Epigenetic processes during early brain development can function as ‘developmental
switches’ that contribute to the stability of long-term effects of early environmental influences by programming
central feedback mechanisms of the HPA axis and other neural networks. In this thematic
review, we summarize accumulated evidence for a dual-activation of stress-related and sensory networks
underlying the epigenetic programming effects of early life stress. We discuss findings indicating
epigenetic programming of stress-related genes with impact on HPA axis function, the interaction
of epigenetic mechanisms with neural activity in stress-related neural networks, epigenetic effects of
glucocorticoid exposure, and the impact of stress on sensory development. Based on these findings,
we propose that the combined activation of stress-related neural networks and stressor-specific sensory
networks leads to both neural and hormonal priming of the epigenetic machinery, which sensitizes
these networks for developmental programming effects. This allows stressor-specific adaptations
later in life, but may also lead to functional mal-adaptations, depending on timing and intensity of the
stressor. Finally, we discuss methodological and clinical implications of the dual-activation hypothesis.
We emphasize that, in addition to modifications in stress-related networks, we need to account for
functional modifications in sensory networks and their epigenetic underpinnings to elucidate the longterm
effects of early life stress.