The role of disturbed circadian clocks in the development of depression-like behavior and metabolic comorbidity in mice

Major depressive disorder (MDD) is often associated with disturbed circadian rhythms. However, a definitive causal role for functioning circadian clocks in mood regulation has not been established. We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN). In these SCN-specific Bmal1 -knockdown (SCN- Bmal1 -KD) mice, circadian rhythms were greatly attenuated in the SCN. In the learned helplessness paradigm, the SCN- Bmal1 -KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN- Bmal1 -KD mice also showed an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Furthermore, they displayed greater weight gain, which is frequently observed in MDD patients. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In fact, circadian rhythm disturbances have been linked to individual psychiatric and metabolic disorders, but circadian aspects of such disorders have not been considered previously in an integrated manner. Treating and preventing disturbances of circadian clocks in patients suffering psychiatric and metabolic symptoms may be a central element for therapies targeting both disorders concurrently.