As we have pointed out above, the adolescent period, in spite of its obvious importance as a period of increased susceptibility to a variety of stress-related mental disorders , has had little to no examination of the impact of stress on epigenetic marks in the brain. Nor has much attention been paid, as yet, to how stress-induced epigenetic changes at one life stage, such as infancy, might interact with stress, and susceptibility to stress in later life stages, such as adolescence or aging.

Much of the research to date on the neuroepigenetics of stress has logically focused on wellknown genes, for example, GR and BDNF. It is likely, however, that these are not the only genomic elements involved in the epigenetics of stress and anxiety. As an example, the mineralocorticoid receptor, which plays a significant role in HPA axis feedback and anxiety , has yet to be examined for epigenetic activity in the brain, although it has been associated with altered histone methylation in the kidney . The availability of cheaper and deeper next-generation sequencing technologies will be of great help in broadening the number of potential genomic elements examined to encompass more than the genes themselves to the other 95% of the genome, most of which may be actively transcribed , although their functions remain largely unexamined.

Conclusion While the interactions between external stressors, epigenetics and brain plasticity across the lifespan have only begun to be explored, it is readily apparent that this area of exploration is offering insights into how the environment produces persistent changes in the brain and behavior. Of greater interest from the translational perspective is the fact that many of these changes appear to be reversible via structured environmental interventions or pharmacologic means.

For basic discoveries about the epigenetics of stress and anxiety to leave the bench and be translated to the bedside, epigenetic pharmacology must advance substantially. While many histone deacetylase inhibitors have been approved for human use, drugs to inhibit or increase histone methylation are relatively few and far between, although some methyltransferase inhibitors are becoming available for research purposes [200,201]. As to the many other histone modifications or ncRNA, still less is known. A problem for the study of epigenetics in the brain is the transient nature of many of the phenomena coupled with the necessity for making ex vivo observations. As we have argued throughout, stress has significant effects on the epigenome, and thus attention to stress history, reducing the stress of sacrificing experimental animals and rapid tissue dissection are very important considerations. It is not evident that these concerns are always 11 Author Proof