Purpose: Clinical studies found that regular aerobic exercise has analgesic and antianxiety effects; however, the underlying neural mechanisms remain unclear. Multiple studies have suggested that regular aerobic exercise may exert brain-protective effects by promoting the release of serotonin, which may be a pain modulator. Anterior cingulate cortex (ACC) is a key brain area for pain information processing, receiving dense serotonergic innervation. As a result, we hypothesized that exercise may increase the release of serotonin in the ACC, thus improving pain and anxiety behaviors. Methods: Integrative methods were used, including behavioral, electrophysiological, pharmacological, biochemical, and genetic approaches, to explore the effects of regular aerobic exercise and the underlying neural mechanisms. Results: Regular aerobic exercise in the form of voluntary wheel running for 30 min daily for 15 d showed significant effectiveness in relieving pain and concomitant anxiety in complete Freund’s adjuvant–induced chronic inflammation pain models. c-Fos staining and multielectrode array recordings revealed alterations in neuronal activities and synaptic plasticity in the ACC. Moreover, systemic pharmacological treatment with 4-chloro-dl-phenylalanine (PCPA) to deplete endogenous serotonin and local delivery of serotonin to the ACC revealed that exercise-related serotonin release in the ACC bidirectionally modulates pain sensitization and anxiety behaviors by modulating synaptic plasticity in the ACC. Furthermore, we found that 5-HT1A and 5-HT7 receptors mediated the serotonin modulation effects under conditions of regular aerobic exercise through local infusion of a selective antagonist and shRNA in the ACC. Conclusions: Our results reveal that regular aerobic exercise can increase serotonin release and modulate synaptic plasticity in the ACC, ultimately improving pain and concomitant anxiety behaviors through the functions of the 5-HT1A and 5-HT7 receptors.

Empathy is a prosocial behavior that perceives the emotional state of others, expresses similar perceptions that match those of others, and mediates different social behaviors. Empathic behaviors for pain and fear also exist in primates and rodents. In the past decades, the neural mechanisms of empathy have been defined as a result of various sensations and perceptions, such as visual and hearing stimuli, which cause mirror activations in brain regions, such as the insular, the inferior frontal, and the medial frontal cortices, among which the anterior cingulate cortex (ACC) has been identified as a core region of the neural network that is associated with the empathic activity in mammals. Most studies on the neural mechanisms underlying empathy have been based on rodent models, which allowed for single-cell resolution mapping of neuronal activity; moreover, the application of optogenetic techniques in rodent models has led to a deeper delineation of neural circuits. Here, we review the role of the ACC in two behavioral paradigms, pain and fear empathy, in rodents at the neuronal and neural circuit levels. Understanding how the ACC mediates empathic behavior in the brain will provide new targets in the treatment for neuropsychiatric disorders characterized by empathic disorders.