The role of hepatic and splenic macrophages in E. coli-induced memory impairments in aged rats

Abstract

Bi-directional communication between the peripheral and central nervous systems has been extensively demonstrated. Aged rats exhibit a prolonged proinflammatory response in the hippocampus region of the brain following a peripheral bacterial infection, and this response in turn causes robust memory declines. Here we aimed to determine whether hepatic or splenic macrophages play a role in the maintenance of this central response. Proinflammatory cytokines measured in liver and spleen four days following an Escherichia coli infection revealed a potentiated proinflammatory response in liver, and to a lesser extent in spleen, in aged relative to young rats. To determine whether this potentiated response was caused by impaired bacterial clearance in these organs, E. coli colony forming units in liver and spleen were measured 4 days after infection, and there were no difference between young and aged rats in either organ. No E. coli was detected in the hippocampus, eliminating the possibility that the aged blood brain barrier allowed E. coli to enter the brain. Depletion of hepatic and splenic macrophages with clodronate-encapsulated liposomes effectively eliminated the proinflammatory response to E. coli at four days in both organs. However, this treatment failed to reduce the proinflammatory response in the hippocampus. Moreover, depletion of peripheral macrophages from liver and spleen did not prevent E. coli-induced memory impairment. These data strongly suggest that hepatic and splenic macrophages do not play a major role in the long-lasting maintenance of the proinflammatory response in the hippocampus of aged rats following a bacterial infection, or the memory declines that this response produces.

Keywords: Aging; Clodronate liposomes; Cognitive decline; Contextual fear conditioning; Hippocampus; Macrophage depletion; Proinflammatory cytokines.