Fig. 1. A drawing of the upper brainstem and basal forebrain (BF), indicating the location of the arousal system, which includes the rapid eye movement (REM) sleep “flip-flop” switch in the pons, a key site at which γ-aminobutyric acid (GABA) is thought to influence wake–sleep states. GABAergic neurons in the mesopontine tegmentum ( red squares ) are REM-off neurons (which fire when the brain is not in an REM state). These neurons inhibit GABAergic REM-on neurons ( red squares ) at the rostral pontine level (which fire during REM sleep). The REM-on neurons in turn inhibit the REM-off population, and this mutual antagonism produces a flip-flop switch in which the two sides are mutually inhibitory. This results in rapid and complete transitions between states. Glutamatergic neurons ( green arrows ) are also found in the REM-on zone, and some of these send ascending outputs to the forebrain to cause electroencephalographic desynchronization seen in both arousal and REM sleep. Other glutamatergic neurons send axons to the lower brainstem, where they control eye movements and muscle tone. Orexin (ORX) neurons excite the REM-off neurons (thus preventing REM sleep). Ventrolateral preoptic (VLPO) neurons promote REM sleep by inhibiting the REM-off neurons. Injections of GABA agonists into the mesopontine tegmentum inhibited the REM-off neurons and caused REM sleep. However, injections of GABA agonists just 1 mm caudally in the rostral pontine tegmentum had the opposite effect.