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 limbic structures, while fever would primarily be due to humoral mechanisms affecting the preoptic area, including interleukin-6 (IL-6) action on the organum vasculosum of the laminae terminalis (OVLT) and induction of prostaglandins. This study assessed the effects of subdiaphragmatic vagotomy in rats on fever, behavioural depression, as measured by the social interaction test, and Fos expression in the brain. These responses were compared with induction of the prostaglandin-producing enzyme cyclooxygenase-2 and the transcription factor Stat3 that translocates after binding of IL-6. Vagotomy blocked behavioural depression after intraperitoneal injection of recombinant rat IL-1beta (25 microg/kg) or lipopolysaccharide (250 microg/kg; LPS) and prevented Fos expression in limbic structures and ventromedial preoptic area, but not in the OVLT. Fever was not affected by vagotomy, but associated with translocation of Stat3 in the OVLT and cyclooxygenase-2 induction around blood vessels. These results indicate that the recently proposed vagal link between the immune system and the brain activates limbic structures to induce behavioural depression after abdominal inflammation. Although the vagus might 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 severe infection by action of circulating IL-6 on the OVLT or prostaglandins induced along blood vessels of the preoptic area.
Konsman
J P
JP
INSERM U394, Neurobiologie Intégrative, Institut François Magendie, Rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France. jpkonsman@hotmail.com
Luheshi
G N
GN
Bluthé
R M
RM
Dantzer
R
R
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D051546:Cyclooxygenase 2; D004926:Escherichia coli; D005334:Fever / Q000503:physiopathology* / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D011301:Preoptic Area / Q000187:drug effects / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012919:Social Behavior; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology*
D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases