Down-regulation of serotonergic genes expression in the raphe nuclei of midbrain under chronic social defeat stress in male mice

Ul’Yana Boyarskikh,Natalya Bondar,Maxim Filipenko,Natalia Kudryavtseva

doi:10.1038/npre.2011.6543.1

Abstract

Abstract Background: There is ample experimental evidence supporting the hypothesis that the brain serotonergic system is involved in the control of chronic social defeat stress (CSDS), depression and anxiety. The study aimed to analyze mRNA levels of the serotonergic genes in the raphe nuclei of the midbrain that may be associated with chronic social defeats consistently shown by male mice in special experimental settings.Methodology/Principal Findings:The serotonergic genes were the Tph2, Sert, Maoa and Htr1a. The Bdnf, Creb, Cphn, Gapdh, Hprt, B2M, 18S and Actb genes were also studied. The experimental groups were composed of male mice with experience of defeats in 21 daily encounters and male mice with the same track record of defeats followed by a no-defeat period without agonistic interactions (relative rest for 14 days). It has been shown that mRNA levels of the Tph2, Maoa, Sert, Htr1a, Bdnf and Creb genes in the raphe nuclei of defeated mice are decreased as compared with the controls. Under CSDS the Cphn, Gapdh, Hprt, B2M, 18S, Actb genes are also down-regulated. The expression of the serotonergic genes as well as the Cphn and Creb genes is not restored to the control level after the 2 weeks of relative rest. mRNA levels of other genes are not recovered to the control levels, although some up-regulation was observed in rested losers. Significant positive correlations were found between the total time of avoidance behavior demonstrated by the 21-day defeaters in agonistic interactions and Sert, Maoa, Bdnf, Gapdh and 18S mRNA levels. Conclusions: CSDS experience inducing the development of mixed anxious/depression-like state in male mice down-regulates the serotonergic genes expression associated with the synthesis, inactivation and reception of serotonin. The Bdnf and Creb genes as well as the cell and metabolic Cphn, Gapdh, Hprt, B2M, Actb and 18S genes in the midbrain raphe nuclei are also down-regulated under CSDS. Period of relative rest is not enough for most genes to recover expression to the control levels.

Highlights

The central role of the brain serotonergic system in the mechanisms of stress, anxiety and depression was shown in numerous preclinical and clinical studies [1,2,3,4,5]. It has been shown in the experiments that prolonged chronic social defeat stress (CSDS) leads to the development of behavioral psychopathology in C57BL/6J male mice, which is similar to mixed anxiety/depression-like state in humans as indicated by similarities of symptoms, etiology, sensitivity to antidepressants and anxiolytics as well as neurochemical changes in the brain of patients [1,3,6]
In particular it has been shown that mRNA levels of the serotonergic Maoa and Sert genes in the raphe nuclei of the midbrain increased in CBA/Lac mice after 10 days of CSDS [8]
The study aimed to explore possible changes in the functional activity of the serotonergic Tph2, Sert, Maoa and Htr1a genes whose proteins are involved in the implications of CSDS: tryptophan hydroxylase is the rate limiting enzyme of the serotonin (5-HT) pathway; serotonin transporter terminates 5-HT action on the postsynaptic membrane by rapidly removing it from the synaptic cleft through reuptake; monoamine oxidase A degrades 5-HT in the synaptic cleft and 5HT1A receptors

Summary

Introduction

The central role of the brain serotonergic system in the mechanisms of stress, anxiety and depression was shown in numerous preclinical and clinical studies [1,2,3,4,5]. In particular it has been shown that mRNA levels of the serotonergic Maoa and Sert genes in the raphe nuclei of the midbrain increased in CBA/Lac mice after 10 days of CSDS [8]. The study aimed to analyze mRNA levels of the serotonergic genes in the raphe nuclei of the midbrain that may be associated with chronic social defeats consistently shown by male mice in special experimental settings. It has been shown that mRNA levels of the Tph, Maoa, Sert, Htr1a, Bdnf and Creb genes in the raphe nuclei of defeated mice are decreased as compared with the controls. The Bdnf and Creb genes as wells as the cell and metabolic Cphn, Gapdh, Hprt, B2M, Actb and 18S genes in the midbrain raphe nuclei are down-regulated under CSDS. Period of relative rest is not enough for most genes to recover expression to the control levels

Methods

Results

Conclusion