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The Journal of Neuroscience, October 18, 2006, 26(42):10709-10716; doi:10.1523/JNEUROSCI.3376-06.2006

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Behavioral/Systems/Cognitive
Interleukin-6 Facilitates Lipopolysaccharide-Induced Disruption in Working Memory and Expression of Other Proinflammatory Cytokines in Hippocampal Neuronal Cell Layers

Nathan L. Sparkman,¹ Jessica B. Buchanan,^1,2 Jonathan R. R. Heyen,¹ Jing Chen,¹ James L. Beverly,^1,2 and Rodney W. Johnson^1,2

¹Laboratory of Integrative Immunology and Behavior, Department of Animal Sciences, and ²Division of Nutritional Sciences, University of Illinois, Urbana, Illinois 61801

Correspondence should be addressed to Rodney W. Johnson, Laboratory of Integrative Immunology and Behavior, Department of Animal Sciences, University of Illinois Urbana-Champaign, 1207 West Gregory Drive, Urbana, IL 61801. Email: rwjohn{at}uiuc.edu

Proinflammatory cytokines inhibit learning and memory but the significance of interleukin-6 (IL-6) in acute cognitive deficits induced by the peripheral innate immune system is not known. To examine the functional role of IL-6 in hippocampus-mediated cognitive impairments associated with peripheral infections, C57BL6/J (IL-6^+/+) and IL-6 knock-out (IL-6^–/–) mice were trained in a matching-to-place version of the water maze. After an acquisition phase, IL-6^+/+ mice injected intraperitoneally with lipopolysaccharide (LPS) exhibited deficits in working memory. However, IL-6^–/– mice were refractory to the LPS-induced impairment in working memory. To determine the mechanism by which IL-6 deficiency conferred protection from disruption in working memory, plasma IL-1 and tumor necrosis factor (TNF), c-Fos immunoreactivity in the nucleus of the solitary tract (NTS), and steady-state levels of IL-1 and TNF mRNA in neuronal layers of the hippocampus were determined in IL-6^+/+ and IL-6^–/– mice after injection of LPS. Plasma IL-1 and TNF and c-Fos immunoreactivity in the NTS were increased similarly in IL-6^+/+ and IL-6^–/– mice after LPS, indicating high circulating levels of IL-1 and TNF and activation of vagal afferent pathways were not sufficient to disrupt working memory in the absence of IL-6. However, the LPS-induced upregulation of IL-1 and TNF mRNA that was evident in hippocampal tissue of IL-6^+/+ mice was greatly attenuated or entirely absent in IL-6^–/– mice. Collectively, these data suggest that humoral and neural immune-to-brain communication pathways are intact in IL-6-deficient mice but that, in the absence of IL-6, the central cytokine compartment is hyporesponsive.

Key words: interleukin-6; lipopolysaccharide; cytokines; working memory; hippocampus; mice

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Received Jan. 9, 2006; revised Aug. 4, 2006; accepted Aug. 30, 2006.

Correspondence should be addressed to Rodney W. Johnson, Laboratory of Integrative Immunology and Behavior, Department of Animal Sciences, University of Illinois Urbana-Champaign, 1207 West Gregory Drive, Urbana, IL 61801. Email: rwjohn{at}uiuc.edu

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