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 post-natal 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 hypothalamo-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. 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.