Rearing in an enriched environment ameliorates the ADHD-like behaviors of Lister hooded rats while suppressing neuronal activities in the medial prefrontal cortex

Abstract Genetic factors play a critical role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD), but environmental factors may also be responsible for ADHD symptoms. In this study, Lister hooded rats (LHRs), which are outbred rats that exhibit more hyperactive, inattentive, and impulsive behaviors than Wistar rats, were used as ADHD model animals. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in a large, tall cage with an enriched environment [EE]) until 9 weeks of age. EE rearing decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. LHRs reared in a large flat cage did not exhibit any apparent change in motor activity. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. The rats reared in an EE for 3 weeks from 6 weeks of age also showed an improvement in their ADHD-like behaviors. RNA sequencing revealed that the expression of immediate-early genes in the medial prefrontal cortex (mPFC) of LHRs reared in a standard cage was higher than that in the mPFC of LHRs reared in an EE. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE from childhood or adolescence improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC.