Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands.
Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany.
J Affect Disord. 2020 Jul 1;272:440-451. doi: 10.1016/j.jad.2020.04.014. Epub 2020 May 1.
The 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+/-).
Tph2+/- 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.
Stressed 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.
Rescue experiments would help to verify causal relationships of reported changes.
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.
导致过度攻击性的基因-环境相互作用的贡献尚不清楚。已知环境应激源和色氨酸羟化酶-2（TPH2）基因的突变会影响攻击性。例如，TPH2 基因缺失突变小鼠（Tph2-/-）天生具有高度攻击性，而杂合子小鼠（Tph2+/-）缺乏行为表型，被认为是内表型正常的。在这里，我们试图发现环境应激源是否会影响具有遗传“易感性”的杂合子（Tph2+/-）小鼠的表型。
将 Tph2+/-雄性小鼠或 Tph2+/+对照小鼠暴露于为期五天的大鼠应激范式中。研究了大脑 5-羟色胺代谢和选定的编码 5-羟色胺受体、AMPA 受体和应激标志物的基因的表达。
应激 Tph2+/-小鼠表现出攻击性和社会支配力增强，而 Tph2+/+动物的攻击性和支配力降低。与非应激动物相比，应激后前额叶皮层、纹状体、杏仁核、海马和背侧中缝核中所有组的 5-羟色胺、其前体羟基色氨酸和代谢物 5-羟吲哚乙酸的脑组织浓度均显著改变。与非应激动物相比，应激后杏仁核中 5-羟色氨酸浓度升高，而其他脑区浓度降低。在应激 Tph2+/-小鼠的大多数脑区中发现了 AMPA 受体亚基 GluA2 的过表达和 5-HT6 受体的下调，以及 c-fos 和糖原合酶激酶-3β（GSK3-β）的过表达。
挽救实验将有助于验证报告变化的因果关系。
TPH2 基因部分缺失与应激的相互作用导致病理性攻击行为和分子变化，并表明遗传易感性的存在可以增强表型似乎具有抗性的个体的攻击性。
