Molecules of mood: the integrated molecular transducers of exercise’s antidepressant effects

Abstract

Regular physical exercise exerts robust antidepressant effects, yet the molecular mechanisms underlying this phenomenon remain incompletely defined. Emerging evidence highlights exercise as a systemic stimulus that orchestrates a network of peripheral and central molecular transducers, collectively modulating mood and resilience to stress. Key mediators include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), myokines like irisin, metabolic regulators including lactate and kynurenine pathway metabolites, and immune-derived cytokines that recalibrate neuroinflammation. These molecules converge on neural circuits of reward, motivation, and affect, promoting synaptic plasticity, neurogenesis, and homeostatic balance in monoaminergic signaling. Integrative frameworks suggest that exercise-induced molecular crosstalk between muscle, liver, adipose tissue, immune system, and brain constitutes a dynamic “molecular transducer network” that underpins its antidepressant efficacy. Understanding this interconnected biology not only advances mechanistic insight into exercise as medicine but also informs the development of novel therapeutic strategies that mimic or potentiate its mood-enhancing effects.