Journal
JOURNAL OF NEUROSCIENCE
Volume 26, Issue 42, Pages 10709-10716Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3376-06.2006
Keywords
interleukin-6; lipopolysaccharide; cytokines; working memory; hippocampus; mice
Categories
Funding
- NIA NIH HHS [R01 AG016710, AG023580, AG16710, R01 AG023580] Funding Source: Medline
- NIDDK NIH HHS [T32 DK059802, T32 DK59802] Funding Source: Medline
- NIMH NIH HHS [MH069148, R01 MH069148] Funding Source: Medline
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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 beta and tumor necrosis factor alpha(TNF alpha), c-Fos immunoreactivity in the nucleus of the solitary tract (NTS), and steady-state levels of IL-1 beta and TNF alpha mRNA in neuronal layers of the hippocampus were determined in IL-6(+/+) and IL-6(-/-) mice after injection of LPS. Plasma IL-1 beta and TNF alpha 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 beta and TNF alpha 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 beta and TNF alpha 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.
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