oa Epigenetic Programming in Psychobiological Development: Evidence for the Dual-Activation Theory and a Mediating Role of Early Life Stress

The term epigenetics describes the study of relatively stable changes in gene expression which occur without changes of the DNA sequence. The three best described mechanisms are: 1, cytosine methylation at cytosine-guanine dinucleotides of the DNA; 2, histone modifications (such as acetylation, methylation, and phosphorylation); and 3, micro RNA interference. The interplay between DNA methylation, histone modifications and micro RNA interference functions as regulatory complex which allows to fine tune cell specific gene expression in cell differentiation and organ development, and which is sensible to environmental signals. More precisely, the sequence of histone deacetylation, histone methylation and DNA methylation has been discussed as ‘molecular switch’ which modifies long-term gene expression patterns and chromatin activity states. In neurons, this epigenetic switch is involved in the transformation of short-term into long-term memory and is propagated across brain areas via neural activity (‘systems heritability of epigenetic marks’, Sultan Day/David Sweatt). Other evidence indicates sensibility of epigenetic marks towards behavioral (maternal care), chemical (nutrients) and hormonal (stress hormones) influences.

In regard to psychobiological development, epidemiological and clinical data shows that early life stress affects later stress responsivity, emotion regulation and cognitive functions, as well as life-time vulnerability to psychopathology. Evidence indicates a multi-level relationship between early life stress, neural structure and function and mental and general health connected via the HPA axis and its feedback mechanisms over time. Associations between early life stress and changes in brain regions involved in stress regulation have been repeatedly reported, including a small hippocampus, reduced medial prefrontal cortical volume, reduced orbitofrontal cortical volume, and increased amygdala volume. Further alterations related to early life stress in humans include glucocorticoid resistance, increased levels of inflammation, increased central corticotropin-releasing hormone activity and decreased levels of oxytocin. These general observations in humans are supported by a more detailed picture derived from animal studies of early life stress. Research in rodents using a maternal stress and/or maternal separation paradigm showed consistently that pre- or postnatal stress results in elevated HPA axis activity as well as structural and functional changes of neural networks in brain regions involved in neuroendocrine control, vigilance and emotion regulation, and that these changes correspond with distinct and persistent physiological response types and behavioral patterns in the adult individual. In addition, the differences between stress responsivity and behavior following early life stress are associated with epigenetic differences. In the context of early life stress, epigenetic modifications represent a plausible pathway by which early experiences are integrated into the molecular regulation of adult hormonal responses and behavior. Life-time stability of epigenetic changes, stress response types and behavioral patterns together with the time-dependence of the induced changes – early in life – indicate an evolutionary and developmental function of the underlying mechanisms: It seems that during a critical period (developmental window) early in life the stress response undergoes adaptive changes regulated via epigenetic programming. Furthermore, the mechanisms involved in epigenetic programming of the HPA axis also seem to impact neural and mental development in general. Preliminary results from animal models indicate, that early life stress affects cognitive abilities such as spatio-visual learning and memory, and that these cognitive differences are associated with epigenetic differences such as different methylation patterns. This would indicate a broad and unspecific developmental impact of pre- and postnatal stress and corresponding epigenetic programming during critical periods of brain development.

Thus, epigenetic mechanisms seem to function as ‘developmental switch’, explaining the stability of long-term effects of early life stress by programming central feedback mechanisms of the HPA axis and other neural networks. The pathway very likely involves a ‘dual activation’ of the epigenetic machinery: First, acute HPA axis activity during critical periods of neurogenesis generally primes the epigenetic machinery in brain tissue for reprogramming effects via the release of glucocorticoids. Second, sensory induced activation of neural networks transforms the epigenetic regulatory system in target brain areas, so that stressor specific adaptive to maladaptive functional modifications are maintained.

The paper outlines the possible underlying molecular mechanisms of epigenetic programming in psychobiological development according to the dual-activitation theory and summarizes the accumulated evidence. The dual-activation theory specifies epigenetic programming in psychobiological development as the result of an interplay between HPA axis activity and neural activity following sensory stimulation in critical periods early in life. Implications for the treatment of stress dependent psychopathologies are discussed.