Involvement of cytokines in slow wave sleep

Abstract

Cytokines such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL1β) play a role in sleep regulation in health and disease. TNFα or IL1β injection enhances non-rapid eye movement sleep. Inhibition of TNFα or IL1β reduces spontaneous sleep. Mice lacking TNFα or IL1β receptors sleep less. In normal humans and in multiple disease states, plasma levels of TNFα covary with EEG slow wave activity (SWA) and sleep propensity. Many of the symptoms induced by sleep loss, for example, sleepiness, fatigue, poor cognition, enhanced sensitivity to pain, are elicited by injection of exogenous TNFα or IL1β. IL1β or TNFα applied unilaterally to the surface of the cortex induces state-dependent enhancement of EEG SWA ipsilaterally, suggesting greater regional sleep intensity. Interventions such as unilateral somatosensory stimulation enhance localized sleep EEG SWA, blood flow, and somatosensory cortical expression of IL1β and TNFα. State oscillations occur within cortical columns. One such state shares properties with whole animal sleep in that it is dependent on prior cellular activity, shows homeostasis, and is induced by TNFα. Extracellular ATP released during neuro- and gliotransmission enhances cytokine release via purine type 2 receptors. An ATP agonist enhances sleep, while ATP antagonists inhibit sleep. Mice lacking the P2X7 receptor have attenuated sleep rebound responses after sleep loss. TNFα and IL1β alter neuron sensitivity by changing neuromodulator/neurotransmitter receptor expression, allowing the neuron to scale its activity to the presynaptic neurons. TNFα's role in synaptic scaling is well characterized. Because the sensitivity of the postsynaptic neuron is changed, the same input will result in a different network output signal and this is a state change. The top-down paradigm of sleep regulation requires intentional action from sleep/wake regulatory brain circuits to initiate whole-organism sleep. This raises unresolved questions as to how such purposeful action might itself be initiated. In the new paradigm, sleep is initiated within networks and local sleep is a direct consequence of prior local cell activity. Whole-organism sleep is a bottom-up, self-organizing, and emergent property of the collective states of networks throughout the brain.

Cytotoxic chemotherapy increases sleep and sleep fragmentation in non-tumor-bearing mice

“…There are several established mechanisms through which the peripheral immune system can influence the brain and subsequent behavior, including via the direct transport of cytokines into the brain or communication of immune status to the brain via the vagus nerve (Wilson et al, 2002;Kelley et al, 2003;Ahles and Saykin, 2007). Many proinflammatory cytokines increase sleep and lethargy following peripheral immune activation (Krueger et al, 2001(Krueger et al, , 2011Opp, 2005). Previous studies have demonstrated that mice receiving doxorubicin, cyclophosphamide, and 5-fluorouracil have increased central inflammation and display a 'fatigue' phenotype (reduced voluntary wheel running behavior) that progressively worsens with each chemotherapy treatment Smith et al, 2014).…”

Sleep fragmentation and sepsis differentially impact blood–brain barrier integrity and transport of tumor necrosis factor-α in aging

“…For example, TNF promotes non-rapid eye movement sleep (NREMS) after central or peripheral administration (Imeri and Opp, 2009; Kapas et al, 1992; Krueger et al, 2011; Zielinski et al, 2013), TNF mRNA and protein are highest during sleep (Bredow et al, 1997; Floyd and Krueger, 1997), and mice lacking the TNF p55 receptor spend less time NREMS (Feng et al, 1997). To reach its CNS receptors, blood-borne TNF must cross the blood–brain barrier (BBB) and it does so by a saturable transport system (Gutierrez et al, 1993).…”

Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome

“…Animal studies have demonstrated the existence of reliable brain-specific markers of sleep homeostasis, such as Homer1a (9, 37-40), but also extremely robust cytokine markers with known functional roles, such as IL-1 and TNF, which show increased levels in response to sleep loss (41,42). As expected, expression of HOMER1 in blood did not show a significant effect of sleep restriction and remained unchanged with time awake in both conditions of our study of the blood transcriptome.…”