The early life period is crucially important to how the individual develops, and environmental and lifestyle challenges during this time can lead to lasting programming effects on the brain and immune system. In particular, poor diet in early development can lead to long-term negative metabolic and cognitive outcomes, with those who over-eat in early development being at risk of obesity and poor learning and memory throughout their adult lives. Current research has identified a neuroinflammatory component to this metabolic and cognitive programming that can potentially be manipulated to restore a healthy phenotype. Thus, early life over-feeding in a rat model leads to microglial priming and an exacerbated microglial response to immune challenge when the rats reach adulthood. Microglial responses to a learning task are also impaired. To specifically investigate the role of microglia in these programming effects our group has developed a novel transgenic rat with a diphtheria toxin receptor insertion in the promoter region for the Cx3cr1 gene, expressed on microglia and monocytes; allowing us to conditionally ablate microglia throughout the brain. With this model we reveal that microglia have a direct role in regulating feeding behavior and modifying cognition, but are not likely to be the sole mechanism by which early life overfeeding confers lasting neuroimmune and cognitive effects. Additional work implicates changes to the hypothalamic-pituitary-adrenal axis in this. Together these data highlight the importance of dietary choices in early life and the potential for positive interventions targeting the neuroimmune and neuroendocrine stress systems to reverse such programming damage.

中文翻译：

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小胶质细胞早期过度喂养的后果——啮齿动物模型的观点

生命早期阶段对个体的发育至关重要，在此期间环境和生活方式的挑战可能会对大脑和免疫系统产生持久的编程影响。特别是早期发育不良的饮食会导致长期的负面代谢和认知结果，那些在早期发育过度饮食的人在整个成年期都有肥胖和学习记忆力差的风险。目前的研究已经确定了这种代谢和认知程序的神经炎症成分，可以通过操纵来恢复健康的表型。因此，大鼠模型中的早期过度喂养会导致小胶质细胞启动，并在大鼠成年后对免疫挑战的小胶质细胞反应加剧。小胶质细胞对学习任务的反应也受损。为了专门研究小胶质细胞在这些编程效应中的作用，我们的小组开发了一种新型转基因大鼠，在 Cx3cr1 基因的启动子区域插入了白喉毒素受体，在小胶质细胞和单核细胞上表达；允许我们有条件地消融整个大脑的小胶质细胞。通过该模型，我们揭示了小胶质细胞在调节进食行为和改变认知方面具有直接作用，但不太可能是早期过度喂养赋予持久神经免疫和认知影响的唯一机制。其他工作涉及下丘脑 - 垂体 - 肾上腺轴的变化。