Abstract
BackgroundThe contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2−/−) are naturally highly aggressive, while heterozygous mice (Tph2+/−) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically ‘susceptible’ heterozygous mice (Tph2+/−). MethodsTph2+/− male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied. ResultsStressed Tph2+/− mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/− mice. LimitationsRescue experiments would help to verify causal relationships of reported changes. ConclusionsThe interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes.
Highlights
Aberrant social behaviours, aggression, violence and antisocial behavior, often accompany neurodevelopmental (De Giacomo et al, 2016) and neurodegenerative (Levenson et al, 2014) conditions, as well as depression (Knox et al, 2000) and stressrelated disorders (Van Voorhees et al, 2014)
In comparison to the non-stressed Tph2+/− group, stressed mutants displayed a decreased latency to attack (p=0.0169; Fig. 2A) and increases in the number and duration of attacks (p=0.023 and p=0.044, respectively; Fig. 2B,C). All these measures indicate that aggression is increased in Tph2+/− mice that are subject to stress
There were significant group differences in the latency to attack on days 3 and 5 (H=8.268, p=0.0408 and H=8.501, p=0.0367, respectively, Kruskal-Wallis test), where the stressed Tph2+/− mice exhibited a decrease in latency in comparison with stressed Tph2+/+ (p=0.0425 and p=0.0417, respectively; Fig. 2D)
Summary
Aggression, violence and antisocial behavior, often accompany neurodevelopmental (De Giacomo et al, 2016) and neurodegenerative (Levenson et al, 2014) conditions, as well as depression (Knox et al, 2000) and stressrelated disorders (Van Voorhees et al, 2014). In mice with complete genetic inactivation of TPH2 function (Tph2−/−), a lack of brain 5-HT results in increased aggression in the absence of an environmental stressor (AngoaPérez et al, 2012). Evident in these animals are impulsivity, anxiety-related behavior, and an increased fear response, which are all behavioural features that often accompany excessive aggression in animals (Coccaro et al, 2011; Neumann et al, 2009; Agis-Balboa et al, 2009). Conclusions: The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes
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