Comparative mRNA analysis of behavioral and genetic mouse models of aggression

Abstract

Mouse models of aggression have traditionally compared strains, most notably BALB/cJ and C57BL/6. However, these strains were not designed to study aggression despite differences in aggression-related traits and distinct reactivity to stress. This study evaluated expression of genes differentially regulated in a stress (behavioral) mouse model of aggression with those from a recent genetic mouse model aggression. The study used a discovery-replication design using two independent mRNA studies from mouse brain tissue. The discovery study identified strain (BALB/cJ and C57BL/6J) × stress (chronic mild stress or control) interactions. Probe sets differentially regulated in the discovery set were intersected with those uncovered in the replication study, which evaluated differences between high and low aggressive animals from three strains specifically bred to study aggression. Network analysis was conducted on overlapping genes uncovered across both studies. A significant overlap was found with the genetic mouse study sharing 1,916 probe sets with the stress model. Fifty-one probe sets were found to be strongly dysregulated across both studies mapping to 50 known genes. Network analysis revealed two plausible pathways including one centered on the UBC gene hub which encodes ubiquitin, a protein well-known for protein degradation, and another on P38 MAPK. Findings from this study support the stress model of aggression, which showed remarkable molecular overlap with a genetic model. The study uncovered a set of candidate genes including the Erg2 gene, which has previously been implicated in different psychopathologies. The gene networks uncovered points at a Redox pathway as potentially being implicated in aggressive related behaviors.

An integrated analysis of genes and functional pathways for aggression in human and rodent models

“…Nevertheless, similar pathways such as synaptic development, axon guidance and MAPK signaling emerge when examining genes from the top GWAS findings (P ≤ 5e-05, 11 ). These pathways were also enriched in genes identified through transcriptomic studies of animal models of aggression in mice 27 , 28 , rats 29 , zebrafish 30 and Drosophila 31 . With increasing sample sizes, some of these genes and, perhaps, additional risk loci may emerge in future GWASs.…”

Transcriptome analysis of genes and gene networks involved in aggressive behavior in mouse and zebrafish

“…For example, both 5‐HT1B ‐ [Saudou et al, ] and MAOA ‐ [Cases et al, ] knockout mice have been shown to display increased aggressive behavior compared to control mice. Transcriptomic characterisation of three pairs of mouse lines selectively bred for aggression found that the NF‐kB and MAPK gene pathways (redox‐signaling pathways) in the prefrontal cortex (PFC) are implicated in aggressive behavior and identified several novel candidate genes [Malki et al, , ; Freudenberg et al, ; Veroude et al, ].…”

Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice

“…Thus, the present study has revealed generalized increases of oxidative stress markers in the brain to parallel elevated scores of aggressive behaviour in mouse model emotional stress and these changes were reversed by the administration of thiamine and benfotiamine. Treatment with benfotiamine had a greater effect on reversing brain oxidative stress than thiamine, supporting previous observations that there may be increased bioavailability for benfotiaine in comparison to thiamine (Pan et al, 2010; (Rammal et al, 2010;Cline et al, 2015a;Malki et al, 2016).…”

“…Both genetic and environmental factors have been shown to regulate aggressive traits via complex codependent mechanisms (Caspi et al 2002;, but a causal role for environmental stress is well documented (Angkaw et al, 2013;Fanning et al, 2015Fanning et al, , 2017 and is associated with overt aggression in humans (Kim and Haller, 2007;Kessler et al, 2015). Experimental models have also provided support for this relationship (Veenema and Neumann, 2007;Rammal et al, 2010;Malki et al, 2016). In particular, emotional stress, which is referred to as state that is primarily triggered by the perception and cognitive evaluation of adverse events rather than a disturbance of physical nature (Chrouses and Gold, 1992;, appears to be the type of stress that most frequently results in overt aggressiveness (Angkaw et al, 2013;Fanning et al, 2015Fanning et al, , 2017.…”