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：
8795233
负责人：
Elizabeth Gould
金额：
$ 20.13万
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 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8795233
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 Health Human Human Characteristics Impaired cognition Incidence Individual Injury Intervention Label Lead Life Link Medial Metabolic syndrome Methods Microglia Neurons Obesity Overweight 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 cognitive performance density design frontal lobe macrophage mild cognitive impairment neural circuit neuroimaging neuronal circuitry novel prevent 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）：肥胖是影响美国人口30％以上的主要公共卫生问题。除了对身体其余部分的负面后果外，肥胖还与深远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，并确定开发新干预措施的最终目标。神经影像学研究表明，肥胖人类在支持更高水平认知（包括前额叶皮层）的大脑区域的体积中表现出减少。在啮齿动物诱发的肥胖症的啮齿动物模型中，已经观察到了西里拉的发现，以及树突状棘的丧失，兴奋性突触的主要部位和突触蛋白。此外，肥胖增加了与认知有关的大脑区域中的小胶质细胞数量。由于在疾病和损害的条件下已知小胶质细胞是吞噬神经元碎片的，因此对这些发现的传统解释是，肥胖脑中的小胶质细胞数量增加，促进了退化突触的清除。然而，发育研究表明，小胶质细胞在雕刻神经回路中起积极作用，这表明了另一种可能性：突触的小胶质细胞吞噬作用是肥胖症突触丧失的原因，而不是认知下降的效果。该探索性建议的重点是检验该假设。首先，饮食引起的野生型和转基因小鼠的肥胖以及免疫标记，蛋白质印迹，DII标记，电子显微镜和行为任务将用于确定凸显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作用与上述方法相结合的阻滞剂将用于检查小胶质细胞是否负责突触丧失和认知能力下降。综上所述，这些实验将探讨小胶质细胞和突触丧失之间的关系，并有助于阐明肥胖引起的认知功能障碍的基础机制。