Repeated, sustained inflammation affects hippocampal dependent learning and neuroinflammation across age and sex

Brain aging results in alterations of baseline neuroimmune signaling and cognitive function. Here, we characterize hippocampal-dependent cognitive function for two behavioral tasks, the T-maze and context object discrimination (COD), following repeated inflammation with peripheral lipopolysaccharide (LPS) treatment in three age groups. Inflammation affected behavior differently across age groups. Males that received LPS were more likely to complete the T-maze task and select the correct arm compared to other groups. Six-month-old female rats were more successful on the COD task following LPS compared to other ages. Three-month-old rats were impaired by previous LPS treatment, while 12-month-old rats were unable to complete the task at all. However, the molecular mechanisms for these behavioral changes remain unclear. Microglial morphology was altered in 6-month-olds, but interleukin-1β and phosphorylated tau expression decreased within the brain across age. The behavioral improvement in the 6-month-olds following LPS indicates a unique response of their brains to peripheral inflammation and shows a distinct trajectory from young to older adults. Specific mechanisms for these behavioral differences remain unexplored.