Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala

• Published in: Frontiers in neuroscience Vol. 13; p. 460
• Main Authors: Weidner, Magdalena T, Lardenoije, Roy, Eijssen, Lars, Mogavero, Floriana, De Groodt, Lilian P M T, Popp, Sandy, Palme, Rupert, Förstner, Konrad U, Strekalova, Tatyana, Steinbusch, Harry W M, Schmitt-Böhrer, Angelika G, Glennon, Jeffrey C, Waider, Jonas, van den Hove, Daniel L A, Lesch, Klaus-Peter
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 10-05-2019; Frontiers Media S.A
• Subjects: Amygdala; Anxiety; Behavior; Brain; Cholecystokinin; Deoxyribonucleic acid; DNA; DNA fingerprinting; DNA methylation; Emotional behavior; Epigenetics; Gene expression; Genomes; Genotypes; maternal separation; Medicine; Mental health; Molecular modelling; mouse; Neonates; Neuroscience; Neurosciences; Phenotypes; Phenotypic variations; Proteins; Psychiatry; Psychotherapy; Ribonucleic acid; RNA; RNA expression; Science; Serotonin; Stress; Stress response; Tryptophan; Tryptophan hydroxylase; Netherlands; Germany; RNA expression; maternal separation; DNA methylation; mouse; serotonin; emotional behavior
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2019.00460

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
null mutant (
) and heterozygous (
) mice, and their wildtype littermates (
) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In
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.
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
genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and
mice when compared to their
littermates. On the genomic level, the interaction of
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.