Control of arousal by the orexin neurons

Abstract

The orexin-producing neurons in the lateral hypothalamus play an essential role in promoting arousal and maintaining wakefulness. These neurons receive a broad variety of signals related to environmental, physiological and emotional stimuli; they project to almost every brain region involved in the regulation of wakefulness; and they fire most strongly during active wakefulness, high motor activation, and sustained attention. This review focuses on the specific neuronal pathways through which the orexin neurons promote wakefulness and maintain high level of arousal, and how recent studies using optogenetic and pharmacogenetic methods have demonstrated that the locus coeruleus, the tuberomammillary nucleus, and the basal forebrain are some of the key sites mediating the arousing actions of orexins.

Figure 1

Some of the key pathways through which the orexin neurons promote wakefulness. Orexin neurons innervate and excite monoaminergic brain regions such as the locus coeruleus, dorsal raphe, ventral tegmental area, and tubermomammillary nucleus. The orexin neurons also activate cortical neurons directly and indirectly via effects in the basal forebrain.

Figure 2

Orexin peptide null mice (orexin KO) have fragmented wakefulness and sleep. (a) Representative hypnograms from the first 6 hours of the active period show that WT mice have long periods of wake and consolidated periods of sleep, whereas orexin KO mice have frequent transitions between wake and sleep. Cataplexy occurs frequently in orexin KO mice. (b) Survival curve analysis shows that during the active period, about 90% of all wake bouts end within 60 s in both mutant and wild-type mice, presumably representing just brief awakenings from sleep. After being awake for 60 s, wild-type mice generally remain awake, though after about 1000 s of wake, transitions into sleep became increasingly frequent. In contrast, wake bouts in orexin null mice more frequently fail after 200 s. Hypnograms are courtesy of Dr. T. Mochizuki, and panel b is adapted with permission from Diniz Behn et al. [33].