Abstract
Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2-/-) and heterozygous (Tph2+/-) mice, and their wildtype littermates (Tph2+/+) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2-/- mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2+/- mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2+/- mice when compared to their Tph2-/- littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.
Highlights
The serotonin (5-hydroxytryptamine; 5-HT) system is one of the brain’s key neuromodulatory systems and as such involved in the regulation of manifold behaviors (Lesch et al, 2012; Paul and Lowry, 2013; Ottenhof et al, 2018)
Post hoc analysis revealed that tryptophan hydroxylase 2 (Tph2)−/− maternal separation (MS) mice spent more time on the open arms than Tph2+/− (U = 21.0, p = 0.010) and Tph2+/+ (U = 9.0, p = 0.004) MS mice
Tph2−/− mice spent less time in the closed arms when compared to Tph2+/− (U = 166.0, p = 0.014) and Tph2+/+ (U = 153.0, p = 0.013) mice
Summary
The serotonin (5-hydroxytryptamine; 5-HT) system is one of the brain’s key neuromodulatory systems and as such involved in the regulation of manifold behaviors (Lesch et al, 2012; Paul and Lowry, 2013; Ottenhof et al, 2018). While the 5-HT system modulates the effects of stress, stress directly affects 5HT system function, reflecting an interaction of genetic and environmental factors. A suggested potential mechanism for this highly specific connectivity pattern is a 5-HT-dependent regulation of brain derived neurotrophic factor (Bdnf ). In support of this view, Bdnf expression was linked to early, 5-HT-induced epigenetic modifications at the Bdnf gene, (Boulle et al, 2016). Most effects of early-life adversity are sex-specific with regard to behavior, stress responses and 5-HT system mediation (McCormick et al, 1995; Veenema et al, 2007; García-Cáceres et al, 2010; van den Hove et al, 2014; Hiroi et al, 2016)
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