Interleukin‐1β modulates state‐dependent discharge activity of preoptic area and basal forebrain neurons: role in sleep regulation

Abstract

Interleukin-1beta (IL-1) is a pro-inflammatory cytokine that has been implicated in the regulation of nonrapid eye movement (nonREM) sleep. IL-1, IL-1 receptors and the IL-1 receptor antagonist (ra) are present normally in discrete brain regions, including the preoptic area (POA) of the hypothalamus and the adjoining magnocellular basal forebrain (BF). The POA/BF have been implicated in the regulation of sleep-wakefulness. We hypothesized that IL-1 promotes nonREM sleep, in part by altering the state-dependent discharge activity of POA/BF neurons. We recorded the sleep-wake discharge profiles of 83 neurons in the lateral POA/BF and assessed the effects of IL-1, IL-1ra, and IL-ra + IL-1 delivered through a microdialysis probe on state-dependent neuronal discharge activity. IL-1 decreased the discharge rate of POA/BF neurons as a group (n = 55) but wake-related and sleep-related neurons responded differently. IL-1 significantly decreased the discharge rate of wake-related neurons. Of 24 wake-related neurons studied, 19 (79%) neurons exhibited a greater than 20% change in their discharge in the presence of IL-1 during waking. IL-1 suppressed the discharge activity of 18 of 19 responsive neurons. Of 13 sleep-related neurons studied, IL-1 increased the discharge activity of five and suppressed the discharge activity of four neurons. IL-1ra increased the discharge activity of four of nine neurons and significantly attenuated IL-1-induced effects on neuronal activity of POA/BF neurons (n = 19). These results suggest that the sleep-promoting effects of IL-1 may be mediated, in part, via the suppression of wake-related neurons and the activation of a subpopulation of sleep-related neurons in the POA/BF.

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

“…Mice lacking functional IL-1 type I receptors spend less time in NREM sleep than genetically intact mice Baracchi and Opp, 2008). IL-1 decreases discharge rates of wake-related neurons and increases the discharge rates of a subpopulation of sleep-related neurons in the preoptic area and basal forebrain (Alam et al, 2004), brain regions implicated in the regulation of NREM sleep. IL-1 microinjected into the dorsal raphe nucleus increases NREM sleep of rats, and in vitro IL-1 inhibits firing rates of dorsal raphe serotonergic neurons (Manfridi et al, 2003).…”

Cytokine mRNA induction by interleukin-1β or tumor necrosis factor α in vitro and in vivo

“…In contrast, inhibition of endogenous IL1β or TNFα, using antibodies or endogenous inhibitors such as their soluble receptors, decreases spontaneous NREMS (Opp and Krueger, 1994;Takahashi et al, 1995aTakahashi et al, -c, 1996. Administration of IL1β or TNFα into the anterior hypothalamus increases NREMS (Alam et al, 2004;Kubota et al, 2002;Terao et al 1998). IL1β increases the firing rate of a subpopulation of anterior hypothalamic, sleep-active neurons while it suppresses the firing rate in most of the wake-active neurons in this region (Alam et al, 2004).…”

“…Administration of IL1β or TNFα into the anterior hypothalamus increases NREMS (Alam et al, 2004;Kubota et al, 2002;Terao et al 1998). IL1β increases the firing rate of a subpopulation of anterior hypothalamic, sleep-active neurons while it suppresses the firing rate in most of the wake-active neurons in this region (Alam et al, 2004). Other cytokines, such as interleukin-6 and interleukin-10 ( Alberti et al, 2003;Hogan et al, 2003;Toth and Opp, 2001;Shearer et al, 2001;Smith et al, 1999) as well as NGF (Kapas et al, 1996) and BDNF , also affect sleep and interact with TNFα and IL1β.…”

Neurobiology of Arousal and Sleep: Updates and Insights Into Neurological Disorders

“…Expression of IL-1β and TNF-α is elevated in multiple brain regions in response to waking neuronal activity [77]. Cellular mechanisms of cytokine-mediated sleep generation are not completely understood but may involve a combination of arousal system inhibition and activation of preoptic sleep regulatory neurons [78][79][80][81].…”