Consequences of early life overfeeding for microglia - Perspectives from rodent models

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.