Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines
Sub-pyrogenic inflammation resulted in changes in a species-typical, untrained behavior (burrowing) that depends on the integrity of the hippocampus. Increased expression of cytokines was observed in the periphery and selected regions of the brain which coincided with changes in behavior. However, peripheral neutralization of LPS-induced pro-inflammatory cytokines IL-1?, IL-6 and TNF-? did not abrogate the LPS-induced behavioral changes nor affect CNS cytokine synthesis. In contrast, pretreatment of mice with indomethacin completely prevented LPS-induced behavior changes, without affecting cytokine levels. Taken together, these experiments suggest a key role for prostaglandins, rather than cytokines, in communicating to the brain.
Communication between systemic infection and inflammation and the brain is well known to occur and underpins the behavioral consequences of systemic infection and inflammatory diseases (sickness behavior). In previous studies, often using severe pyrogenic systemic challenges, a key role for the cytokines IL-1?, IL-6 and TNF-? has been suggested. The present study demonstrates that systemic, low grade inflammation impacts on the brain independently of peripheral cytokine production. We have shown that sub-pyrogenic inflammation induces marked changes in immune activation, such as leukocyte mobilization, macrophage and dendritic cell activation, and increased peripheral and central cytokine production, without causing overt signs of sickness but inducing anhedonia. To our knowledge, the marked changes in cellular immune activation, especially dendritic cells, have not been addressed before in studies of sickness behavior. The effect of low dose LPS on burrowing could be reversed by pretreatment with a COX inhibitor (indomethacin), indicating a pivotal role of prostaglandins. Interestingly, indomethacin did not affect the LPS-induced peripheral or central cytokine production. Most previous studies on the biological mechanisms underlying sickness behavior have been performed under conditions using higher doses of LPS than those used here. We believe that the model described in the present paper could be particular relevant to humans, who more commonly experience sub-pyrogenic infections or inflammation, rather than septic shock.