Voluntary Exercise During Adolescence Mitigated Negative the Effects of Maternal Separation Stress on the Depressive-Like Behaviors of Adult Male Rats: Role of NMDA Receptors.

Evidence indicates that experiencing early-life stress (ELS) is a risk factor for the development of mental disorders such as depression. Maternal separation stress (MS) is a valid animal model of ELS that caused to induce long-lasting effects on the brain and behaviors of animals. It hypothesized that adolescence is a critical stage in which the brain is still developing, and applying (non)pharmacological therapies in this period may attenuate the effects of ELS on the brain and behavior. Male rats were subjected to MS from postnatal day (PND) 2-14, and the stressed animals were then treated with (1) chronic fluoxetine (FLX) (5 mg/kg) and (2) voluntary running wheel exercise (RW) from PND 30, for 30 days. Then, we subjected the animals to behavioral and molecular assessments at PND 60. Our data showed that MS provoked depressive-like behaviors in rats, tested by the forced swimming test, splash test, and sucrose preference test. Additionally, we found that MS increased the gene expression of the NR2A (and not NR2B) subunit of N-methyl-D-aspartate (NMDA) receptors in the hippocampus of adult rats. Both FLX and RW treatments during adolescence were able to mitigate the negative effects of ELS on stressed animals. These results highlighted the importance of adolescence in treating stressed animals with FLX/voluntary RW exercise to alleviate the depressive effects of ELS. In addition, we found that ELS altered the transcriptional level of Grin2a (and not Grin2b) in the hippocampus. Finally, our results showed that FLX/voluntary RW exercise during adolescence could normalize altered expression of Grin2a in the hippocampus of adult rats.