Enriched environment exposure restores behavioral alterations and transcriptional dysregulation of hippocampal steroidogenic enzymes in a small litter model.

We previously reported that rats raised in small litters (SL) exhibited increased anxiety-like behavior and poor performance in the episodic-like memory (ELM) test compared to normal litters (NL). Additionally, mRNA expression of aromatase was increased, and 5α-reductase 1 was reduced in the dentate girus (DG) of SL compared to NL rats. In this work, the objective was to analyze whether environmental enrichment (EE) can reverse or attenuate the behavioral and molecular effects observed in SL animals. Thus, male rats were raised in SL (4 pups/mother; SL), where pups consumed larger amounts of milk and gained more body weight compared to rats raised in normal litters (10 pups/mother; NL). On postnatal day (PND) 21, male rats were housed under standard conditions (SE, 4 rats/cage) or EE (8 rats/cage). For EE, cages were equipped with objects and tunnels that were changed daily. At PND75, the animals underwent locomotion activity, episodic-like memory (ELM) and elevated plus maze (EPM) tests. At PND90, the animals were euthanized, and their brains were microdissected. dentate girus (DG), CA1, and CA3 regions were isolated for mRNA quantification and methylation studies. We found that EE attenuates anxiety-like behavior and rescues spatial memory deficits in SL animals. Furthermore, EE prevented the increase in aromatase and decline in 5α-reductase 1, expression associated with SL. Some of these changes were correlated with alterations in methylation patterns of the promoter regions of these genes. These findings demonstrate that environmental interventions can mitigate the long-term effects observed in the SL model and restore brain and behavioral functions.