Mechanisms underlying single-bout exercise-induced rapid antidepressant effects in stressed mice

Chronic physical exercise can effectively alleviate depressive symptom in humans. Animal studies have demonstrated that this antidepressant effect can be mediated by an adipokine: adiponectin via its action on enhancing hippocampal adult neurogenesis and synaptic plasticity.
Emerging clinical studies have demonstrated the rapid onset of antidepressant effects of single-bout physical exercise. However, the neural mechanisms underlying this rapid antidepressant action is largely unknown. Our recent data have shown that single bout of high intensity interval treadmill running for 30 mins elicits rapid (30 mins post-exercise) and sustained (24 hr post-exercise) antidepressant effects in adult male C57BL/6J mice with 4-week chronic unpredictable stress exposure. The rapid onset of antidepressant effects is correlated with increase in serum adiponectin levels. We therefore further investigate the neural mechanism underlying rapid antidepressant effects of single-bout exercise. Our results showed that anterior cingulate cortex (ACC) of the prefrontal cortex is one of the most responsive brain regions to single bout of treadmill running, as indicated by significant increase in numbers of c-fos immune-positive cells when compared to control mice without treadmill running. Co-labelling of c-fos and CAMKII positive cells indicated that majority of activated neurons are glutamatergic neurons located in the ACC 30-min post single bout of exercise. Chemogenetic inhibition of ACC-glutamatergic neurons abolished the rapid onset of antidepressant effects in exercised mice, whereas acute activation of ACC-glutamatergic neurons mimicked the effects of exercise in control mice. Knockout adiponectin receptor adaptor protein APPL1 diminished the antidepressant effects of physical exercise, suggesting adiponectin signalling in ACC-glutamatergic neurons may play a key role in eliciting rapid antidepressant effects of single bout of running.