An adiponectin-frontothalamic pathway mediates the rapid antidepressant effects of acute exercise

Abstract Conventional antidepressants suffer from a therapeutic lag, highlighting an urgent need for rapid-acting interventions vital to preventing clinical escalation and acute depressive crises. While acute exercise provides immediate antidepressant effects, the underlying body-brain mechanisms remain elusive. Here, we identify a frontothalamic circuit mediating the rapid behavioral benefits of acute running exercise. In rodents, glutamatergic projections from the anterior cingulate cortex (ACC) to the anterodorsal thalamus (AD) are necessary and sufficient to drive post-exercise behavioral rescue. This pathway is activated by the exercise-induced release of the systemic exerkine adiponectin, which acts via AdipoR1 in the ACC to recruit downstream AD projections. Translationally, adiponectin levels after a single session of acute exercise in humans correlate with increased frontothalamic functional connectivity. Our findings map an endocrine-frontothalamic axis governing rapid mood state transitions, offering a mechanistic blueprint for targeted "exercise prescriptions" to prevent acute depressive episodes.