Hao Shuai, Dey Aditi, Yu Xiaolin, Stranahan Alexis M
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, 1120 15th St, CA3064, Augusta, GA 30912, USA.
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, 1120 15th St, CA3064, Augusta, GA 30912, USA.
Brain Behav Immun. 2016 Jan;51:230-239. doi: 10.1016/j.bbi.2015.08.023. Epub 2015 Aug 31.
Obesity increases risk of age-related cognitive decline and is accompanied by peripheral inflammation. Studies in rodent models of obesity have demonstrated that impaired hippocampal function correlates with microglial activation, but the possibility that neuron/microglia interactions might be perturbed in obesity has never been directly examined. The goal of this study was to determine whether high fat diet-induced obesity promotes synaptic stripping by microglia, and whether any potential changes might be reversible by a return to low-fat diet (LFD). Time course experiments revealed that hippocampal inflammatory cytokine induction and loss of synaptic protein expression were detectable after three months of HFD, therefore subsequent groups of mice were maintained on HFD for three months before being switched to LFD for an additional two months on LFD (HFD/LFD). Additional HFD mice continued to receive HFD during this period (HFD/HFD), while another group of mice were maintained on LFD throughout the experiment (LFD/LFD). Dietary obesity impaired hippocampus-dependent memory, reduced long-term potentiation (LTP), and induced expression of the activation marker major histocompatibility complex II (MHCII) in hippocampal microglia. Diet reversal only partially attenuated increases in adiposity in HFD/LFD mice, but plasticity deficits and MHCII induction were normalized to within the range of LFD/LFD mice. Microglial activation and deficits in hippocampal function were accompanied by perturbation of spatial relationships between microglial processes and synaptic puncta. Analysis of primary microglia isolated from HFD/HFD mice revealed selective increases in internalization of synaptosomes labeled with a pH-sensitive fluorophore. Taken together, these findings indicate that dietary obesity reversibly impairs hippocampal function, and that deficits may be attributable to synaptic stripping by microglia.
肥胖会增加与年龄相关的认知衰退风险，并伴有外周炎症。在肥胖啮齿动物模型中的研究表明，海马体功能受损与小胶质细胞激活相关，但肥胖可能扰乱神经元/小胶质细胞相互作用这一可能性从未被直接研究过。本研究的目的是确定高脂饮食诱导的肥胖是否会促进小胶质细胞介导的突触剥离，以及恢复低脂饮食（LFD）是否能逆转任何潜在变化。时间进程实验显示，高脂饮食三个月后可检测到海马体炎性细胞因子的诱导和突触蛋白表达的丧失，因此后续几组小鼠先接受三个月的高脂饮食，然后改为低脂饮食再持续两个月（HFD/LFD）。在此期间，额外的高脂饮食组小鼠继续接受高脂饮食（HFD/HFD），而另一组小鼠在整个实验过程中一直保持低脂饮食（LFD/LFD）。饮食性肥胖损害了海马体依赖性记忆，降低了长时程增强（LTP），并诱导了海马体小胶质细胞中激活标记物主要组织相容性复合体II（MHCII）的表达。饮食逆转仅部分减轻了HFD/LFD小鼠的肥胖增加，但可塑性缺陷和MHCII诱导恢复到了LFD/LFD小鼠的范围内。小胶质细胞激活和海马体功能缺陷伴随着小胶质细胞突起与突触小点之间空间关系的扰动。对从HFD/HFD小鼠中分离出的原代小胶质细胞的分析显示，用pH敏感荧光团标记的突触体的内化选择性增加。综上所述，这些发现表明饮食性肥胖会可逆性损害海马体功能，且缺陷可能归因于小胶质细胞介导的突触剥离。
