Elucidation of the Landscape of Alternatively Spliced Genes and Features in the Dorsal Striatum of Aggressive/Aggression-Deprived Mice in the Model of Chronic Social Conflicts

Abstract

Both aggressive and aggression-deprived (AD) individuals represent pathological cases extensively studied in psychiatry and substance abuse disciplines. We employed the animal model of chronic social conflicts curated in our laboratory for over 30 years. In the study, we pursued the task of evaluation of the key events in the dorsal striatum transcriptomes of aggression-experienced mice and AD species, as compared with the controls, using RNA-seq profiling. We evaluated the alternative splicing-mediated transcriptome dynamics based on the RNA-seq data. We confined our attention to the exon skipping (ES) events as the major AS type for animals. We report the concurrent posttranscriptional and posttranslational regulation of the ES events observed in the phosphorylation cycles (in phosphoproteins and their targets) in the neuron-specific genes of the striatum. Strikingly, we found that major neurospecific splicing factors (Nova1, Ptbp1, 2, Mbnl1, 2, and Sam68) related to the alternative splicing regulation of cAMP genes (Darpp-32, Grin1, Ptpn5, Ppp3ca, Pde10a, Prkaca, Psd95, and Adora1) are upregulated specifically in aggressive individuals as compared with the controls and specifically AD animals, assuming intense switching between isoforms in the cAMP-mediated (de)phosphorylation signaling cascade. We found that the coding alternative splicing events were mostly attributed to synaptic plasticity and neural development-related proteins, while the nonsense-mediated decay-associated splicing events are mostly attributed to the mRNA processing of genes, including the spliceosome and splicing factors. In addition, considering the gene families, the transporter (Slc) gene family manifested most of the ES events. We found out that the major molecular systems employing AS for their plasticity are the ‘spliceosome’, ‘chromatin rearrangement complex’, ‘synapse’, and ‘neural development/axonogenesis’ GO categories. Finally, we state that approximately 35% of the exon skipping variants in gene coding regions manifest the noncoding variants subject to nonsense-mediated decay, employed as a homeostasis-mediated expression regulation layer and often associated with the corresponding gene expression alteration.

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

“…The transcriptomic changes of gene expression get reversed only partially after a period of no fights. Similar data have been obtained about the STR [21].…”

“…Research on the influence of positive fighting experience in daily agonistic interactions on mice has also been the focus of N.N. Kudryavtseva with colleagues for a long period [e.g., [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Experimental data indicate that male mice that had a repeated aggressive experience accompanied by wins develop a behavioral psychopathology [11][12][13]17,18], which has been verified by data on the development of psychoneurological symptoms.…”

“…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].…”