Bidirectional modulation of sleep and wakefulness via prefrontal cortical chemogenetics

The drive to sleep is inescapable but its biological substrate remains largely elusive. Until recently, the search for sleep centres in the mammalian brain focussed on subcortical neurons that promote sleep or wakefulness, or induce state transitions. However, the regulatory elements of mammalian sleep circuitry, which govern the timing, amount and intensity of sleep, have proven difficult to elucidate. Growing evidence suggests an essential role for the cerebral cortex. Here we used a chemogenetic approach to test whether prefrontal cortex (PFC) layer 5 pyramidal neurons partake in the regulation of sleep. We found that inhibiting or exciting Rbp4-Cre neurons in the PFC with hM4Di/hM3Dq Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) increases and decreases sleep, respectively. Targeted PFC DREADD inhibition of Rbp4-Cre neurons induces sleep that electrophysiologically and architecturally resembles spontaneous sleep. In contrast, widespread cortical DREADD inhibition induces sleep that is punctuated by frequent brief awakenings, has suppressed rapid-eye-movement (REM) sleep, and is followed by a rebound in electroencephalogram (EEG) slow wave activity (SWA), typically observed after disrupted or lost sleep. Our work demonstrates that local modulation of cortical activity can bidirectionally change the amount of global sleep. This represents an important step in the dissection of sleep circuitry, aids the identification of molecular counterparts of sleep pressure, and accelerates the delineation of top-down sleep-regulatory pathways. Together, these lay the foundation for neurobiologically-informed sleep treatments, such as targeted non-invasive brain stimulation and cell-type specific pharmaceuticals, to better modulate sleep in humans.