Interleukin‐1β enhances non‐rapid eye movement sleep when microinjected into the dorsal raphe nucleus and inhibits serotonergic neuronsin vitro

Abstract

Interleukin-1 (IL-1) and IL-1 receptors are constitutively expressed in normal brain. IL-1 increases non-rapid eye movements (NREM) sleep in several animal species, an effect mediated in part by interactions with the serotonergic system. The site(s) in brain at which interactions between IL-1 and the serotonergic system increase NREM sleep remain to be identified. The dorsal raphe (DRN) is the origin of the major ascending serotonergic pathways to the forebrain, and it contains IL-1 receptors. This study examined the hypothesis that IL-1 increases NREM sleep by acting at the level of the DRN. IL-1beta (0.25 and 0.5 ng) was microinjected into the DRN of freely behaving rats and subsequent effects on sleep-wake activity were determined. IL-1beta 0.5 ng increased NREM sleep during the first 2 h post-injection from 33.5 +/- 3.7% after vehicle microinjection to 42.9 +/- 3.0% of recording time. To determine the effects of IL-1beta on electrophysiological properties of DRN serotonergic neurons, intracellular recordings were performed in a guinea-pig brain stem slice preparation. In 26 of 32 physiologically and pharmacologically identified serotonergic neurons, IL-1beta superfusion (25 ng/mL) decreased spontaneous firing rates by 50%, from 1.6 +/- 0.2 Hz (before IL-1beta superfusion) to 0.8 +/- 0.2 Hz. This effect was reversible upon washout. These results show that IL-1beta increases NREM sleep when administered directly into the DRN. Serotonin enhances wakefulness and these novel data also suggest that IL-1beta-induced enhancement of NREM sleep could be due in part to the inhibition of DRN serotonergic neurons.

The Proinflammatory Cytokines Interleukin-1beta and Tumor Necrosis Factor-Alpha Activate Serotonin Transporters

“…The reduced firing rate is associated with a hyperpolarization of the neurons that is rapidly reversed with washout of IL-1b. Consistent with this effect, when microinjected into the DRN in vivo, IL-1b induces sleep without rapid eye movements (Manfridi et al, 2003), early in the sleep cycle. Similarly, short-term exposure of hippocampal neurons to TNF-a (15-30 min) has been found to induce endocytosis of GABA-A receptors and increase trafficking of excitatory AMPA receptors to the plasma membrane (Stellwagen et al, 2005).…”

“…Brief in vivo exposure of orbitoprefrontal neurons to IL-1b is associated with either hyperpolarizing or depolarizing potentials in different neuronal populations (Lukáts et al, 2005). In guinea-pig brain slice preparations, IL-1b induces a rapid reduction in the firing rates of neurons in the serotonergic dorsal raphe nucleus (DRN; Manfridi et al, 2003), an area replete with IL receptors (Cunningham et al, 1992). The reduced firing rate is associated with a hyperpolarization of the neurons that is rapidly reversed with washout of IL-1b.…”

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

“…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). Collectively these and other data indicate a role for IL-1 in regulating spontaneous NREM sleep, in healthy animals not subjected to immune challenge [interested readers are referred to comprehensive reviews (Krueger et al, 2001; Opp and Toth, 2003;Opp, 2005)].…”

Biochemical Regulation of Sleep and Sleep Biomarkers

“…These include IL1, TNF and growth hormone releasing hormone (GHRH) for non-rapid eye move-Microinjection of TNF or IL1 into or near hypothalamic and other sleep regulatory circuits enhances NREMS. [26][27][28][29] In addition to increasing time spent sleeping, these cytokines after central injection can enhance electroencephalographic (EEG) δ power (a measure of sleep intensity) during NREMS. This effect is similar to that seen after sleep deprivation 30 suggesting that IL1 and TNF injection mimics the effect of sleep loss.…”