Vagotomy Attenuates Brain Cytokines and Sleep Induced by Peripherally Administered Tumor Necrosis Factor-alpha and Lipopolysaccharide in Mice

Study Objective: Systemic tumor necrosis factor-alpha (TNF-alpha) is linked to sleep and sleep altering pathologies in humans. Evidence from animals indicates that systemic and brain TNF-alpha have a role in regulating sleep. In animals, TNF-alpha or lipopolysaccharide (LPS) enhance brain pro-inflammatory cytokine expression and sleep after central or peripheral administration. Vagotomy blocks enhanced sleep induced by systemic TNF-alpha and LPS in rats, suggesting that vagal afferent stimulation by TNF-alpha enhances pro-inflammatory cytokines in sleep-related brain areas. However, the effects of systemic TNF-alpha on brain cytokine expression and mouse sleep remain unknown. Design: We investigated the role of vagal afferents on brain cytokines and sleep after systemically applied TNF-alpha or LPS in mice. Measurements and Results: Spontaneous sleep was similar in vagotomized and sham-operated controls. Vagotomy attenuated TNF-alpha- and LPS-enhanced non-rapid eye movement sleep (NREMS); these effects were more evident after lower doses of these substances. Vagotomy did not affect rapid eye movement sleep responses to these substances. NREMS electroencephalogram delta power (0.5-4 Hz range) was suppressed after peripheral TNF-alpha or LPS injections, although vagotomy did not affect these responses. Compared to sham-operated controls, vagotomy did not affect liver cytokines. However, vagotomy attenuated interleukin-1 beta (IL-1 beta) and TNF-alpha mRNA brain levels after TNF-alpha, but not after LPS, compared to the sham-operated controls. Conclusions: We conclude that vagal afferents mediate peripheral TNF-alpha-induced brain TNF-alpha and IL-1 beta mRNA expressions to affect sleep. We also conclude that vagal afferents alter sleep induced by peripheral pro-inflammatory stimuli in mice similar to those occurring in other species.