First, direct recordings from neurons in the cell groups that constitute the model show that their behavior is very close to what the model would predict. Recordings from VLPO neurons in both rats and mice show a sharp increase in firing just before or at the transition from waking to NREM sleep and DAPT datasheet a sharp decrease in firing just before the transition from NREM or REM to waking (Szymusiak et al., 1998 and Takahashi et al., 2009). Individual VLPO neurons differ somewhat in their onset of firing relative to the onset of NREM sleep, presumably because the individual cells differ slightly in

their inputs and responses. A neural network model of these neurons permitted the 2000 neurons on each side of the switch to have independent behavior, and this arrangement demonstrated a similar variability in the onset of firing compared to the actual state transition (Chou, 2003). A key feature in both the modeled neuronal behavior and the actual recordings

was the bistable nature of the firing, with abrupt transitions between rapid and slow firing right around the actual state transitions. Another interesting aspect of this system is the time relationship between changes in VLPO neuron firing and cortical activity. The onset of firing began about 200 msec before the EEG synchronization and did not reach a peak until 300 msec after the transition, whereas the fall in firing occurred over about 200 msec beginning ABT-263 just before the loss of EEG synchronization (Takahashi et al., 2009). The neural network model (Chou, 2003) predicts this behavior, and suggests that it underlies the hysteresis in the response

of the brain to homeostatic sleep drive, as suggested by Borbély and Achermann (1999). Thus, the threshold at which homeostatic not drive triggers sleep is higher than the threshold at which falling homeostatic sleep drive terminates sleep. This property may arise from a key aspect of the mutually inhibitory sleep-wake circuitry: sleep-promoting VLPO neurons can only be activated during wakefulness by stimuli that overcome their inhibition by wake-promoting neurons, but during sleep, when VLPO neurons are not inhibited by wake-promoting neurons, they can be activated by relatively weak stimuli such as low levels of homeostatic sleep drive. The activity of LC and TMN neurons also anticipates state transitions (Figure 3). The firing of LC neurons slows many seconds before sleep onset and then gradually increases 1–2 s prior to wake onset (Aston-Jones and Bloom, 1981 and Takahashi et al., 2010). The firing of TMN neurons also slows about 1 s prior to EEG signs of NREM sleep, but, unlike the LC, TMN neurons only start to fire about 1 s after wakefulness is established (Takahashi et al., 2006).