Environmental enrichment preserves retrosplenial parvalbumin density and cognitive function in female 5xFAD mice

The rate of cognitive decline in Alzheimer’s disease (AD) varies considerably from person to person. Numerous epidemiological studies point to the protective effects of cognitive, social, and physical enrichment as potential mediators of cognitive decline in AD; however, there is much debate as to the mechanism underlying these protective effects. The retrosplenial cortex (RSC) is one of the earliest brain regions with impaired functions during AD pathogenesis, and its activity is affected by cognitive, social, and physical stimulation, making it a particularly interesting region to investigate the influences of an enriched lifestyle on AD pathogenesis. In the current study, we use the 5xFAD mouse mode of AD to examine the impact of enriched housing conditions on cognitive function in AD and the viability of a particularly vulnerable cell population within the RSC – parvalbumin interneurons (PV-INs). Enriched housing conditions improved cognitive performance in female 5xFAD mice. These changes in cognitive performance coincided with restored functional connectivity of the RSC and preserved PV-IN density within this region. Along with preserved PV-IN density, there was an increase in the density of Wisteria floribunda agglutinin -positive perineuronal nets (WFA+PNNs) across the RSC of 5xFAD mice housed in enriched conditions. Direct manipulation of WFA+PNNs revealed that these extracellular matrix structures protect PV-INs from amyloid toxicity and may be the mechanisms underlying the protective effects of enrichment. Together, these results provide support for the WFA+PNN-mediated maintenance of PV-INs in the RSC as a potential mechanism mediating the protective effects of enrichment against cognitive decline in AD. Significance statement The rate of progression of Alzheimer’s Disease is highly variable. The extent to which individuals engage in an enriched lifestyle is one factor that has been proposed to promote cognitive resiliency to AD pathology. Understanding how enrichment promotes resiliency is critical for promoting healthy cognitive aging. Recent work has demonstrated that the retrosplenial cortex, and especially parvalbumin interneurons in this region are highly vulnerable to AD pathology and their impairments relate to early cognitive impairments. Here, we show that environmental enrichment promotes cognitive performance and the survival of parvalbumin interneurons in the retrosplenial cortex through a mechanism dependent on perineuronal net maintenance. These results help to explain the mechanisms that mediate the influence of environmental enrichment on cognitive resiliency.