Transcriptomic changes in the prefrontal cortex of rats as a function of age and cognitive engagement

Although changes in cognitive functions including attention are well documented in aging, the neurobiological basis for such alterations is not fully understood. Increasing evidence points towards the contribution of genetic factors in age-related cognitive decline. However, genetic studies have remained inconsistent in characterizing specific genes that could predict functional decline in aging. Here we utilized next generation RNA sequencing (RNA-seq) to identify patterns of differentially expressed genes in the prefrontal cortex (PFC), a brain region implicated in attention, of young and aged animals that were either cognitively trained or had limited cognitive engagement. Consistent with previous investigations, aging alone was associated with increased expression of genes involved in multiple facets of innate and adaptive immune responses. On the contrary, the expression of immunity-related transcripts was reduced by cognitive engagement. In addition, transcripts across a wide range of cellular processes, including those associated with neuronal remodeling and plasticity, were upregulated by this behavioral manipulation. Surprisingly, aged subjects accounted for higher mean counts of upregulated transcripts and lower mean counts for downregulated transcripts as compared to the young subjects. Because aged rats exhibited lower attentional capacities, it is plausible that transcriptional changes associated with performance in these animals were reflective of compensatory changes that occurred to cope with the declining integrity of PFC functioning. Interestingly, the effects of both aging and cognitive engagement resulted in an upregulation of transcripts linked to extracellular exosomes, suggesting such extracellular vesicles may moderate a reciprocal gene by environment interaction in order to facilitate the reorganization of PFC circuitry and maintain functionality. Taken together, these findings provide novel insights into the capacities of both cognitive engagement as well as aging to alter gene expression in the PFC, and how the effects of such dynamic factors relate to variation in age-related cognitive abilities.