Depression involves disrupted circadian rhythms, but the role of internal clocks in mood-regulating brain areas was unclear. In a mouse model of depression, the medial prefrontal cortex (mPFC) showed increased expression of circadian negative-loop genes and decreased positive-clock regulators, and the rapid antidepressant ketamine counteracted these changes. Removing the clock gene Bmal1 from excitatory neurons prevented both depression-like behavior and ketamine's effects. Silencing the clock gene Per2 in mPFC produced antidepressant-like effects, while activating REV-ERB worsened depression and blocked ketamine. Boosting the clock activator ROR had antidepressant-like effects, increasing plasticity-related proteins and synaptic receptors in mPFC. The mPFC molecular clock critically regulates depression-like behavior, and targeting it therapeutically may influence glutamatergic plasticity.
Disruptions in sleep, circadian rhythms, and neural plasticity are closely linked to depression. Using a mouse model of stress-induced depression, the authors found altered sleep architecture, impaired sleep homeostasis, and disrupted day-night oscillations of glutamatergic plasticity markers Homer1a and synaptic AMPAR expression in the medial prefrontal cortex (mPFC). Sleep deprivation (SD) and ketamine, both rapid-acting antidepressants, exerted opposing effects on mPFC circadian gene expression: SD enhanced negative clock loop genes (Per, Cry), while ketamine downregulated them. Targeted deletion of the core clock gene Bmal1 in mPFC excitatory neurons disrupted sleep-wake architecture and abolished the behavioral and molecular response to SD. Pharmacological activation of the clock repressor REV-ERB suppressed SD's antidepressant effects. The mPFC molecular clock is essential for sleep consolidation and homeostasis and mediates SD's behavioral effects.