Voluntary wheel running from early adolescence reduces disease progression, and anxiety- and depression-related symptoms in an adult male mouse model of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease that progressively destroys synovial joints and leads to chronic systemic inflammation. This autoimmune disorder is associated with increased anxiety- and depression-related symptoms, which reduces quality of life. Clinical and experimental evidence suggests that higher physical activity from early adolescence may prevent chronic diseases and reduce the risk of mental health problems in adulthood. This study aimed to assess whether voluntary wheel running from early adolescence can decrease clinical symptoms, anxiety- and depression-related behaviors in adult mice with rheumatoid arthritis. Adolescent male mice were exposed to voluntary wheel running until adulthood and got collagen-induced arthritis. We measured body weight, the thickness of the hind paw and knee joint (clinical signs), anxiety- and depression-related behaviors, serum testosterone, and cytokines (IFN-γ IL-1ß, IL-6, TNF-α, IL-10). The findings showed that collagen-induced arthritis resulted in anxious-like behavior, increased anhedonia, elevated IL-6, IL-1ß, TNF-α, and IFN-γ, and decreased testosterone levels in the serum of mice. However, no change was observed in behavioral despair. We found that higher physical activity from early adolescence significantly reduced the severity of clinical signs, anxiety- and anhedonia-like behaviors, and decreased behavioral despair in RA-induced mice. In addition, the running wheel exposure normalized RA-induced abnormalities in testosterone and inflammatory cytokines in mice. Altogether, this study suggests that higher physical activity from early adolescence may make mice less vulnerable or resistant to RA-induced clinical symptoms and anxiety- and depression-related behaviors by changing testosterone and inflammatory cytokines productions in adulthood.

Diazepam and exercise training combination synergistically reduces lipopolysaccharide-induced anxiety-like behavior and oxidative stress in the prefrontal cortex of mice.

Anxiety-related disorders are among the most important risks for global health, especially in recent years due to the COVID-19 pandemic. Benzodiazepines like diazepam are generally used to treat anxiety disorders, but the overall outcome is not always satisfactory. This is why psychiatrists encourage patients with anxiety to change their lifestyle habits to decrease the risk of anxiety recurrence. However, the effect of diazepam and exercise in combination is unknown. This study aimed to investigate the effect of diazepam alone or in combination with swimming exercise on lipopolysaccharide (LPS)-induced anxiety-like behavior and oxidative stress in the hippocampus and prefrontal cortex of mice. Mice were exposed to diazepam and swimming exercise alone or in combination with each other and then received LPS. We assessed anxiety-like behavior using open field and light-dark box and measured oxidative markers including glutathione (GSH), malondialdehyde (MDA), and glutathione disulfide (GSSG) in the hippocampus and prefrontal cortex. The findings showed that LPS increased anxiety-related symptoms and oxidative stress by decreasing GSH and increasing MDA and GSSG levels in the prefrontal cortex but not in the hippocampus. Although diazepam alone did not reduce anxiety-like behavior and oxidative stress, it in combination with exercise significantly decreased anxiety-like behavior and oxidative stress in the prefrontal cortex of LPS-treated mice. This drug and exercise combination also displayed a more effective effect in comparison with exercise alone. Overall, this study suggests that diazepam in combination with swimming exercise has higher efficacy on anxiety-like behavior and oxidative stress than when they are used alone.

The role of the oxytocinergic system in the antidepressant-like effect of swimming training in male mice.

Increasing evidence shows that higher physical activity such as running and swimming exercises is associated with decreased depression-related symptoms. However, underlying mechanisms are not fully understood. This study aimed to investigate whether oxytocinergic system can mediate the antidepressant effect of swimming exercises in mice. First, male NMRI mice were subjected to swimming training for eight weeks, then animals intraperitoneally received oxytocin antagonist (L-368899) 1 h before behavioral tests. We assessed anhedonia and social behavior and behavioral despair using the sucrose preference test, social interaction test, and tail suspension test. Oxytocin levels in the brain and serum were also measured. The results showed that swimming training decreased anhedonia and behavioral despair, whereas it increased social behavior and oxytocin levels in male mice. On the other hand, a subthreshold dose of oxytocin antagonist treatment in exercised mice prevented the antidepressant effect of swimming exercise via increased anhedonia and behavioral despair and decreased social behavior compared to the swimming training group. However, the blockade of oxytocin receptors did not affect oxytocin levels in exercised mice. Overall, these findings suggest that oxytocinergic system can play a role in mediating the antidepressant-like effect of swimming training in mice.

Swimming exercise strain-dependently affects maternal care and depression-related behaviors through gestational corticosterone and brain serotonin in postpartum dams.

Pregnancy is a very complex and highly stressful time in which women become more physically and emotionally vulnerable. Therefore, mothers are more likely to face decreased self-esteem and increased postpartum depression. Despite the high prevalence of postpartum depression, more than 50 % of mothers are undiagnosed or untreated, showing an urgent need to explore an effective preventive strategy. A healthy lifestyle and regular physical activity have been suggested to be associated with an increased quality of life in pregnant and postpartum women. The purpose of this study was to determine whether swimming exercise before and during pregnancy can affect maternal care and postpartum depression-related behaviors in dams. To this end, female NMRI and C57BL/6 J mice were subjected to swimming exercise before conception and throughout pregnancy. On postpartum days 1-2, maternal behavior including nest building, active nursing, and licking/grooming were monitored. A battery of behavioral tests was also used to measure depression-related symptoms including anhedonia- and anxiety-like behavior, social behavior, and behavioral despair. To identify the underlying mechanisms, corticosterone and inflammatory cytokines during late pregnancy, and corticosterone and brain serotonin during the postpartum period were measured in dams. The findings indicated that swimming exercise increased gestational corticosterone, decreased maternal care and brain serotonin, and increased all depression-related behaviors in postpartum C57BL/6 J dams, while only increased licking/grooming and social behavior, and reduced anhedonia-like behavior in postpartum NMRI dams. Taken together, this study suggests that swimming exercise before and during pregnancy could alter maternal care and postpartum depression-like behavior in a strain-dependent manner.

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.