Running Reverses Chronic Stress‐Induced Changes in Serotonergic Modulation of Hippocampal Granule Cells and Altered Behavioural Responses

ABSTRACT Chronic stress increases susceptibility to anxiety and depression disorders, recurrent and common psychiatric conditions. Current antidepressant medications have varying degrees of efficacy and often have multiple side effects limiting treatment adherence. Physical exercise has beneficial effects on stress‐related mental disorders. However, the underlying mechanisms are unclear. Dentate gyrus granule cells (GCs) excitability may mediate stress resilience. Here, we expose young adult C57Bl6 mice to chronic restraint stress (CRS) for 14 days followed by 30 days of running treatment. Behavioural evaluation before and after treatment showed that the behavioural alterations elicited by CRS were mitigated by running. Next, we evaluated serotonergic modulation of GC excitability, as a potential mechanism underlying running‐induced stress resilience. Electrophysiological recordings indicate that CRS alters serotonergic modulation of GC excitability. Utilising (S)‐WAY 100135 and Tropisetron, antagonists of 5‐HT 1A and 5‐HT 3 receptors respectively, we show that running recovers 5‐HT 1A receptor activity lost by CRS. Additionally, running promotes the indirect modulation of GCs through 5‐HT 3 receptor activation. Thus, 5‐HT 1A and 5‐HT 3 receptors may be potential targets for the treatment of stress‐related psychiatric disorders.