School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
Brain Behav Immun. 2014 Oct;41:32-43. doi: 10.1016/j.bbi.2014.06.014. Epub 2014 Jun 27.
The early life period is one of significant vulnerability to programming effects from the environment. Given the sensitivity of microglial cells to early life programming and to adult diet, we hypothesized overfeeding during the neonatal period would acutely alter microglial profiles within the developing brain, predisposing the individual to a lasting central pro-inflammatory profile that contributes to overactive immune responses long-term. We tested this idea by manipulating litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of 4 (neonatally overfed) or 12 (control). This manipulation induces obesity and susceptibility to lipopolysaccharide (LPS) long-term. We then examined microglial and central pro-inflammatory profiles during development and in adulthood as well as susceptibility to neuroimmune challenge with LPS. Neonatally overfed rats have evidence of microgliosis in the paraventricular nucleus of the hypothalamus (PVN) as early as postnatal day 14. They also show changes in hypothalamic gene expression at this time, with suppressed hypothalamic interleukin 1β mRNA. These effects persist into adulthood, with basal PVN microgliosis and increased hypothalamic toll-like receptor 4, nuclear factor κB, and interleukin 6 gene expression. These neonatally overfed rats also have dramatically exacerbated microglial activation in the PVN 24h after an adult LPS challenge, coupled with changes in inflammatory gene expression. Thus, it appears neonatal overfeeding sensitizes PVN microglia, contributing to a basal pro-inflammatory profile and an altered response to a neuroimmune challenge throughout life. It remains to be seen if these effects can be reversed with early interventions.
生命早期是易受环境编程影响的关键时期。鉴于小胶质细胞对生命早期编程和成年饮食的敏感性，我们假设在新生儿期过度喂养会急性改变发育中大脑内的小胶质细胞谱，使个体易患持续的中枢促炎表型，从而导致长期过度的免疫反应。我们通过操纵新生 Wistar 大鼠的窝仔数来检验这一假设，使仔鼠在 4 只（新生儿期过度喂养）或 12 只（对照）的窝中哺乳。这种操作会长期诱导肥胖和对脂多糖（LPS）的易感性。然后，我们在发育过程中和成年期检查小胶质细胞和中枢促炎谱，以及对 LPS 神经免疫挑战的易感性。新生期过度喂养的大鼠在生后第 14 天就出现下丘脑室旁核（PVN）小胶质细胞增生的证据。此时它们还表现出下丘脑基因表达的变化，下丘脑白细胞介素 1βmRNA 受到抑制。这些影响持续到成年期，表现为基础 PVN 小胶质细胞增生和下丘脑 Toll 样受体 4、核因子 κB 和白细胞介素 6 基因表达增加。这些新生期过度喂养的大鼠在成年 LPS 挑战后 24 小时，PVN 中的小胶质细胞激活也明显加剧，同时炎症基因表达也发生变化。因此，似乎新生儿期过度喂养使 PVN 小胶质细胞敏感化，导致基础促炎表型和对整个生命周期神经免疫挑战的反应改变。这些影响是否可以通过早期干预来逆转还有待观察。
