Differential effect of repeated lipopolysaccharide treatment and aging on hippocampal function and biomarkers of hippocampal senescence

Aging is associated with low-grade chronic systemic inflammation. Elevated peripheral serum cytokines and chemokines contribute to age-related diseases and correlate with cognitive decline. This study compared the effects of repeated lipopolysaccharide (LPS) treatment in young rats to age-related changes in hippocampal-dependent cognition, synaptic transmission, and transcription. Young (5-7 months) Fischer 344 X Brown Norway hybrid rats were injected intraperitoneally once a week for 6-7 weeks with either LPS (1 mg/kg) or vehicle. Older (14-16 months) rats received a similar injection schedule of vehicle. Older-vehicle animals and young-LPS rats exhibited impaired retention of spatial memory. Examination of the transcriptome of the CA1 and the dentate gyrus indicated that older-vehicle and young-LPS animals exhibited an increase in immune response genes. In contrast to aging, young-LPS animals exhibited an increased expression of genes related to the synapse. Even though young-LPS animals increased the expression of synaptic genes, LPS treatment reduced hippocampal CA3-CA1 total synaptic response and N-methyl-D-aspartate receptor (NMDAR)-mediated component of the synaptic response. Interestingly, the decrease in NMDAR function was not redox-sensitive. This study demonstrates that repeated exposure to LPS has long-term effects on hippocampal synaptic transmission and memory; however, young animals exhibited transcriptional recovery after LPS treatment. Recovery likely results from the acute nature of repeated LPS injections, relative to chronic systemic inflammation observed during aging.衰老与低度慢性全身性炎症密切相关。外周血清细胞因子与趋化因子水平升高，可诱发年龄相关性疾病，并与认知功能衰退存在显著关联。本研究对比了年轻大鼠反复接受脂多糖（lipopolysaccharide, LPS）处理后的效应，与衰老相关的海马依赖性认知、突触传递及转录组变化之间的差异。选取5~7月龄的Fischer 344 X Brown Norway杂交大鼠，每周腹腔注射一次脂多糖（1 mg/kg）或溶剂对照，持续6~7周；14~16月龄的老年大鼠则接受相同频次的溶剂对照注射方案。结果显示，老年溶剂对照组大鼠与年轻脂多糖处理组大鼠均表现出空间记忆保留能力受损。对海马CA1区与齿状回的转录组分析表明，老年溶剂对照组与年轻脂多糖处理组大鼠的免疫应答相关基因表达均出现上调。与衰老过程不同的是，年轻脂多糖处理组大鼠的突触相关基因表达水平升高。尽管年轻脂多糖处理组大鼠的突触基因表达上调，但脂多糖处理会降低海马CA3-CA1通路的总突触反应，以及N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptor, NMDAR）介导的突触反应组分。值得注意的是，NMDAR功能的降低并不受氧化还原状态调控。本研究证实，反复暴露于脂多糖会对海马突触传递与记忆产生长期影响，但年轻大鼠在脂多糖处理后会出现转录组层面的恢复。相较于衰老过程中出现的慢性全身性炎症，这种恢复可能源于反复脂多糖注射的急性作用特性。