Effects of chronic lithium treatment on anxious behaviors and serotonergic genes expression in the midbrain raphe nuclei in defeated male mice

AbstractThere are experimental data that mixed anxiety/depression-like state induced by chronic social defeat stress is accompanied by development of anxiety and downregulation of serotonergic gene expression in the midbrain raphe nuclei of male mice. The paper aimed to study the effect of chronic lithium chloride (LiCl) on anxious behaviors and the expression of serotonergic genes (Tph2, Slc6a4, Htr1a, Htr5b) in the midbrain raphe nuclei of defeated mice. Slight anxiolytic effects of LiCl were found on the commucativeness in the partition test, and anxiogenic-like effects, estimated by the elevated plus-maze and social interactions tests. Chronic LiCl treatment induced overexpression of the serotonergic genes in the midbrain raphe nuclei of defeated mice. We can assume that effects of LiCl, rather anxiogenic, may be due to activation of serotonergic system induced by hyperexpression of serotonergic genes. Our findings will allow to understand the factors involved in the positive and side effects of lithium on anxiety and function of serotonergic genes which are involved into mechanisms of depression.

Download Full-text

Chronic Lithium Treatment Affects Anxious Behaviors and theExpression of Serotonergic Genes in Midbrain Raphe Nuclei of Defeated Male Mice

Biomedicines ◽

10.3390/biomedicines9101293 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1293

Author(s):

Dmitry A. Smagin ◽

Irina L. Kovalenko ◽

Anna G. Galyamina ◽

Irina V. Belozertseva ◽

Nikolay V. Tamkovich ◽

...

Keyword(s):

Lithium Treatment ◽

Social Defeat ◽

Raphe Nuclei ◽

Male Mice ◽

Social Defeat Stress ◽

Agonistic Interactions ◽

Chronic Social Defeat Stress ◽

Partition Test ◽

Midbrain Raphe Nuclei ◽

Raphé Nuclei

There is experimental evidence that chronic social defeat stress is accompanied by the development of an anxiety, development of a depression-like state, and downregulation of serotonergic genes in midbrain raphe nuclei of male mice. Our study was aimed at investigating the effects of chronic lithium chloride (LiCl) administration on anxiety behavior and the expression of serotonergic genes in midbrain raphe nuclei of the affected mice. A pronounced anxiety-like state in male mice was induced by chronic social defeat stress in daily agonistic interactions. After 6 days of this stress, defeated mice were chronically treated with saline or LiCl (100 mg/kg, i.p., 2 weeks) during the continuing agonistic interactions. Anxiety was assessed by behavioral tests. RT-PCR was used to determine Tph2, Htr1a, Htr5b, and Slc6a4 mRNA expression. The results revealed anxiolytic-like effects of LiCl on social communication in the partition test and anxiogenic-like effects in both elevated plus-maze and social interaction tests. Chronic LiCl treatment upregulated serotonergic genes in midbrain raphe nuclei. Thus, LiCl effects depend on the treatment mode, psycho-emotional state of the animal, and experimental context (tests). It is assumed that increased expression of serotonergic genes is accompanied by serotonergic system activation and, as a side effect, by higher anxiety.

Download Full-text

Correlation of Expression Changes between Genes Controlling 5-HT Synthesis and Genes Crh and Trh in the Midbrain Raphe Nuclei of Chronically Aggressive and Defeated Male Mice

Genes ◽

10.3390/genes12111811 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1811

Author(s):

Olga E. Redina ◽

Vladimir N. Babenko ◽

Dmitry A. Smagin ◽

Irina L. Kovalenko ◽

Anna G. Galyamina ◽

...

Keyword(s):

Gene Networks ◽

Raphe Nuclei ◽

Male Mice ◽

Gene Encoding ◽

Physiological Processes ◽

Expression Of Genes ◽

Tph2 Gene ◽

System Functioning ◽

Midbrain Raphe Nuclei ◽

Raphé Nuclei

Midbrain raphe nuclei (MRNs) contain a large number of serotonergic neurons associated with the regulation of numerous types of psychoemotional states and physiological processes. The aim of this work was to study alterations of the MRN transcriptome in mice with prolonged positive or negative fighting experience and to identify key gene networks associated with the regulation of serotonergic system functioning. Numerous genes underwent alterations of transcription in the MRNs of male mice that either manifested aggression or experienced social defeat in daily agonistic interactions. The expression of the Tph2 gene encoding the rate-limiting enzyme of the serotonin synthesis pathway correlated with the expression of many genes, 31 of which were common between aggressive and defeated mice and were downregulated in the MRNs of mice of both experimental groups. Among these common differentially expressed genes (DEGs), there were genes associated with behavior, learning, memory, and synaptic signaling. These results suggested that, in the MRNs of the mice, the transcriptome changes associated with serotonergic regulation of various processes are similar between the two groups (aggressive and defeated). In the MRNs, more DEGs correlating with Tph2 expression were found in defeated mice than in the winners, which is probably a consequence of deeper Tph2 downregulation in the losers. It was shown for the first time that, in both groups of experimental mice, the changes in the transcription of genes controlling the synthesis and transport of serotonin directly correlate with the expression of genes Crh and Trh, which control the synthesis of corticotrophin- and thyrotropin-releasing hormones. Our findings indicate that CRH and TRH locally produced in MRNs are related to serotonergic regulation of brain processes during a chronic social conflict.

Download Full-text