The Neural Mechanism of Rapid and Sustained Antidepressant Effects of Single-bout Physical Exercise: The Involvement of Nuclear Translocation of APPL1 Protein in ACC-glutamatergic Neurons

Abstract

Physical exercise is a safe and effective non-pharmacological intervention for depression. Clinical studies indicate that single-bout physical exercise can rapidly improve mood in healthy individuals and depressed patients. However, the neural mechanisms responsible for this rapid onset of antidepressant effects remain unexplored. Adiponectin, an exerkine secreted by adipocytes, binds to its receptor adiponectin receptor (AdipoR) 1 or 2 and interacts with the adapter protein APPL1 to trigger downstream signaling pathways. Previous studies showed that adiponectin is crucial for the antidepressant effects of chronic physical exercise, and an acute increase in brain adiponectin can elicit rapid antidepressant effects within hours. Based on that, we hypothesized that adiponectin-AdipoR-APPL1 signaling may mediate the rapid antidepressant effects of single-bout physical exercise. Here we confirmed the rapid antidepressant effect of single-bout treadmill running in participants with/without depressive symptoms, which was replicated in control and stressed mice. Using the mouse model, our further investigation into neural basis through the whole-brain c-Fos mapping identified the anterior cingulate cortex (ACC) subregion of the medial prefrontal cortex (mPFC) as a pivotal region involved in the exercise-elicited rapid antidepressant effects. ACC-glutamatergic neurons underwent rapid and persistent activation after exercise, which was essential for the antidepressant response elicited by exercise. In addition, increased adiponectin levels in the medial prefrontal cortex were negatively correlated with a decrease in depressive behavior 30 min-post exercise. Adiponectin global knockout by KO mice or AdipoR1 knockdown in ACC-glutamatergic neurons significantly abolished neural activation and the rapid antidepressant response elicited by single-bout physical exercise. Furthermore, the adapter protein APPL1 in the ACC-glutamatergic neurons rapidly translocated into the nuclear after exercise, a process contingent upon adiponectin-AdipoR1 signaling. Nuclear APPL1 facilitated histone acetylation and promoted synaptic gene transcription and synaptic protein expression. Inhibiting APPL1 translocation negated changes in synaptic protein expression, spinogenesis, and the antidepressant effects of single-bout physical exercise, whereas re-introduction of APPL1 to the ACC-glutamatergic neurons of APPL1 knockout mice restored the effects of single-bout physical exercise. Together, the adiponectin-AdipoR1-APPL1 pathway plays a significant role in mediating the rapid antidepressant effect of single-bout physical exercise via promoting histone acetylation to enhance synaptic protein expression and spinogenesis in the mPFC. The study highlights the clinical significance of a rapid onset of antidepressant effect of single-bout physical exercise, in addition to well-recognized antidepressant effects elicited by chronic exercise training.

Date of Award	19 Mar 2025
Original language	English
Awarding Institution	The Hong Kong Polytechnic University
Supervisor	Suk Yu Yau (Chief supervisor)