The mPFC molecular clock mediates the effects of sleep deprivation on depression-like behavior and regulates sleep consolidation and homeostasis
Molecular Psychiatry March 1, 2026 Wilf Gardner, David H. Sarrazin, Martin Balzinger et al.
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.