Programming the brain and behaviour by early-life stress: a focus on neuroactive steroids.

Animal studies have amply demonstrated that stress exposure during pregnancy or in early postnatal life can adversely influence brain development and have long-term 'programming' effects on future brain function and behaviour. Furthermore, a growing body of evidence from human studies supports the hypothesis that some psychiatric disorders may have developmental origins. Here, the focus is on three adverse consequences of early-life stress: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, heightened anxiety behaviour and cognitive impairments, with review of what is known about the underlying central mechanisms. Neuroactive steroids modulate neuronal activity and play a key role in neurodevelopment. Moreover they can negatively modulate activity of the HPA axis, exert anxiolytic actions and influence cognitive performance. Thus, neuroactive steroids may provide a link between early-life stress and the resultant adverse effects on the brain and behaviour. Here, a role for neuroactive steroids, in particular the 5α-reduced/3α-hydroxylated metabolites of progesterone, testosterone and deoxycorticosterone, is discussed in the context of early-life stress. Furthermore, the impact of early-life stress on the brain's capacity to generate neurosteroids is considered and the evidence for an ability of neuroactive steroids to over-write the negative effects of early-life stress on the brain and behaviour is examined. An enhanced understanding of the influence of early-life stress on brain neurosteroid systems could aid the identification of new targets for developing treatments for stress-related conditions in humans.