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

Abstract

The main neurotransmitters in the brain—dopamine, γ-aminobutyric acid (GABA), glutamate, and opioids—are recognized to be the most important for the regulation of aggression and addiction. The aim of this work was to study differentially expressed genes (DEGs) in the main reward-related brain regions, including the ventral tegmental area (VTA), dorsal striatum (STR), ventral striatum (nucleus accumbens, NAcc), prefrontal cortex (PFC), and midbrain raphe nuclei (MRNs), in male mice with 20-day positive fighting experience in daily agonistic interactions. Expression of opioidergic, catecholaminergic, glutamatergic, and GABAergic genes was analyzed to confirm or refute the influence of repeated positive fighting experience on the development of “addiction-like” signs shown in our previous studies. High-throughput RNA sequencing was performed to identify differentially expressed genes in the brain regions of chronically aggressive mice. In the aggressive mice, upregulation of opioidergic genes was shown (Oprk1 in VTA, Pdyn in NAcc, Penk in PFC, and Oprd1 in MRNs and PFC), as was downregulation of genes Opcml and Oprk1 in STR and Pomc in VTA and NAcc. Upregulation of catecholaminergic genes in VTA (Ddc and Slc6a2) and in NAcc (Th and Drd2) and downregulation of some differentially expressed genes in MRNs (Th, Ddc, Dbh, Drd2, Slc18a2, and Sncg) and in VTA (Adra2c, Sncg, and Sncb) were also documented. The expression of GABAergic and glutamatergic genes that participate in drug addiction changed in all brain regions. According to literature data, the proteins encoded by genes Drd2, Oprk1, Oprd1, Pdyn, Penk, and Pomc are directly involved in drug addiction in humans. Thus, our results confirm our earlier claim about the formation of addiction-like signs following repeated positive fighting experience in mice, as shown previously in our biobehavioral studies.

Whole‐brain mapping of monosynaptic afferent inputs to the CRH neurons in the medial prefrontal cortex of mice

“…The DR has previously been proven to be involved in the regulation of sleep–wake behavior (Cai et al., 2022), aggression, addiction (Smagin et al., 2022), depressive‐like behavior (Lin et al., 2022), thermal hypersensitivity (Liu et al., 2023), pain processing (Akbar et al., 2023), feeding inhibition (Aklan et al., 2023), mood control, and resilience to stress (Lopez‐Terrones et al., 2023). Previous studies have revealed that DR has more extensive connectivity with the cerebral cortex and basal ganglia.…”

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

“…This procedure was performed once a day for 20 days and yielded equal numbers of losers and winners. In this study, intermittent aggression was chosen for the experiment, in contrast to the strong daily aggression that was used in our previous study [16] (we distinguish three types of winners: strongly aggressive, aggressive, and intermittently aggressive). After that, the winners were deprived of the agonistic interactions for 14 days: the partition was not removed.…”

“…In our previous publication [16], we wrote that the expression of the same genes can increase in some brain regions and diminish in others. This likely means that gene expression can depend on the function of the brain region and on the cellular environment.…”

“…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].…”

“…There has been interest in the role of the mesolimbic dopaminergic circuit in the control over aggression reward [review [35][36][37] because dopaminergic projections from the VTA to the nucleus accumbens (NAcc) modulate both aggression intensity and dopamine (DA) levels [38,39]. Our attention in this research has been concentrated on neurotransmitter genes in the NAcc, which is involved in reward mechanisms [36,40,41] and in consequences of the repeated experience of aggression in mice [16,19,21,24].…”