Parallel declines in cognition, motivation, and locomotion in aging mice: Association with immune gene upregulation in the medial prefrontal cortex

Aging in humans is associated with parallel changes in cognition, motivation, and motoric performance. Based on the human aging literature, we hypothesized that this constellation of age-related changes is mediated by the medial prefrontal cortex and that it would be observed in aging mice. Toward this end, we performed detailed assessments of cognition, motivation, and motoric behavior in aging mice. We assessed behavioral and cognitive performance in C57Bl/6 mice aged 6, 18, and 24 months, and followed this with microarray analysis of tissue from the medial prefrontal cortex and analysis of serum cytokine levels. Multivariate modeling of these data suggested that the age-related changes in cognition, motivation, motor performance, and prefrontal immune gene expression were highly correlated. Peripheral cytokine levels were also correlated with these variables, but less strongly than measures of prefrontal immune gene upregulation. To determine whether the observed immune gene expression changes were due to prefrontal microglial cells, we isolated CD11b-positive cells from the prefrontal cortex and subject them to next-generation RNA sequencing. Many of the immune changes present in whole medial prefrontal cortex were enriched in this cell population. These data suggest that, as in humans, cognition, motivation, and motoric performance in the mouse change together with age and are strongly associated with CNS immune gene upregulation.

Research highlights
► Detailed cognitive, motor, and behavioral assessments as well as microarray analysis of tissue from the medial prefrontal cortex and serum cytokine analyses were performed.
► Multivariate analysis of these data is consistent with association of the upregulation of inflammatory, and especially interferon regulated, genes in the prefrontal cortex and the behavioral and cognitive measures.
► Next-generation RNA sequencing of Cd11+ cells shows enrichment of these genes in that specific cell population.
► These results shed light on the mechanism by which aging causes parallel changes in cognition, motor performance, and affective behavior.