Hypocortisolism and impaired stress responses in Bmal1-deficient mice

The transcription factor BMAL1 is at the core of the molecular clockwork, which coordinates circadian periodicity of physiology and behavior in mammals. Basal production of stress hormones, glucocorticoids (GCs), is also under control of central and peripheral circadian clocks, e.g. in hypothalamic neurons and adrenocortical cells. Daily rhythms of GC synthesis are ablated in mice lacking Bmal1, but little is known about the contribution of the circadian clock to the regulation of stress responses. We found that already under unstressed conditions Bmal1-deficient mice suffer from hypocortisolism with impaired adrenal responsiveness to adrenocorticotropin (ACTH) and down-regulated transcription of genes involved in cholesterol transport in the adrenal gland. Under stress they show diminished GC and behavioral responses and develop behavioral resistance to acute and sub-chronic stressors, as shown using forced swim, tail suspension and sucrose preference tests. These data suggest that the clock gene Bmal1 regulates circadian and acute secretion of GCs by the adrenal gland. Bmal1 disruption – probably via its effect on adrenal clock function – modulates stress axis activity and, thus, may promote resistance to both acute and repeated stress.