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

Abstract

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.

Altered Expression of Genes Associated with Major Neurotransmitter Systems in the Reward-Related Brain Regions of Mice with Positive Fighting Experience

“…In this work and in our previous studies [ 25 , 26 , 45 , 46 , 47 , 48 , 59 ], we focus on DEGs encoding proteins that are related to reward-associated neurotransmitters in the brain: opioid-, catecholamine-, GABA-, and glutamatergic systems, which partake in the regulation of aggression in the VTA, STR, and NAcc (which are considered the main regions implicated in aggression stimulation) and in the MRNs and PFC, which as a rule, perform inhibitory functions toward aggressive behavior [ 6 ].…”

“…Analysis of the RNA-Seq database of MRNs [ 48 ] revealed the largest number of DEGs of interest in this main region processes ( Figure 5 A, Supplementary Table S1 ). Opioidergic gene Oprd1 was upregulated ( p = 0.009) and CAergic genes were downregulated: Th ( p < 0.001; q = 0.035), Ddc ( p < 0.001; q = 0.005), Dbh ( p < 0.001; q = 0.005), Sncg ( p < 0.046), Drd2 ( p = 0.03), and Slc18a2 ( p = 0.04).…”

“…[ 50 ]. + These data were obtained by the RT-PCR method [ 26 , 27 ]; # full transcriptomic data are presented in [ 45 , 46 , 47 , 48 ].…”

Neurotransmitter Genes in the Nucleus Accumbens that Are Involved in the Development of Behavioral Pathology After Positive Fighting Experiences and Their Deprivation. A Conceptual Paradigm for Neurogenomic Data Analysis

“…It has been well known that the main neurotransmitter systems-catecholaminergic (CAergic), serotonergic, opioidergic, GABAergic, and glutamatergic-are involved in the mechanisms of reward, drug abuse, addiction, and aggression [e.g., 6,12,[28][29][30][31][32][33]. Our neurotranscriptomic and cellular studies on mice experienced in aggression have revealed alterations of the expression of numerous genes specific for brain regions depending on their main functions in the regulation of aggression mechanisms [16,[18][19][20][21][22][23][24]34]. For example, in the VTA, which is the main brain region involved in reward mechanisms, an increase has been revealed in the expression of CAergic (Th, Ddc, Slc6a2, and Slc6a3), glutamatergic (Slc17a7 and Slc17a8), and opioidergic (Oprk1) genes (and others) encoding relevant proteins [16].…”

Advances of Brain Transcriptomics

“…It is known that MRNs contain a large number of serotonergic neurons associated with the regulation of numerous types of psycho-emotional states and physiological processes. The article by Redina and colleagues focuses on an analysis of the co-expression of DEGs and Tph2-encoding tryptophan hydroxylase 2, the rate-limiting enzyme of the serotonin synthesis pathway [ 4 ]. The results showed that Tph2 expression correlated with the expression of many DEGs, associated with behavior, learning, memory, and synaptic signaling.…”