Neural embedding of stress reactivity

Abstract

A report in this issue of Nature Neuroscience demonstrates that stress in infancy leading to altered cortisol levels in childhood culminates in vulnerability to dysregulated affect in adolescent girls by biasing the functional dynamics of core neural regions mediating the generation and regulation of emotional responsiveness.

Figure 1

Biological pathways linking early life stress to later psychopathology. (a) In girls but not boys, a history of maternal stress during infancy predicts heightened basal afternoon cortisol during childhood, which predicts reduced resting- state amygdala-vmPFC functional connectivity during adolescence. Variability in this functional connectivity, in turn, mediates the association between childhood cortisol and adolescent symptoms of anxiety and depression. (b) Plausible epigenetic mechanisms contributing to links between early life stress, amygdala-vmPFC connectivity and symptoms of depression and anxiety. The glucocorticoid receptor (GR) is critical for negative feedback of the HPA axis, and increased promoter methylation (red ovals) of the GR gene (NR3C1), which results in decreased gene expression, is associated with childhood adversity. Hence epigenetic regulation of the GR may result in impaired negative feedback of the HPA axis that is gender independent. In contrast, childhood adversity may contribute to gender- dependent promoter demethylation (gray ovals) of the estrogen receptor-α (ERα) gene (ESR1), which results in increased gene expression and, possibly, anxiogenic changes in corticolimbic circuit function. It is further possible that epigenetic regulation of the GR can contribute to these gender-dependent effects through downstream regulation of ESR1 transcription (dashed lines). In the absence of early adversity, stress-related GR activation may result in downregulation of ERα, which is associated with anxiogenic effects. In contrast, the methylation and subsequent downregulation of GR following early adversity leads to increased ERα expression and anxiogenic effects, possibly through alterations of functional connectivity between the amygdala and vmPFC.