Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice

Lise Gutknecht, Sandy Popp, Jonas Waider, Frank M. J. Sommerlandt, Corinna Goeppner, Antonia Post, Andreas Reif, Daniel van den Hove, Tatyana Strekalova, Angelika Schmitt, Maria B. N. Colaco, Claudia Sommer, Rupert Palme, Klaus-Peter Lesch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

65 Citations (Web of Science)


While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2(-/-)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2(-/-) males displayed increased impulsivity and high aggressiveness. Tph2(-/-) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2(-/-) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.
Original languageEnglish
Pages (from-to)2429-2441
Issue number14
Publication statusPublished - Jul 2015


  • Serotonin
  • Tryptophan hydroxylase-2 (Tph2)
  • Chronic stress
  • Gene-by-environment interaction
  • Anxiety
  • Fear
  • Depression
  • Aggression

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