Early-stress regulates resilience, vulnerability and experimental validity in laboratory rodents through mother–offspring hormonal transfer

The role of early-life stressors in the calibration of individual responses to future challenges has long been investigated in laboratory rodents. Specifically, countless studies show that exposure to early-life stres- sors – in the form of various periods of maternal separation, administration of exogenous corticosterone and variable feeding conditions – modulate the regulation of defensive responses (e.g. behavioral fear- fulness/anxiety and endocrine stress reactivity) in adulthood. Yet, the link between early-life stress and adult defensive responses is not linear. Specifically, while neonatal moderate stress is generally associated with adult subjects characterized by reduced stress reactivity, neonatal elevated stress is often reported to relate to opposite responses. Not only are these findings relevant to the understanding of individ- ual plasticity to contextual features, but also they can have direct implications in the development of rodent models of human disorders. Specifically, these studies demonstrate that the experimental indi- vidual responds to early environmental cues with the consequence of adjusting its adaptation to the future environment. If neglected, this aspect may have detrimental consequences in laboratory animal experimentation. For example, neonatal conditions increasing adult responses to moderate stress may result in experimental subjects showing abnormal hypothalamic-pituitary-adrenocortical (HPA) activa- tion to routine husbandry conditions, test environment and general laboratory procedures. The aim of the present review is threefold: (i) propose that neonatal circulating levels of corticosteroids may constitute a potential mediator connecting early and adult defensive systems; (ii) propose that the link between early and adult stress follows a U-shaped curve, with low levels down-regulating individual reactivity to external stressors and high levels exerting opposite effects; (iii) discuss the methodological implications of these considerations in the development of rodent models of human disorders.