EPA-1343 – Chronic Psychosocial Stress in Mice Causes Neuro-immune-monoamine Changes in Brain and Depression-relevant Behaviour that is Reversible by Anti-inflammatory Treatment

Abstract

Introduction

Valid animal models are essential to understanding the aetio-pathophysiology of depression psychopathology and therefore its pharmacological treatment.

Aims

To establish a mouse model with aetiological and face validity, investigate the mediating pathophysiology, and the effects of reference antidepressants and novel-target pharmacology.

Methods

Adult male C57BL/6 mice were exposed to chronic social defeat (CSD) in the form of 15-day distal exposure to, and 1-min daily attack without wounding by, dominant CD-1 mice. Behavioural effects were studied in terms of changes in fear conditioning, generalized helplessness and fatigue. Physiological effects were studied in terms of in plasma levels of pro-inflammatory cytokines and tryptophan catabolites. CNS transcriptome-level effects were studied in terms of de-regulated gene expression in hippocampus, amygdala and medial prefrontal cortex. Pharmacological reversal of CSD behavioural effects were studied using escitalopram and an indoleamine 2,3-dioxygenase (IDO) inhibitor.

Results

Relative to controls, CSD mice exhibited increased acquisition and expression of fear conditioning to CS and context, increased generalized helplessness in terms of 2-way escape failure, and increased fatigue on a 1-way escape-avoidance treadmill. CSD mice exhibited increased plasma levels of TNF and IL-6, increased tryptophan catabolites and decreased serotonin, and splenomegaly. CSD mice exhibited deregulation of immune-inflammation genes in hippocampus and of dopamine and serotonin genes in amygdala. CSD-induced behavioural dysfunction was moderately reversed by escitalopram and more robustly reversed by an IDO inhibitor.

Conclusion

This valid mouse model provides comprehensive evidence for immune-inflammation – monoamine aetio-pathophysiology of depression and the therapeutic importance of targeting this pathway in novel anti-depressant treatment strategies.