Neonatal overfeeding by small‐litter rearing sensitises hippocampal microglial responses to immune challenge: Reversal with neonatal repeated injections of saline or minocycline

Abstract

The early-life period is extremely vulnerable to programming effects from the environment, many of which persist into adulthood. We have previously demonstrated that adult rats overfed as neonates have hypothalamic microglia that are hyper-responsive to an immune challenge, as well as hippocampal microglia that respond less efficiently to learning. We therefore hypothesised that neonatal overfeeding would alter the ability of hippocampal microglia to respond to an immune challenge with lipopolysaccharide (LPS) and that concomitant minocycline, a tetracycline antibiotic that suppresses microglial activity, could restore these responses. We induced neonatal overfeeding by manipulating the litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of four (neonatally overfed) or 12 (control-fed). We then examined the hippocampal microglial profiles 24 hour after an immune challenge with LPS and found that the neonatally overfed rats had dramatically increased microglial numbers in the hippocampus after immune challenge compared to control-fed rats. Attempts to reverse these effects with minocycline revealed repeated that neonatal injections, whether with minocycline or with saline, markedly suppressed microglial number and density throughout the hippocampus and abolished the difference between the groups in their responses to LPS. These data suggest that neonatal overfeeding not only can have lasting effects on hippocampal immune responses, but also that neonatal exposure to a protocol of repeated injections, irrespective of treatment, has a pronounced long-term impact, highlighting the importance of considering these effects when interpreting experimental data.

Effect of maternal antioxidant supplementation and/or exercise practice during pregnancy on postnatal overnutrition induced by litter size reduction: Brain redox homeostasis at weaning

“…On the other hand, overfeeding during lactation cause a positive response in the hippocampus antioxidant enzymes activities, evidenced by an increase in SOD, GPx, and GLO 1. We thought that this occurs in response to the pro‐inflammatory environment found in this structure in the litter size reduction model as a possible explanation to the antioxidant network improvement (De Luca et al, 2017, 2016). Despite on adult mice exposed to overfeeding during lactation decreased spatial memory was already demonstrated (Salari et al, 2018), at weaning we did not found oxidative stress markers elevated.…”

Obesity after neonatal overfeeding is independent of hypothalamic microgliosis

“…In our previous work, we demonstrated that neonatal overfeeding increases microglial numbers in the adult PVN, as well as Il‐6 gene expression in the hypothalamus and Tlr4 expression in the hippocampus, relative to normally fed controls. LPS further increases PVN, ARC and hippocampal microglial numbers in the neonatally overfed after 24 hours. In the present study, we examined whether this effect of neonatal overfeeding on central inflammatory profiles after LPS could be attenuated with minocycline.…”

“…Both low and high dose treatments robustly reduced the increase in activated microglia. We used these findings as guidance for our own selection of minocycline dose in this and our previous study . For these experiments, we used n = 6 per group, with the members of each group being derived from at least four litters.…”

“…In previous work, we attempted to examine the effects of minocycline concomitant with the neonatal overfeeding. However, the impact of handling and injecting the pups in these experiments obscured any potential impact of the drug . In the present study, we administered minocycline during the immediate post‐weaning period and into young adulthood.…”

Newborn feeding recommendations and practices increase the risk of development of overweight and obesity

“…The early-life period has been increasingly studied as the most optimal time to intervene in this epidemic. It is suggested that the early life period is particularly susceptible to environmental "programming" effects that have been evidenced to remain present much later in life [2,3]. Specifically, rapid weight gain early in life due to improper feeding practices has been shown to be a risk factor for obesity later in childhood [3,4].…”