James M. Krueger

Sleep as a fundamental property of neuronal assemblies

Sleep is vital to cognitive performance, productivity, health and well-being. Earlier theories of sleep presumed that it occurred at the level of the whole organism and that it was governed by central control mechanisms. However, evidence now indicates that sleep might be regulated at a more local level in the brain: it seems to be a fundamental property of neuronal networks and is dependent on prior activity in each network. Such local-network sleep might be initiated by metabolically driven changes in the production of sleep-regulatory substances. We discuss a mathematical model which illustrates that the sleep-like states of individual cortical columns can be synchronized through humoral and electrical connections, and that whole-organism sleep occurs as an emergent property of local-network interactions.

The Role of Cytokines in Physiological Sleep Regulation

Abstract: 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.

A neuronal group theory of sleep function

SUMMARY  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.

The Role of Cytokines in Sleep Regulation

Interleukin-1 beta (IL1) and tumor necrosis factor alpha (TNF) promote non-rapid eye movement sleep under physiological and inflammatory conditions. Additional cytokines are also likely involved but evidence is insufficient to conclude that they are sleep regulatory substances. Many of the symptoms induced by sleep loss, e.g. sleepiness, fatigue, poor cognition, enhanced sensitivity to pain, can be elicited by injection of exogenous IL1 or TNF. We propose that ATP, released during neurotransmission, acting via purine P2 receptors on glia releases IL1 and TNF. This mechanism may provide the means by which the brain keeps track of prior usage history. IL1 and TNF in turn act on neurons to change their intrinsic properties and thereby change input-output properties (i.e. state shift) of the local network involved. Direct evidence indicates that cortical columns oscillate between states, one of which shares properties with organism sleep. We conclude that sleep is a local use-dependent process influenced by cytokines and their effector molecules such as nitric oxide, prostaglandins and adenosine.

Inhibition of nitric oxide synthesis inhibits rat sleep.

Previous findings indicate that nitric oxide (NO) may play a role in the regulation of sleep-wake activity. In rabbits, blocking the production of endogenous NO by a nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NAME) suppresses spontaneous sleep and interferes the somnogenic actions of interleukin 1. In the present experiments we extended our earlier work by studying the long-term effects of L-NAME treatment on sleep-wake activity including power spectra analyses of the electroencephalogram (EEG) in rats. Rats implanted with EEG electrodes, brain thermistor, and intracerebroventricular (i.c.v.) guide cannula were injected i.c.v. with vehicle or 0.2, 1, or 5 mg L-NAME at light onset. In separate experiments, rats were injected intraperitoneally (i.p.) with L-NAME three times (50, 50, 100 mg/kg), 12-12 h apart. Both i.c.v. and i.p. injections of L-NAME elicited decreases in time spent in NREMS and REMS. After i.c.v. injection of 5 mg L-NAME the sleep responses were long-lasting; NREMS did not return to baseline even 72 h after injection. EEG delta-wave activity during NREMS (slow wave activity) was also suppressed after 0.2 and 5 mg L-NAME. Brain temperature was slightly increased after the two lower doses of L-NAME, whereas there was a transient decrease in Tbr after 5 mg L-NAME. Acute i.p. injection of 50 mg/kg L-NAME elicited an immediate decrease in NREMS which lasted for approximately 2 h. The second injection of 50 mg/kg L-NAME and the following injection of 100 mg/kg L-NAME induced biphasic decreases in NREMS but not REMS.

Humoral Links between Sleep and the Immune System

Abstract: In the last twenty years we have realized that the immune system synthesizes a class of peptides, termed cytokines, that play a central role in alerting the brain to ongoing inflammation in peripheral tissues. Among the brains responses to proinflammatory cytokines, or agents that induce these cytokines, are certain alterations in sleep profiles. Characteristically there is an increase in non‐rapid eye movement sleep (NREMS), and NREMS intensity is often accompanied by a decrease in rapid eye movement sleep (REMS). Cytokines appear to play a role in normal sleep regulation; during pathology, higher levels of cytokines amplify the physiological cytokine sleep mechanisms. In this review we summarize the extensive literature on the roles of interleukin‐1 (IL‐1) and tumor necrosis factor‐α (TNF‐α) in sleep regulation, and their interactions with the neuropeptides growth hormone‐releasing hormone (GHRH) and corticotropin‐releasing hormone (CRH). We reach the tentative conclusion that the sleep‐promoting actions of IL‐1 and GHRH are mediated via anterior hypothalamic neurons that are receptive to these substances. It also seems likely that TNF‐α and CRH also influence these neurons. In addition, we discuss an array of research issues raised by these studies that remain to be resolved.

Sleep as a prognostic indicator during infectious disease in rabbits

Abstract Infectious disease alters sleep patterns in rabbits, but the recuperative value of enhanced sleep during infectious disease has not been experimentally verified. To evaluate the relationship between specific sleep patterns and the clinical response to infectious disease, we classified sleep patterns in rabbits inoculated with E. coli, S. aureus, or C. albicans on the basis of the duration of the period of enhanced sleep. Patterns characterized by a long period of enhanced sleep were associated with a more favorable prognosis and less severe clinical signs than were patterns characterized by relatively short periods of enhanced sleep followed by prolonged sleep suppression. A contrasting analysis of these data indicated that animals that eventually died demonstrated reduced sleep compared to rabbits that survived the infection. These observations are consistent with the hypothesis that dynamic changes in sleep over the course of an infectious disease aid in recuperation.

Effects of interleukin-1β on sleep are mediated by the type I receptor

Interleukin-1β (IL-1β) is a well characterized sleep regulatory substance. To study receptor mechanisms for the sleep-promoting effects of IL-1β, sleep patterns were determined in control and IL-1 type I receptor knockout (IL-1RI KO) mice with a B6x129 background after intraperitoneal injections of saline or murine recombinant IL-1β. The IL-1RI KO mice had slightly but significantly less sleep during the dark period compared with the controls. IL-1β dose dependently increased non-rapid eye movement sleep (NREMS) and suppressed rapid eye movement sleep (REMS) in the controls. The IL-1RI KO mice did not respond to IL-1β. In contrast, the IL-1RI KO mice increased NREMS and decreased REMS after administration of tumor necrosis factor-α (TNF-α), another well characterized sleep-promoting substance. These results 1) provide further evidence that IL-1β is involved in sleep regulation, 2) indicate that the effects of IL-1β on sleep are mediated by the type I receptor, and 3) suggest that TNF-α is capable of inducing sleep without the involvement of IL-1.

Brain organization and sleep function

A view of brain organization and sleep function is presented. Sleep is hypothesized to begin at the neuronal group level. Sleep results in the use and thus maintenance, of synapses that are insufficiently stimulated during wakefulness thereby serving to preserve a constancy of a synaptic superstructure. It is further hypothesized that sleep at the neuronal group level is regulated by the production of substances whose rate of production or catabolism is synaptic use-dependent. If sufficient number of neuronal groups are in a sleep state (also called disjunctive state) then the perception of sleepiness occurs. Coordination of neuronal group sleep results from humoral and neuronal projection systems previously linked to sleep regulation. The theory presented is unique in that it: (a) hypothesizes an organizational level at which sleep occurs; (b) hypothesizes that sleep is neuronal--use-dependent, not wakefulness-dependent; (c) hypothesizes that sleep first occurs in evolution when complex ganglia evolved; and (d) hypothesizes the both non-rapid eye movement sleep (NREMS) and REMS serve the same function of synaptic reorganization. The theory is consistent with past theories of sleep function, yet provides a fundamentally new paradigm for sleep research.

Diurnal variation of TNFα in the rat brain

TUMOR necrosis factor-α (TNFα) is thought to play a physiological role in the brain. These studies were performed to determine whether a diurnal rhythm of TNFα exist in the rat brain. Samples were collected from hippocampus, hypothalamus, cerebral cortex, cerebellum, pons and midbrain at light onset and at 6 h intervals thereafter over a day. A TNFα bioassay was used to measure TNFα in each area. TNFα was highest at light onset in the hypothalamus, hippocampus and cerebral cortex. Levels at light onset were about 10-fold greater than minimal night-time levels. Changes in TNFα activity in other brain areas were also evident, but smaller. These results support the hypothesis that TNFα has physiological roles in the brain.