RESUMO
Neuroinflammatory conditions such as traumatic brain injury, aging, Alzheimer's disease, and Down syndrome are often associated with cognitive dysfunction. Much research has targeted inflammation as a causative mediator of these deficits, although the diverse cellular and molecular changes that accompany these disorders obscure the link between inflammation and impaired memory. Therefore, we used a transgenic mouse model with a dormant human IL-1beta excisional activation transgene to direct overexpression of IL-1beta with temporal and regional control. Two weeks of hippocampal IL-1beta overexpression impaired long-term contextual and spatial memory in both male and female mice, while hippocampal-independent and short-term memory remained intact. Human IL-1beta overexpression activated glia, elevated murine IL-1beta protein and PGE(2) levels, and increased pro-inflammatory cytokine and chemokine mRNAs specifically within the hippocampus, while having no detectable effect on inflammatory mRNAs in the liver. Sustained neuroinflammation also reduced basal and conditioning-induced levels of the plasticity-related gene Arc.
Assuntos
Hipocampo/metabolismo , Hipocampo/fisiologia , Interleucina-1beta/biossíntese , Rememoração Mental/fisiologia , Percepção Espacial/fisiologia , Estimulação Acústica , Animais , Condicionamento Psicológico , Proteínas do Citoesqueleto/metabolismo , DNA Complementar/biossíntese , DNA Complementar/genética , Dinoprostona/biossíntese , Medo/psicologia , Feminino , Humanos , Vírus da Imunodeficiência Felina/imunologia , Imuno-Histoquímica , Interleucina-1beta/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Microinjeções , Proteínas do Tecido Nervoso/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Caracteres Sexuais , Vacinas Virais/imunologiaRESUMO
We previously reported that aging F344XBN rats are more vulnerable to disruptions of memory consolidation processes following an injection of Escherichia coli than are young rats. Furthermore, this disruption was specific to hippocampal-dependent memory. In the present study we examined the time course of the proinflammatory cytokine IL-1 beta in young and old rats following a peripheral injection of E. coli. Compared to young rats, aging rats treated with E. coli showed an exaggerated and prolonged up-regulation of IL-1 beta protein in the hippocampus, but not in hypothalamus, parietal cortex, prefrontal cortex, serum or spleen. Aging rats showed greater hippocampal IL-1 beta protein levels than their young counterparts 4h after E. coli, and these levels remained significantly elevated for 8 but not 14 days after E. coli. In a second experiment, aging rats exhibited anterograde memory consolidation impairments 4 and 8 days after an E. coli injection, but not after 14 days. A third experiment revealed that following an E. coli injection, bacterial clearance from the spleen and peritoneum was not impaired in aged rats, suggesting that elevations in hippocampal IL-1 beta were not mediated by impaired clearance in the periphery in aging rats. These data suggest that the exaggerated and prolonged elevation of IL-1 beta, specifically in the hippocampus, may be responsible for hippocampal-dependent memory impairments observed in aging rats following a bacterial infection.