Several growth factors (GFs) are implicated in sleep regulation. It is posited that these GFs are produced in response to neural activity and affect input‐output relationships within the neural circuits where they are produced, thereby inducing a local state shift. These GFs also influence synaptic efficacy. All the GFs currently identified as sleep regulatory substances are also implicated in synaptic plasticity. Among these substances, the most extensively studied for their role in sleep regulation are interleukin‐1β (IL‐1) and tumor necrosis factor a (TNF). Injection of IL‐1 or TNF enhances non‐rapid eye movement sleep (NREMS). Inhibition of either IL‐1 or TNF inhibits spontaneous sleep and the sleep rebound that occurs after sleep deprivation. Stimulation of the endogenous production of IL‐1 and TNF enhances NREMS. Brain levels of IL‐1 and TNF correlate with sleep propensity; for example, after sleep deprivation, their levels increase. IL‐1 and TNF are part of a complex biochemical cascade regulating sleep. Downstream events include nitric oxide, growth hormone releasing hormone, nerve growth factor, nuclear factor kappa B, and possibly adenosine and prostaglandins. Endogenous substances moderating the effects of IL‐1 and TNF include anti‐inflammatory cytokines such as IL‐4, IL‐10, and IL‐13. Clinical conditions altering IL‐1 or TNF activity are associated with changes in sleep, for example, infectious disease and sleep apnea. As our knowledge of the biochemical regulation of sleep progresses, our understanding of sleep function and of many clinical conditions will improve.

To determine the relationships among plasma ghrelin and leptin concentrations and hypothalamic ghrelin contents, and sleep, cortical brain temperature (Tcrt), and feeding, we determined these parameters in rats in three experimental conditions: in free-feeding rats with normal diurnal rhythms, in rats with feeding restricted to the 12-h light period (RF), and in rats subjected to 5-h of sleep deprivation (SD) at the beginning of the light cycle. Plasma ghrelin and leptin displayed diurnal rhythms with the ghrelin peak preceding and the leptin peak following the major daily feeding peak in hour 1 after dark onset. RF reversed the diurnal rhythm of these hormones and the rhythm of rapid-eye-movement sleep (REMS) and significantly altered the rhythm of Tcrt. In contrast, the duration and intensity of non-REMS (NREMS) were hardly responsive to RF. SD failed to change leptin concentrations, but it promptly stimulated plasma ghrelin and induced eating. SD elicited biphasic variations in the hypothalamic ghrelin contents. SD increased plasma corticosterone, but corticosterone did not seem to influence either leptin or ghrelin. The results suggest a strong relationship between feeding and the diurnal rhythm of leptin and that feeding also fundamentally modulates the diurnal rhythm of ghrelin. The variations in hypothalamic ghrelin contents might be associated with sleep-wake activity in rats, but, unlike the previous observations in humans, obvious links could not be detected between sleep and the diurnal rhythms of plasma concentrations of either ghrelin or leptin in the rat.

A new theory of sleep function is presented within the context of the neuronal group selection hypothesis, which emphasizes that neuronal groups compete for neurons via use-dependent synaptic formation and atrophy. It is hypothesized that sleep serves to stabilize these competitive processes by providing a pattern of stimulation that serves to maintain a synaptic infrastructure upon which wakefulness-driven synaptic changes are superimposed. Sleep is 'quantal' in nature in that sleep is a statistical property of a population of neuronal groups in different states. The theory unifies past theories of sleep function yet simultaneously provides a fundamental new paradigm for sleep research.

Rats received various doses of interleukin 1 (IL-1) (range, 0.5-25.0 ng) or pyrogen-free saline intracerebroventricularly during the rest (light) and the active (dark) cycles of the day, and sleep-wake activity and brain temperature were determined for 6 h. Low doses of IL-1 (0.5 ng at night, 2.5 ng during the day) increased both the duration of non-rapid-eye-movement sleep (NREMS) and electroencephalogram (EEG) slow-wave activity during NREMS episodes. Increasing doses of IL-1 had divergent effects on NREMS duration and EEG slow-wave activity, and the direction of the changes depended on the diurnal cycle. Thus NREMS duration was promoted at night and EEG slow-wave amplitudes during the day, whereas NREMS duration during the day and EEG slow-wave amplitudes at night were suppressed after higher doses of IL-1. High doses of IL-1 also induced decreases in rapid-eye-movement sleep during both phases of the day. Each dose of IL-1 that promoted NREMS also tended to increase brain temperature. These results demonstrate that IL-1 promotes NREMS in the rat. However, unlike previously reported findings in rabbits, the circadian rhythm of sleep regulation strongly interferes with the sleep-promoting activity of IL-1 in rats.

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