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.

Fig. 1

Interleukin-1 beta enhances NREMS in mice. IL1β (400 ng) was i.p.-injected at dark (shaded area) onset (time 0) and sleep was recorded for the next 24 h. Duration of NREMS was much greater after IL1β (open circles) than that observed during the control recordings (closed circles) for about 6 h. REMS (triangles) was slightly inhibited by IL1β (open triangles). Data from Krueger et al. (submitted for publication). Similar effects are observed after i.p. TNFα (Fang et al., 1997).

Fig. 2

Biochemical cascades operate within local networks to alter state. Within any one network, ATP is released in proportion to cell activity. ATP via its P2 receptors drives processing and release of cytokines that in turn induce their own production and thereby create a positive feedback loop useful for amplification. Damping mechanisms are needed for control and are involved in driving oscillations between states. Cytokines activate transcription factors such as nuclear factor kappa B (NFκB) and activator protein-1 (AP-1). These in turn enhance production of multiple substances including the enzymes involved in the production of sleep effector molecules such as adenosine, prostaglandins, and nitric oxide (NO). The sleep state feeds back to alter the activity-dependent initiation events. It is envisioned that multiple local networks are undergoing this process and they synchronize state with each other via the known sleep regulatory circuits. They also influence each other depending upon proximity (diffusion of ATP) and neural connections to each other (Roy et al., 2008). Abbreviations not given elsewhere in this review. CRH, corticotrophin releasing hormone; sTNFR, soluble TNFα receptor; IL1RA, interleukin-1 receptor antagonist; NOS, nitric oxide synthase; COX, cyclooxygenase; CD73, cluster density 73; AMPA, a glutamate receptor; A1a, adenosine 1a receptor; gabaR, gamma-aminobutyric acid receptor.

Fig. 3

Both the P2Y1 and the P2X7 receptor mRNAs vary with the light dark cycle in the rat somatosensory cortex. Highest levels occur during daylight hours when sleep propensity is high. Sleep deprivation also enhances P2X7 and P2Y1 mRNA levels in brain. These receptors bind ATP and are associated with TNFα release and IL1β processing. Data derived in part from Krueger et al. (submitted for publication). Data are double plotted. * indicates p < 0.05.