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

## TL;DR

Running helps reverse the effects of chronic stress on brain cells linked to anxiety and depression, suggesting new treatment targets.

## Contribution

Running reverses chronic stress-induced changes in serotonergic modulation of hippocampal granule cells and behavioral responses.

## Key findings

- Chronic restraint stress alters serotonergic modulation of granule cell excitability.
- Running recovers 5-HT1A receptor activity lost due to chronic stress.
- Running promotes indirect modulation of granule cells through 5-HT3 receptor activation.

## 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‐HT1A and 5‐HT3 receptors respectively, we show that running recovers 5‐HT1A receptor activity lost by CRS. Additionally, running promotes the indirect modulation of GCs through 5‐HT3 receptor activation. Thus, 5‐HT1A and 5‐HT3 receptors may be potential targets for the treatment of stress‐related psychiatric disorders.

Chronic stress restraint (CRS) induces altered behavioural responses that are mitigated by running treatment. We evaluated serotonergic modulation of hippocampal granule cells (GC) excitability, as a potential mechanism underlying exercise‐induced anxiolytic and antidepressive effects. CRS modifies the serotonergic modulation of GC excitability. Running recovered 5‐HT1A receptor activity lost by CRS, and promoted the indirect modulation of GCs through 5‐HT3 receptor activation, suggesting these two receptors as potential targets for the treatment of stress‐related psychiatric disorders.