The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals; a functional anatomical analysis

Cytokines act on the brain to induce fever and behavioural depression after infection. Although several mechanisms of cytokine-to-brain communication have been proposed, their physiological significance is unclear. We propose that behavioural depression is mediated by the vagus nerve activating limb ic structures, while fever would primarily be due to humoral mechanisms aff ecting the preoptic area, including interleukin-6 (IL-6) action on the orga num vasculosum of the laminae terminalis (OVLT) and induction of prostaglan dins. This study assessed the effects of subdiaphragmatic vagotomy in rats on fever, behavioural depression, as measured by the social interaction tes t, and Fos expression in the brain. These responses were compared with indu ction of the prostaglandin-producing enzyme cyclooxygenase-2 and the transc ription factor Stat3 that translocates after binding of IL-6, Vagotomy bloc ked behavioural depression after intraperitoneal injection of recombinant r at IL-1 beta (25 mug/kg) or lipopolysaccharide (250 mug/kg; LPS) and preven ted Fos expression in limbic structures and ventromedial preoptic area, but not in the OVLT. Fever was not affected by vagotomy, but associated with t ranslocation of Stat3 in the OVLT and cyclooxygenase-2 induction around blo od vessels. These results indicate that the recently proposed vagal link be tween the immune system and the brain activates limbic structures to induce behavioural depression after abdominal inflammation. Although the vagus mi ght play a role in fever in response to low doses of LPS by activating the ventromedial preoptic area, it is likely to be overridden during more sever e infection by action of circulating IL-6 on the OVLT or prostaglandins ind uced along blood vessels of the preoptic area.