Effect of fragmented maternal care on the development of the circadian system: implications for stress and metabolic regulation in the offspring

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Genetic and environmental factors early in life interact to shape normal and aberrant brain development, with major implications for health and disease. The major focus of my research program is to understand some of the mechanisms mediating the effects of early stress on brain development and long term physiological and behavioral outcomes. Using the limited bedding (LB) paradigm as a rodent model of early-life adversity, which produces fragmented maternal care, we identified multiple consequences on the activity of the stress axis and amygdala function in neonatal rats. What remains unclear is how the signal from fragmented maternal care can influence the development of neonatal physiology controlled by circadian oscillating systems in central and peripheral tissues. Our overall hypothesis is that the fragmented maternal care caused by limited bedding will disturb the establishment of rhythmic variations of clock genes in brain regions and peripheral tissues, leading to inappropriate regulation of key neuronal functions and the control of homeostatic systems, in particular those related to stress and metabolic regulation. Clock genes and the proteins they regulate are key elements of the central clock in the suprachiasmatic nucleus (SCN) as well as peripheral oscillators in the brain and periphery. The relationships established between central and peripheral oscillators are essential to control homeostasis and might be critical in development, to establish neuronal and organ responsiveness under specific challenges. Maternal rhythmicity imposed mainly through sequences of maternal care and feeding bouts is critical in the early establishment of the circadian rhythmicity in the pups. Indeed, we recently found that the circadian rhythm of Per2 expression in the SCN and liver was abolished in neonatal rats exposed to LB compared to control pups. Overall, this set of studies should help identify the circadian oscillators (CNS and periphery) that are most critically affected by early stress and fragmentation in maternal care, some of the potential effectors of long term vulnerability that are altered and the mechanisms that link early modifications in clock oscillations to adult physiological outcomes. These studies will provide many training opportunities for students with a diverse expertise in chronobiology as well as molecular, cellular and behavioral neuroscience.