine whether microglial engulfment of synapses is associated with cognitive decline. Second, blockers of microglial activation and microglial phagocytosis combined with the above methods will be used to examine whether microglia are responsible for synapse loss and cognitive decline. Taken together, these experiments will explore the relationship between microglia and synapse loss and help elucidate mechanisms underlying obesity-induced cognitive dysfunction.