Enriched environment requires the remodeling of hippocampal perineuronal nets to trigger memory improvement in Alzheimer’s mouse model

Alzheimer's disease (AD) is a major neurodegenerative disorder influenced by both genetic and environmental factors. Mentally stimulating activities are believed to reduce cognitive decline by establishing a cognitive reserve, although the underlying neurobiological mechanisms remain elusive. In this study, we investigate the role of parvalbumin-expressing inhibitory neurons (PV+) and their perineuronal nets (PNN) in the establishment of cognitive reserve using a mouse model of AD. We demonstrate that 10 days in an enriched environment (EE) significantly restores both spatial and social memory, which is accompanied by an increase in PV+ and PV+/PNN+ cells in the hippocampus. Notably, preventing PV/PNN remodeling in CA1 during EE abolishes the spatial memory improvements, whereas localized neuregulin-1 (NRG1) injections induce PV/PNN remodeling and restore memory performance. These findings indicate that hippocampal PV/PNN remodeling is a key contributor to the cognitive benefits of EE in AD, highlighting this neuronal population as a substrate for cognitive reserve.