Molecular Mechanisms of Exercise-induced Hippocampal Neurogenesis and Antidepressant Effects

Depression affects an estimated 280 million individuals globally, imposing significant socioeconomic burdens. Current antidepressants, including selective serotonin reuptake inhibitors (SSRIs), prove ineffective for a substantial portion of patients, highlighting the urgent need for novel therapeutic strategies. Exercise has demonstrated preventive and ameliorative effects on depression, with serotonin implicated in these antidepressant effects. Serotonin, a neurotransmitter influencing various physiological functions, including mood and memory, is released in the brain during exercise. This study focuses on clarifying the detailed mechanism by which exercise-induced serotonin increase in the hippocampus promotes hippocampal neurogenesis and exerts antidepressant effects, particularly focusing on the role of the 5-HT3 receptor, a subtype of serotonin receptors expressed in limbic brain regions, including the hippocampus. The hippocampus, specifically the dentate gyrus, is crucial for neurogenesis in the adult brain. Previous research has demonstrated that serotonin promotes hippocampal neurogenesis and that this process is important for the antidepressant effects of both exercise and some antidepressants. However, the precise mechanism remains unclear. The 5-HT3 receptor, an ionotropic receptor unlike most other serotonin receptors, is present in the hippocampus and has been associated with emotion and memory, though its role in neurogenesis and depression was previously unknown. Therefore, the study aims to investigate the link between 5-HT3 receptors, exercise-induced hippocampal neurogenesis, and antidepressant effects, utilizing 5-HT3 receptor knockout mice to explore the mechanistic details.

Extensive literature supports the benefits of exercise for various physical and mental health conditions. Studies have shown exercise promotes hippocampal neurogenesis in both animals and humans, improves mood, and enhances learning ability. Serotonin's involvement in depression and hippocampal neurogenesis is well-established. Previous research demonstrated that exercise increases hippocampal serotonin release, suggesting its role in exercise-induced neurogenesis and antidepressant effects. However, the precise mechanism remained unclear, particularly concerning the specific serotonin receptor subtypes involved. The serotonin receptor family comprises seven subfamilies (5-HT1 to 5-HT7), with 5-HT3 being the only ionotropic receptor. Its presence in limbic regions like the hippocampus, amygdala, and prefrontal cortex has been reported, along with its potential roles in emotion and memory. However, its role in hippocampal neurogenesis and depression required further investigation.

The study employed 5-HT3 receptor knockout (Htr3a-/-) mice alongside wild-type mice. Mice were subjected to either exercise (access to a running wheel) or non-exercise conditions for three weeks. Neurogenesis was assessed using bromodeoxyuridine (BrdU) labeling of dividing cells and immunohistochemistry to identify mature granule cells. Depressive-like behavior was evaluated using the forced swimming test and tail suspension test. The effects of a 5-HT3 receptor agonist (SR 57227A) and a commonly used SSRI (fluoxetine) were examined on depressive-like behavior and hippocampal neurogenesis. Immunohistochemistry and in situ hybridization were used to analyze the expression patterns of 5-HT3 receptors and insulin-like growth factor-1 (IGF-1) in the hippocampus. In vivo microdialysis was employed to assess hippocampal IGF-1 release after 5-HT3 receptor agonist stimulation. The role of the IGF-1 signaling pathway in mediating the effects of the 5-HT3 receptor agonist on hippocampal neurogenesis was investigated using an IGF-1 receptor antagonist (AG 1024). The study also compared the effects of the 5-HT3 receptor agonist with those of fluoxetine to determine if the mechanisms were different. 5-HT3 receptor-EGFP reporter mice were utilized for detailed analysis of 5-HT3 receptor expression patterns.

Wild-type mice exposed to exercise showed increased hippocampal neurogenesis and reduced immobility time in behavioral tests, indicating antidepressant effects. Conversely, Htr3a-/- mice showed no such improvements with exercise, demonstrating the necessity of 5-HT3 receptors for both exercise-induced neurogenesis and antidepressant effects. The 5-HT3 receptor agonist (SR 57227A) reduced immobility time in wild-type mice but not in Htr3a-/- mice, confirming its antidepressant action via 5-HT3 receptors. In contrast, fluoxetine's antidepressant effects were unaffected by the absence of 5-HT3 receptors, suggesting distinct mechanisms. The 5-HT3 receptor agonist acutely increased neural progenitor cells, unlike fluoxetine, which required chronic treatment. Combined treatment with fluoxetine and the 5-HT3 receptor agonist showed additive effects on neurogenesis, reinforcing the distinct nature of these mechanisms. Detailed analysis revealed that 5-HT3 receptors are highly expressed in neurons of the hippocampal dentate gyrus, often co-localized with IGF-1. The 5-HT3 receptor agonist stimulated IGF-1 release in the hippocampus, whereas fluoxetine did not. Blocking IGF-1 receptors inhibited the 5-HT3 receptor agonist's effect on neurogenesis, establishing the IGF-1 signaling pathway's importance in the observed effects. Furthermore, the administration of a 5-HT3 receptor agonist to a LPS-induced depression model mouse improved depressive-like behavior and promoted hippocampal neurogenesis.

The findings strongly support a novel mechanism for exercise-induced antidepressant effects. The 5-HT3 receptor plays a critical role in this process, distinct from the mechanisms of action for SSRIs. The acute increase in neurogenesis induced by 5-HT3 receptor stimulation contrasts with the chronic effects observed with SSRIs, suggesting faster-acting therapeutic options may be possible. The identification of the IGF-1 signaling pathway as a key downstream mediator provides a promising target for drug development. The additive effects of combining the 5-HT3 receptor agonist with fluoxetine suggest that targeting both pathways could enhance therapeutic efficacy for individuals with treatment-resistant depression. The results provide a strong rationale for exploring 5-HT3 receptor agonists as a new class of antidepressants.

This study establishes a crucial role for 5-HT3 receptors in exercise-induced hippocampal neurogenesis and antidepressant effects. The identification of the 5-HT3 receptor-IGF-1 pathway presents a novel therapeutic mechanism distinct from existing antidepressants, offering potential avenues for developing new treatments for depression, especially for those unresponsive to SSRIs. Further research could focus on optimizing 5-HT3 receptor agonists for clinical applications and exploring the precise interactions between the 5-HT3 receptor-IGF-1 pathway and other neurobiological processes involved in depression.

The study primarily used mouse models, which may not fully translate to human responses. Further research is needed to confirm these findings in humans and to identify potential side effects associated with 5-HT3 receptor agonists. The study focused on a specific type of exercise (running wheel access), and the generalizability of these results to other forms of exercise needs additional investigation. The sample size could be considered for future studies to strengthen the statistical power of the findings.