Mechanisms underlying the transition from adaptation to pathology are poorly understood. Part of the problem in defining this progression lies in determining when responses meant to be adaptive “cross over” into the realm of maladaptation. For example, at what point does elevated glucocorticoid secretion start to take a toll on the brain and body? The answer likely lies at the level of the individual, and is dependent on numerous processes including hormone clearance, MR and GR expression levels, interactions of bound receptors with nuclear co-activators and co-repressors, genetic predispositions and epigenetic modifications of receptor targets. From a neural perspective, the progression from “adaptive” to “maladaptive” is likely dependent on the degree to which the brain engages physiological responses in an appropriate context. It is appropriate to mount a glucocorticoid response in response to an imminent threat; however, engaging the HPA axis chronically or in response to innocuous cues is not.
