Early life overfeeding impairs spatial memory performance by reducing microglial sensitivity to learning.
Early life overfeeding impairs spatial memory performance by reducing microglial sensitivity to learning.
复制标题
DOI：
10.1186/s12974-016-0578-7
复制
发表时间：
2016-05-18
影响因子：
9.3
通讯作者：
Spencer SJ
中科院分区：
文献类型：
--
作者：
De Luca SN;Ziko I;Sominsky L;Nguyen JC;Dinan T;Miller AA;Jenkins TA;Spencer SJ
肥胖可导致认知功能障碍，包括记忆任务表现不佳。然而，记忆力差并不是在所有肥胖的人身上都能看到，而且在动物模型中需要几个月的时间才能发展出来，这表明成年人的大脑对肥胖的认知影响具有相对的抵抗力。我们已经看到，在大鼠中，在生命早期的3周内过度喂养会导致持久的肥胖和下丘脑中的小胶质细胞启动。在这里，我们假设，小胶质细胞的超敏性在过度喂养的大鼠延伸到下丘脑以外的记忆相关的大脑区域，导致认知缺陷。我们通过操纵Wistar大鼠的窝仔数来测试这一想法，以4只（过度喂养）或12只（对照）的窝仔数来喂养幼鼠。新生期过度喂养的大鼠在过度喂养仅14天后海马体中就出现了小胶质细胞增生，并且这种情况一直持续到成年。这些变化伴随着相对于对照组在径向臂迷宫和新物体识别测试中的较差表现。在对照组中，放射状臂迷宫的经历减少了齿状回中的细胞增殖和CA 3中的神经元数量。学习任务也抑制了海马和压后皮质中小胶质细胞的数量和密度。新生儿过度喂养的大脑对学习的敏感性受损，没有神经元或细胞增殖作用，并且小胶质细胞抑制效果较差。因此，早期生活中的过度喂养会导致学习和记忆的长期损害，小胶质细胞可能发挥作用。这些数据可以部分解释为什么一些肥胖个体表现出认知功能障碍，而另一些则没有，即早期生活饮食环境可能具有重要的长期贡献。本文的在线版本（doi：10.1186/s12974-016-0578-7）包含补充材料，可供授权用户使用。
Obesity can lead to cognitive dysfunction including poor performance in memory tasks. However, poor memory is not seen in all obese humans and takes several months to develop in animal models, indicating the adult brain is relatively resistant to obesity’s cognitive effects. We have seen that, in the rat, overfeeding for as little as 3 weeks in early life leads to lasting obesity and microglial priming in the hypothalamus. Here we hypothesized that microglial hyper-sensitivity in the neonatally overfed rats extends beyond the hypothalamus into memory-associated brain regions, resulting in cognitive deficits. We tested this idea by manipulating Wistar rat litter sizes to suckle pups in litters of 4 (overfed) or 12 (control). Neonatally overfed rats had microgliosis in the hippocampus after only 14 days overfeeding, and this persisted into adulthood. These changes were coupled with poor performance in radial arm maze and novel object recognition tests relative to controls. In controls, the experience of the radial arm maze reduced cell proliferation in the dentate gyrus and neuron numbers in the CA3. The learning task also suppressed microglial number and density in hippocampus and retrosplenial cortex. Neonatally overfed brains had impaired sensitivity to learning, with no neuronal or cell proliferative effects and less effective microglial suppression. Thus, early life overfeeding contributes to a long-term impairment in learning and memory with a likely role for microglia. These data may partially explain why some obese individuals display cognitive dysfunction and some do not, i.e. the early life dietary environment is likely to have a vital long-term contribution. The online version of this article (doi:10.1186/s12974-016-0578-7) contains supplementary material, which is available to authorized users.