Interleukin 1β enhances non-rapid eye movement sleep and increases c-Fos protein expression in the median preoptic nucleus of the hypothalamus

Abstract

Interleukin 1beta (IL-1) is a key mediator of the acute phase response in an infected host and acts centrally to coordinate responses to an immune challenge, such as fever and increased non-rapid eye movement (NREM) sleep. The preoptic area (POA) is a primary sleep regulatory center in the brain: the ventrolateral POA (VLPO) and median preoptic nucleus (MnPN) each contain high numbers of c-Fos protein immunoreactive (IR) neurons after sleep but not after waking. We hypothesized that IL-1 mediates increased NREM sleep through activation of these sleep-active sites. Rats injected intracerebroventricularly with IL-1 (10 ng) at dark onset spent significantly more time in NREM sleep 4-5 h after injection. This increase in NREM sleep was associated with increased numbers of Fos-IR neurons in the MnPN, but not in the VLPO. Fos IR in the rostral MnPN was significantly increased 2 h post IL-1 injection, although the percentage of NREM sleep in the preceding 2 h was the same as controls. Fos IR was also increased in the extended VLPO 2 h postinjection. Finally, Fos IR in the MnPN did not differ significantly between IL-1 and vehicle-treated rats that had been sleep deprived for 2 h postinjection, but it was increased in VLPO core. Taken together, these results suggest that Fos IR in the MnPN after IL-1 is not independent of behavioral state and may require some threshold amount of sleep for its expression. Our results support a hypothesis that IL-1 enhances NREM sleep, in part, through activation of neurons in the MnPN of the hypothalamus.

Effects of i.c.v. administration of interleukin-1 on sleep and body temperature of interleukin-6-deficient mice

“…In rats however, there appears to be a difference in time course and magnitude of responses to IL-1 depending on the species-specificity of the IL-1 injected. Rat recombinant IL-1β injected ICV into rats (Baker et al, 2005) increases NREM sleep and induces fever with a slower time course than does huIL-1β Opp and Imeri, 2001). To our knowledge, studies have not been conducted that directly compare effects of huIL-1β vs. muIL-1β on sleep or thermoregulation of mice.…”

“…These data suggest that IL-6 is not an essential mediator of IL-1-induced alterations in NREM sleep. There are numerous mechanisms by which IL-1 can increase NREM sleep, including direct actions on sleep-active neurons of the preoptic area of the hypothalamus (Alam et al, 2004;Baker et al, 2005) and on arousal-promoting serotonergic neurons of the dorsal raphe (Brambilla et al, 2007). Endogenous IL-6 exerts negative feedback control on TNF, and IL-6 KO mice exhibit an approximately threefold higher increase in serum TNF after immune challenge with LPS than do control mice (Fattori et al, 1994;Kozak et al, 1998).…”

Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity

“…IL-1 inhibits discharge rates of serotonergic (Manfridi et al, 2003;Brambilla et al, 2007) and cholinergic (Brambilla et al, 2010) neurons in brainstem. Within the hypothalamus, IL-1 increases c-Fos (Baker et al, 2005) and inhibits wake-active neurons (Alam et al, 2004). TNF promotes sleep if microinjected into the anterior hypothalamus, whereas injection of a soluble TNF receptor into this area reduces sleep (Kubota et al, 2002).…”

Homeostatic Regulation of Sleep: A Role for Preoptic Area Neurons

“…Infusion of A 2A receptor agonists adjacent to the vlPOA (Methippara et al, 2005) and into the ventral striatum immediately rostral to the MnPN (Satoh et al, 2006) promote sleep. The cytokine interleukin-1␤ (IL-1␤) has also been implicated as a homeostatic sleep factor (Obal and Krueger, 2003), and ICV administration of IL-1␤ promotes sleep and activates Fos-IR in MnPN neurons (Baker et al, 2005).…”