Hypothalamic-Pituitary-Adrenal Axis Abnormalities in Response to Deletion of 11β-HSD1 is Strain-Dependent

Inter-individual differences in hypothalamic-pituitary-adrenal (HPA) axis activity underlie differential vulnerability to neuropsychiatric and metabolic disorders, although the basis of this variation is poorly understood. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has previously been shown to influence HPA axis activity. 129/MF1 mice null for 11β-HSD1 (129/MF1 HSD1(−/−)) have greatly increased adrenal gland size and altered HPA activity, consistent with reduced glucocorticoid negative feedback. On this background, concentrations of plasma corticosterone and adrenocorticotrophic hormone (ACTH) were elevated in unstressed mice, and showed a delayed return to baseline after stress in HSD1-null mice with reduced sensitivity to exogenous glucocorticoid feedback compared to same-background genetic controls. In the present study, we report that the genetic background can dramatically alter this pattern. By contrast to HSD1(−/−) mice on a 129/MF1 background, HSD1(−/−) mice congenic on a C57Bl/6J background have normal basal plasma corticosterone and ACTH concentrations and exhibit normal return to baseline of plasma corticosterone and ACTH concentrations after stress. Furthermore, in contrast to 129/MF1 HSD1(−/−) mice, C57Bl/6J HSD1(−/−) mice have increased glucocorticoid receptor expression in areas of the brain involved in glucocorticoid negative feedback (hippocampus and paraventricular nucleus), suggesting this may be a compensatory response to normalise feedback control of the HPA axis. In support of this hypothesis, C57Bl/6J HSD1(−/−) mice show increased sensitivity to dexamethasone-mediated suppression of peak corticosterone. Thus, although 11β-HSD1 appears to contribute to regulation of the HPA axis, the genetic background is crucial in governing the response to (and hence the consequences of) its loss. Similar variations in plasticity may underpin inter-individual differences in vulnerability to disorders associated with HPA axis dysregulation. They also indicate that 11β-HSD1 inhibition does not inevitably activate the HPA axis.