THE NEURAL MECHANISM UNDERLYING THE ANTIDEPRESSANT EFFECTS ELICITED BY A SINGLE BOUT OF PHYSICAL EXERCISE
Authors: Cheng *Tong , Formolo Douglas Affonso , Zonghao Ma , Yau Suk-Yu 
Published: February 2025

Abstract

Background
Major depressive disorder (MDD) is one of the leading causes of disability worldwide (Kessler et al., 2003). Despite rapid-acting antidepressants ketamine elicits rapid and sustained antidepressant effects, chronic use causes side effects like addiction or hallucinogenic(Smith-Apeldoorn et al., 2022). Emerging clinical studies have demonstrated the rapid onset of antidepressant effects of single-bout physical exercise (Brush et al., 2021, Ge et al., 2021). However, the neural mechanisms underlying this action have not been identified.

Aims & Objectives
We investigated whether enhanced glutamatergic system activity in the frontal cortex underlies the rapid antidepressant action of a single bout of physical exercise in animal models.

Method
We used CAMKII-cre transgenic mice and two-photon calcium imaging to examine the involvement of glutamatergic neurons in the frontal cortex in the rapid antidepressant effects of a single bout of high- intensity treadmill training. Behavioral despair was assessed by splash test, tail suspension test, and forced swim test post-exercise. Neural activation was examined by quantifying c-FOS-positive cells in different brain regions. Chemogenetic activation and inhibition of glutamatergic neurons were examined respectively in mice with a single bout of physical exercise.

Results
Our pilot data have shown that a single bout of physical exercise elicited a rapid (30 min post-exercise) and sustained antidepressant effect (last to 24 hours post-exercise). Whole brain c-fos mapping indicated that the anterior cingular cortex (ACC) could be a key brain region mediating the rapid onset of the antidepressant effect of a single bout of exercise, as evidenced by a significant increase in c-Fos positive cells when compared to non-exercised control. Co-labeling has identified glutamatergic neurons as the major neuronal type responding to exercise training. Acute chemogenetic activation of glutamatergic neurons in the ACC mimicked the effects of exercise whereas inhibition of glutamatergic neurons abolished the rapid antidepressant effects of exercise.

Discussion and conclusion
This study has suggested the critical role of ACC-glutamatergic neurons in the rapid antidepressant effect induced by a single bout of exercise.

References
BRUSH, C. J., BURANI, K., SCHMIDT, K. M., SANTOPETRO, N. J. &HAJCAK, G. 2021. The impact of a single session of aerobic exercise on positive emotional reactivity in depression: Insight into individual differences from the late positive potential. Behav Res Ther, 144, 103914.
GE, L. K., HU, Z., WANG, W., SIU, P. M. &WEI, G. X. 2021. Aerobic Exercise Decreases Negative Affect by Modulating Orbitofrontal-Amygdala Connectivity in Adolescents. Life (Basel), 11.
KESSLER, R. C., BERGLUND, P., DEMLER, O., JIN, R., KORETZ, D., MERIKANGAS, K. R., RUSH, A. J.,WALTERS, E. E. &WANG, P. S. 2003. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA, 289, 3095-3105.
SMITH-APELDOORN, S. Y., VERAART, J. K., SPIJKER, J., KAMPHUIS, J. &SCHOEVERS, R. A. 2022. Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. The Lancet. Psychiatry, 9, 907-921.