Several studies have attempted to determine to what extent the findings from model animals are transferable to humans. Examination of post-mortem brain tissue from healthy human subjects found that the human equivalent of the glucocorticoid receptor gene promoter (NR3C1 exon 1F promoter) is also unique to the individual ( Turner, Pelascini, Macedo, & Muller, 2008 ). A similar study examining newborns showed that methylation of the glucocorticoid receptor gene promoter maybe an early epigenetic marker of maternal mood and risk of increased hormonal responses to stress in infants 3 months of age ( Oberlander et al., 2008 ). Although further studies are required to examine the functional consequence of this DNA methylation, these findings are consistent with our studies in the neonate and adult offspring of low licking and grooming mothers that show increased DNA methylation of the promoter of the glucocorticoid receptor gene, decreased glucocorticoid receptor gene expression, and increased hormonal responses to stress ( Weaver et al., 2004 ). Examination of brain tissue from suicide victims found that the human glucocorticoid receptor gene promoter is also more methylated in the brains of individuals who had experienced maltreatment during childhood ( McGowan et al., 2009 ). These finding suggests that DNA methylation mediates the effects of early environment in both rodents and humans and points to the possibility of new therapeutic approaches stemming from translational epigenetic research. Indeed, similar processes at comparable epigenetic labile regions could explain why the adult offspring of high and low licking/grooming mothers exhibit widespread differences in hippocampal gene expression and cognitive function ( Weaver, Meaney, & Szyf, 2006 ).
As a manner of providing contextual and spatial data to an individual’s experiences, the hippocampus (associated primarily with episodic memory and contributing to executive functioning) can aid in decreasing activation of the amygdala [ 73 ], countering (based on experience) the primarily salience-based amygdala response. The amygdala, particularly in cases of hyperactivation when faced with stimuli which are sensed to be dangerous, can inhibit the hippocampus as well, blocking access to contextual memories which could allay fear-based responses. This is relevant, for instance, in posttraumatic stress disorder (PTSD), as the reexperiencing component heightens one’s reactivity, creating an inflexible and conditioned reaction to situations removed from the original traumatic event [ 74 ], with impaired access to hippocampal contextual input which could allow for a more informed and less reactive response. From an early developmental perspective, this becomes highly relevant given the infantile amnesia phenomenon, which has posited that early memories (prior to around age four years) [ 75 ] will be erased by subsequent ones within the hippocampal circuitry (though it has been recently suggested that there may be mnemonic traces which could be subsequently activated) [ 76 ]. Given the earlier and later consolidation of amygdala and hippocampal nuclei, respectively, an individual can attribute strongly positive or negative salience to environmental components but not have access to hippocampal function as a manner of creating some “perspective” on the situation. This may be internalized as a template and default response to situations which may be very difficult to modify based on later experience, particularly if subsequent environmental factors are adverse as opposed to nurturing. Certain conditions (., BPD, anxiety disorders, and MDD) which show preferential activation of the amygdala over the hippocampus may be characterized by all-or-none thinking, indicating a more crystallized conditioned response. The neural correlates of these conditions will be expanded upon later. Importantly, even when information is being integrated into the hippocampus, it may be distorted by the emotionally driven response informed by the amygdala, leading to faulty processing during information compression from the dentate gyrus to layer CA3 [ 77 ], both areas which have shown decreased volume in childhood abuse [ 78 ].