Physiological ReviewTumor necrosis factor alpha in sleep regulation
Introduction
Sleep remains a fundamental scientific enigma. Although significant progress has been made in elucidating roles for sleep in cognition and brain health, the primary functions of sleep have not been firmly established. Moreover, the regulation of sleep and wake is complex and not fully understood, and newer questions have arisen regarding the role and need for local sleep within a specific brain region versus more generalized sleep states. We do, however, appreciate that sleep manifestations are systemic. Sleep affects almost every physiological function, e.g., body temperature, hormone secretions, and respiratory, cardiac, kidney, and immune functions. Sleep actions on the brain range from altering multiple pathologies to recovery from them, as well as performance, mentation, emotion, learning and memory, etc. At the same time, many physiological functions affect sleep, e.g., body temperature, hunger, sexual drive, development, respiration, etc. and extracellular signals involved in the regulation of these functions affect sleep [1]. This latter point is critical to appreciate, as these physiological effects are not accounted for within the two-process (homeostasis and circadian) regulation of sleep model [2]. Fig. 1 illustrates some of the known components of tumor necrosis factor alpha (TNF) regulation and TNF biological activities that are also linked to sleep. Although the biochemical network shown is incomplete, it and the more extensive network (not shown) are likely beyond the capacity of any individual's ability to fully understand the dynamic nuances of such networks. Further, how the components interact with other TNF-regulated processes to orchestrate sleep niche adaptation further challenges comprehension. Herein we focus on only one sleep regulatory substance, TNF. We do so in recognition that other molecules are also involved in sleep regulation, but focus on TNF to illustrate principles of physiological sleep regulation and function. The reader is referred to other reviews for broader treatments of sleep regulation, both biochemical [3], [4], [5], [6], ∗[7], [8], [9], neurobiological [10], [11], and glialogical [12], [13], [14], [15].
Section snippets
TNF biology
Within the brain, TNF has many functions including mediation of brain damage, e.g., cerebral ischemia [17], cerebral blood flow, neuro-protection, responses to infection, and synaptic scaling [18]. TNF is expressed by microglia, astrocytes, and neurons [19], [20], [21], [22]. The actions of TNF depend not only on the receptor type – either 55 kilo-Daltons (kD) or 75 kD – and adaptor proteins, but also on the context of the stimulus and the interaction with substances that modify TNF activity.
TNF in sleep regulation; animal studies
A sleep regulatory substance should be able to satisfy several basic criteria [50], [51], [52]. In animal studies, a sleep regulatory substance should enhance a sleep phenotype, such as duration of non-rapid eye movement sleep (NREMS). Inhibition or reduction of the substance should reduce the sleep phenotype. The levels of the purported sleep regulatory substance measured in the brain should correlate with the duration of sleep loss and sleep propensity. Additionally, the sleep regulatory
Linking TNF to human sleep
TNF blood levels correlate with EEG δ power during spontaneous sleep in humans [79]. During sleep in healthy young men, serum TNF levels decrease [80]; this finding is consistent with the reduction of brain TNF across the rat daytime sleep period [64]. After sleep deprivation in humans, circulating levels of the 55 kD soluble TNFR, but not the 75 kD soluble TNFR, increase [81], ∗[82]. The soluble 55 kD R is a component of normal cerebrospinal fluid [83]. The TNF system may play a role in normal
Etanercept (ETA)
ETA is a recombinant TNFR protein that binds TNF thereby reducing the effects of naturally present TNF [102]. It is not known if ETA can bind to the 26 kD trans-membrane form of TNF to reverse signal (see above), thus interpretation of clinical studies is speculative. Nevertheless, because TNF is a key inflammatory regulator, ETA is used to treat autoimmune diseases [103]. ETA was the first FDA approved medicine for rheumatoid arthritis and polyarticular-course juvenile rheumatoid arthritis
TNF sleep biology within the context of brain organization of sleep
Despite millions of human stroke cases and many animal brain lesion studies, if the subject survived, sleep always ensues. Although post-lesion sleep may not have normal structure with oscillations between NREMS and REMS and periodic awaking, sometimes duration of sleep recovers [141], [142], [143]. This strongly suggests that no specific circuit is required for sleep and that sleep has self-organizing properties in any viable brain tissue that remains after lesions. Further, several marine
Conclusion
There is ample evidence from animals and humans that TNF is involved in sleep regulation. TNF biology and TNF sleep mechanisms reveal much about sleep regulation, the minimal amount of tissue required for sleep, and sleep function. Local application of TNF to small circuits, such as cortical columns or to co-cultures of neurons and glia induces sleep-like states. The in vivo and in vitro sleep-like states suggest that sleep is a fundamental property of very small circuits. TNF is expressed in
Conflicts of interest
The authors do not have any conflicts of interest to disclose.
Acknowledgements
This work was supported by grants to JMK from The National Institutes of Health (USA), grant numbers NS025378, NS096250 and HD36520 and HL123331 to both JMK and SCV.
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Equal contributions by Rockstrom and Chen as first author.
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