“
“The influential

two-process model of sleep regulation posits that sleep pressure (i.e., the internal drive to sleep) is regulated by the interaction of circadian and homeostatic processes (Borbély, 1982). In this model, the circadian process synchronizes sleep drive to the 24 hr day-night cycle, while the homeostatic process steadily builds sleep pressure in response to wakefulness, then dissipates this pressure during sleep. Normally working in concert, the homeostatic process can be decoupled from the circadian process by sleep deprivation; as wakefulness is extended beyond normal physiological amounts, sleep pressure will also continue to build until it is homeostatically “reset” by subsequent rebound sleep. Although the mechanisms for coupling the circadian process to downstream sleep output remain murky, work in Drosophila and rodents over the past 40 years has painted a detailed picture this website of both the core molecular machinery (e.g., interlocking feedback loops among circadian clock proteins) as well as the critical pacemaker neurons (e.g., lateral

neurons in Drosophila, Tofacitinib datasheet the suprachiasmatic nucleus in mammals). Meanwhile, the homeostatic regulation of sleep is still shrouded in mystery. What aspects of prolonged waking drive sleep need? What are the molecular substrates by which this signal is transmitted? Where in the brain do these signals work to drive changes in sleep behavior? Some progress see more has been made in identifying critical sleep-wake circuits. In the mammalian hypothalamus, sleep-active GABAergic neurons

of the ventrolateral preoptic area (VLPO) form reciprocal inhibitory connections with a diverse set of wake-promoting neurons, known as the ascending arousal system (Saper et al., 2010). These circuits are considered critical drivers of sleep and wake, as ablation of the VLPO in rodents leads to insomnia, while pharmacological or optogenetic activation of components of the ascending arousal system promote waking (Rihel and Schier, 2013). An analogous sleep-wake circuit has recently been discovered in Drosophila. When directly activated by temperature-sensitive Trp channels, a set of neurons that project to the dorsal fan-shaped body (FB) induce sleep ( Donlea et al., 2011). These neurons are directly connected to and inhibited by wake-promoting, FB-projecting dopaminergic neurons via the dopamine receptor DopR. Curiously, both the mammalian VLPO and the Drosophila FB sleep neurons are sensitive to the anesthetic isoflurane, and, at least in flies, this sensitivity is increased with sleep deprivation ( Rihel and Schier, 2013). Given the central role that these neurons play as drivers of sleep/wake behavior, a natural hypothesis is that they will ultimately be sensitive, directly or indirectly, to the signal(s) of homeostatic sleep pressure.