Postnatal Enrichment Corrects Deficits in Perineuronal Net Formation and Reversal Learning in Adult Mice Exposed to Early Adversity.

Childhood neglect is associated with cortical thinning, hyperactivity, and deficits in cognitive flexibility that are difficult to reverse later in life. Despite being the most prevalent form of early adversity, little is currently understood about the mechanisms responsible for these neurodevelopmental abnormalities, and no animal models have yet replicated key structural and behavioral features of childhood neglect/deprivation. To address these gaps, we have recently demonstrated that mice exposed to impoverished conditions, specifically limited bedding (LB), exhibit behavioral and structural changes that resemble those observed in adolescents who have experienced severe neglect. Here, we show that LB leads to long-term deficits in reversal learning, which can be fully reversed by briefly exposing LB pups to enrichment (toys) in their home cage from postnatal days 14 to 25. Reversal learning failed to induce normal c-fos activation in the orbitofrontal cortex (OFC) of LB mice, a deficit that was normalized by early enrichment. Additionally, LB decreased the density of parvalbumin-positive cells surrounded by perineuronal nets (PV+PNN+) and increased the ratio of glutamatergic to inhibitory synapse densities in the OFC, deficits that were also reversed by enrichment. Degradation of PNN in the OFC of adult mice impaired reversal learning, reduced c-fos activation, and increased the ratio of glutamatergic to inhibitory synapse densities in the OFC to levels comparable to those observed in LB mice. Collectively, our findings suggest that postnatal deprivation and enrichment impact the formation of PV+PNN+ cells in the OFC, a developmental process that is essential for cognitive flexibility in adulthood.