Epigenetic Programming of Sustained AVP Expression by Early-Life Stress in Mice

The quality of early life represents a critical vulnerable period during which exposure to stress can bias the development towards increased risk for anxiety and depression. This so-called 'environmental programming', seems to occur through changes in the neuronal circuits controlling hypothalamic-pituitary-adrenal (HPA) activity, or additionally, through changes in key elements of the HPA axis itself. While the HPA axis, in response to stressors, is driven by the release of corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus, animal models suggest that in chronic stress AVP plays a more major role. Indeed, our studies revealed that maternal separation (MS) in neonatal mice, led to a sustained AVP mRNA increase which corresponded with long-lasting hyperactivity of the HPA axis. Interestingly, AVP expression inversely correlated with the methylation of CpG dinucleotides in the gene locus and furthermore, those animals subjected to MS revealed significantly lower levels of methylation than controls. Reporter gene studies confirmed that methylation in the AVP locus regulates expression. This led us to conclude that persistent AVP expression is co-opted by early-life environmental programming to pave adult stress responsiveness.