The neurons that normally produce orexin help sustain wakefulness by stimulating a variety of wakefulness-promoting neurons in the cortex, brainstem, and basal forebrain (Panel A). With loss of the orexin-producing neurons in people with narcolepsy, neurons in these target regions may fire less consistently, leading to sleepiness and lapses into sleep. These neurons also excite brainstem regions that suppress rapid-eye-movement (REM) sleep (Panel B). Strong positive emotions are thought to activate neurons in the medial prefrontal cortex that excite the orexin-producing neurons and the amygdala. With loss of the orexin neurons in narcolepsy, imbalance in this pathway inhibits brain regions that suppress REM sleep, thus permitting the activation of descending pathways that strongly inhibit motor neurons; the result is partial or complete cataplexy. Pathways shown in green are excitatory; those shown in red are inhibitory. Open circles indicate neuron-cell bodies, and dotted lines indicate reduced activity.
