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

Psychopharmacology 2015 Jul

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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.

Citation

Lise Gutknecht, Sandy Popp, Jonas Waider, Frank M J Sommerlandt, Corinna Göppner, Antonia Post, Andreas Reif, Daniel van den Hove, Tatyana Strekalova, Angelika Schmitt, Maria B N Colaςo, Claudia Sommer, Rupert Palme, Klaus-Peter Lesch. Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice. Psychopharmacology. 2015 Jul;232(14):2429-41