Ventromedial prefrontal cortex regulates depressive-like behavior and rapid eye movement sleep in the rat

Major depressive disorder (MDD) is a debilitating disease with symptoms like persistent depressed mood and sleep disturbances. The prefrontal cortex (PFC) has been implicated as an important structure in the neural circuitry of MDD, with pronounced abnormalities in blood flow and metabolic activity in PFC subregions, including the subgenual cingulate cortex (sgACC, or Brodmann area 25). In addition, deep brain stimulation in the sgACC has recently been shown to alleviate treatment-resistant depression. Depressed patients also show characteristic changes in sleep: insomnia, increased rapid-eye-movement (REM) sleep and shortened REM sleep latency. We hypothesized that sleep changes and depressive behavior may be a consequence of the abnormal PFC activity in MDD. The rat ventromedial PFC (vmPFC, prelimbic and infralimbic cortices) is considered to be the homolog of the human sgACC, so we examined the effect of excitotic lesions in the vmPFC on sleep-wake and depressive behavior. We also made lesions in the adjacent dorsal region (dmPFC) to compare the effect of this similar but distinct mPFC region. We found that both dmPFC and vmPFC lesions led to increased REM sleep, but only vmPFC-lesioned animals displayed increased sleep fragmentation, shortened REM latency and increased immobility in the forced swim test. Anatomic tracing suggests that the mPFC projects to the pontine REM-off neurons that interact with REM-on neurons in the dorsal pons. These results support our hypothesis that neuronal loss in the rat vmPFC resembles several characteristics of MDD and may be a critical area for modulating both mood and sleep.