Cortical neuronal activity does not regulate sleep homeostasis

- Atropine induces a state of high-amplitude slow-wave EEG and movements.
- Atropine reduces c-Fos expression throughout the cortex but induces c-Fos expression in subcortical arousal systems.
- The atropine-induced state is followed by a sleep rebound.

The neural substrate of sleep homeostasis is unclear, but both cortical and subcortical structures are thought to be involved in sleep regulation. To test whether prior neuronal activity in the cortex or in subcortical regions drives sleep rebound, we systemically administered atropine (100 mg/kg) to rats, producing a dissociated state with slow-wave cortical electroencephalogram (EEG) but waking behavior (e.g. locomotion). Atropine injections during the light period produced 6 h of slow-wave cortical EEG but also subcortical arousal. Afterward, rats showed a significant increase in non-rapid eye movement (NREM) sleep, compared to the same period on a baseline day. Consistent with the behavioral and cortical EEG state produced by systemic atropine, c-Fos expression was low in the cortex but high in multiple subcortical arousal systems. These data suggest that subcortical arousal and behavior are sufficient to drive sleep homeostasis, while a sleep-like pattern of cortical activity is not sufficient to satisfy sleep homeostasis.