| Author: | Formolo, Douglas Affonso |
| Title: | Physical exercise as a rapid antidepressant intervention : a circuit-based investigation of its mechanisms of action |
| Advisors: | Yau, Sonata (RS) |
| Degree: | Ph.D. |
| Year: | 2025 |
| Department: | Department of Rehabilitation Sciences |
| Pages: | vi, 131 pages : color illustrations |
| Language: | English |
| Abstract: | Background: Depression is a highly prevalent disease and one of the world’s leading causes of disability. Nevertheless, existing drugs still lack efficacy and have a delayed therapeutic onset. Ketamine elicits rapid antidepressant effects by strengthening synaptic connections in prefrontal cortex (PFC)-associated circuits, which sparked the investigation of novel therapeutic approaches. Recent studies suggest a single session of physical exercise rapidly improves mood in participants with depressive symptoms. Nonetheless, the central and peripheral mechanisms underlying the rapid antidepressant proprieties of physical exercise remain unknown. High-intensity exercise rapidly increases PFC activity and raises the peripheral levels of the adipokine adiponectin, which is associated with improved depressed mood. Since adiponectin receptors are highly expressed in the PFC, we hypothesize that physical exercise induces rapid antidepressant effects by modulating a PFC-associated circuit via increased central adiponectin signaling. Objective: To uncover the neural circuits mediating the rapid antidepressant effects of physical exercise and determine whether adiponectin is the critical peripheral factor underlying the circuit activation. Methods: Adult male mice performed a single session of high-intensity interval running on a treadmill (exercise) or remained in their home cages (sedentary) and were then subjected to the splash test (ST) and tail suspension test (TST) 2 h and 24 h after exercise for assessing depression-like behaviors. Data from a whole-brain c-Fos mapping and network analysis were used to identify key brain regions modulated by exercise. Chemogenetic and optogenetic approaches in combination with CaMKII-Cre transgenic mice were used for neural circuit studies. Intracerebroventricular adiponectin administration, adiponectin knockout mice, and the chronic unpredictable stress (CUS) animal model were used to implicate the role of adiponectin in the acute antidepressant effects of exercise. Results: The anterior cingulate cortex (ACC) and the anterodorsal nucleus of the thalamus (AD) were identified as central nodes in the exercise-related network, which was associated with increased activation of glutamatergic neurons. Chemogenetic inactivation of glutamatergic neurons in the ACC (ACC-Glu) or AD (AD-Glu) before exercise blocked the rapid antidepressant effects. Retrograde and anterograde neural tracing confirmed that the ACC sends glutamatergic projections to the AD. Optogenetic inhibition of the ACC-AD glutamatergic circuit during exercise blocked the rapid antidepressant effects, while optogenetic activation mimicked them. Moreover, manipulations of the adiponectin signaling system were used to determine how exercise activated the ACC-AD circuit. Intracerebroventricular administration of adiponectin replicated the effects of exercise, while adiponectin deficiency and selective knockdown of the adiponectin receptor 1 (AdipoR1) in the ACC-Glu neurons prevented the rapid antidepressant effect of exercise. Finally, intracerebroventricular adiponectin reversed the CUS-induced depressive phenotype dependent on activation of ACC glutamatergic neurons. Conclusion: The current findings uncover the ACC-AD pathway as a novel brain circuit mediating the rapid antidepressant effects of exercise and implicate adiponectin/AdipoR1 as a critical exerkine underlying such effects. The rapid antidepressant properties of exercise could help offset the delayed therapeutic onset of pharmacological treatments, further supporting physical exercise as an essential adjunct intervention for treating depression. Moreover, these findings highlight the potential of targeting the central adiponectin signaling system as a novel therapeutic strategy. |
| Rights: | All rights reserved |
| Access: | open access |
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