Chronic Unpredictable Stress Alters Brain Tryptophan Metabolism and Impairs Working Memory in Mice without Causing Depression-Like Behaviour.

Jason C O’Connor,Grace A Porter

doi:10.31487/j.nnb.2021.03.03

Abstract

Chronic stress is a well-known risk factor in major depressive disorder and disrupts the kynurenine and serotonin pathways of tryptophan metabolism. Here, we characterize the temporal central and peripheral changes in tryptophan metabolism and concomitant depressive-like behavioural phenotype induced during the progression of chronic unpredictable stress (CUS). Mice were exposed to 0, 10, 20, or 30 days of CUS followed by a panel of behavioural assays to determine depressive-like phenotypes. Immediately after behavioural testing, plasma and brain tissue were collected for metabolic analysis. While anhedonia-like and anxiety-like behaviours were unaffected by stress, nesting behaviour and cognitive deficits became apparent in response to CUS exposure. While CUS caused a transient reduction in circulating quinolinic acid, no other tryptophan metabolites significantly changed in response to CUS. In the brain, tryptophan, kynurenine, picolinic acid, and 5-hydroxyindoleacetic acid concentrations were significantly elevated in CUS-exposed mice compared with non-stress control animals, while kynurenic acid, xanthurenic acid, and serotonin decreased in CUS-exposed mice. Metabolic turnover of serotonin to the major metabolite 5- hydroxyindoleacetic acid was markedly increased in response to CUS. These results suggest that CUS impairs hippocampal-dependent working memory and enhances nascent nesting behaviour in C57BL/6J male mice, and these behaviours are associated with increased brain kynurenine pathway metabolism leading to accumulation of picolinic acid and a significant reduction in serotonin levels.

Highlights

Depression is a major public health concern affecting approximately 300 million people globally [1]
Metabolic turnover of serotonin to the major metabolite 5hydroxyindoleacetic acid was markedly increased in response to Chronic unpredictable stress (CUS). These results suggest that CUS impairs hippocampal-dependent working memory and enhances nascent nesting behaviour in C57BL/6J male mice, and these behaviours are associated with increased brain kynurenine pathway metabolism leading to accumulation of picolinic acid and a significant reduction in serotonin levels
Mice were tested in saccharin preference, nesting, open field test, and working memory Y-maze after 0, 10, 20, or 30 days of CUS exposure

Summary

Introduction

Depression is a major public health concern affecting approximately 300 million people globally [1]. Chronic stress is a well-characterized risk factor in the development of depression [2]. Chronic unpredictable stress (CUS), social defeat, restraint, and other stressors are common pre-clinical models used in the investigation of the pathogenesis of depression [6]. Pro-inflammatory markers in the central nervous system (CNS) have been highly implicated in the pathogenesis of depression [11,12,13,14]. Mounting evidence suggests that chronic stress up-regulates the expression of pro-inflammatory cytokines in the CNS through activation of resident microglia [15,16,17]. Over the past two decades, alterations in the kynurenine pathway of tryptophan metabolism have been implicated in the pathogenesis of inflammation-induced depression, and preclinical models have largely recapitulated these findings [12, 20]. Relatively less is known pertaining to the potential pathogenic role of tryptophan metabolism along the kynurenine pathway

Methods

Results

Conclusion