Fig. 67. The
flip-flop switch
A model for reciprocal
interactions between sleep- and wake-promoting brain
regions, which produces a flip–flop switch. Inhibitory pathways are shown in red, and the excitatory pathways in green. The blue circle indicates neurons of the LDT and PPT; green boxes indicate aminergic nuclei; and the red box indicates the VLPO. Aminergic regions such as the TMN, LC and DR promote wakefulness by direct excitatory effects on the cortex and by inhibition of sleep-promoting neurons of the VLPO. During sleep, the VLPO inhibits amine-mediated arousal regions through GABAergic and galaninergic (GAL) projections. Most innervation of the TMN originates in the VLPO core, and input to the LC and DR predominantly comes from the extended eVLPO. This inhibition of the amine-mediated arousal system disinhibits VLPO neurons, further stabilizing the production of sleep. The PPT and LDT also contain REM-promoting cholinergic neurons. The extended VLPO (eVLPO) might promote REM sleep by disinhibiting the PPT–LDT; its axons innervate interneurons within the PPT–LDT, as well as aminergic neurons that normally inhibit REM-promoting cells in the PPT–LDT. Orexin/hypocretin neurons (ORX) in the lateral hypothalamic area might further stabilize behavioral state by increasing the activity of aminergic neurons, thus maintaining consistent inhibition of sleep-promoting neurons in the VLPO and REM-promoting neurons in the PPT–LDT (Saper et al., 2001).