Microglia in obesity-induced synapse loss and cognitive decline

小胶质细胞在肥胖引起的突触丧失和认知能力下降中的作用

基本信息

批准号：
8682457
负责人：
Elizabeth Gould
金额：
$ 24.15万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8682457
关键词：
Address Adult Affect Aging Alzheimer&apos s Disease Animal Model Behavioral Biochemical Body mass index Brain Brain region Childhood Chronic stress Clinical Research Cognition Cognitive Cognitive deficits Consumption Data Dementia Dendritic Spines Development Diabetes Mellitus Diet Disease Electron Microscopy Excitatory Synapse Exhibits Goals Human Human Characteristics Impaired cognition Incidence Individual Injury Intervention Label Lead Life Link Medial Metabolic syndrome Methods Microglia Neurons Obesity Overweight Performance Phagocytosis Play Population Prefrontal Cortex Proteins Public Health Reporting Research Rest Rodent Model Role Site Structure Synapses Testing Transgenic Mice Vascular Diseases Western Blotting brain volume cerebral atrophy cognitive function density design frontal lobe macrophage mild cognitive impairment neural circuit neuroimaging neuronal circuitry novel prevent public health relevance relating to nervous system research study response restoration

项目摘要

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.

描述（由申请人提供）：肥胖是影响超过 30% 的美国人口的主要公共卫生问题。除了对身体其他部位产生负面影响外，肥胖还与严重的神经和认知缺陷有关。该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。神经影像学研究表明，肥胖的人支持更高水平认知的大脑区域（包括前额叶皮层）的体积减少。在饮食引起的肥胖的啮齿动物模型中，观察到了类似的结果，以及树突棘、兴奋性突触的主要部位和突触蛋白的丧失。此外，肥胖会增加大脑中参与认知的区域小胶质细胞的数量。由于已知小胶质细胞在疾病和损伤的情况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中发挥着积极作用，这表明了另一种可能性：小胶质细胞对突触的吞噬作用是肥胖症突触损失的原因而不是结果，并且是认知能力下降的一个因素。这个探索性提案的重点是检验这个假设。首先，饮食诱导的野生型和转基因小鼠肥胖以及免疫标记、蛋白质印迹、DiI 标记、电子显微镜和行为任务将被用来确定小胶质细胞吞噬突触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作用的阻断剂与上述方法相结合，将用于检查小胶质细胞是否与突触丢失和认知能力下降有关。总而言之，这些实验将探索小胶质细胞和突触损失之间的关系，并有助于阐明肥胖引起的认知功能障碍的机制。