TY  - JOUR
A1  - Gutknecht, Lise
A1  - Popp, Sandy
A1  - Waider, Jonas
A1  - Sommerlandt, Frank M. J.
A1  - Göppner, Corinna
A1  - Post, Antonia
A1  - Reif, Andreas
A1  - van den Hove, Daniel
A1  - Strekalova, Tatyana
A1  - Schmitt, Angelika
A1  - Colaςo, Maria B. N.
A1  - Sommer, Claudia
A1  - Palme, Rupert
A1  - Lesch, Klaus-Peter
T1  - Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice
JF  - Psychopharmacology
N2  - Rationale
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.

Objective
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.

Results
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.

Conclusions
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.
KW  - Serotonin
KW  - Tryptophan hydroxylase-2 (Tph2)
KW  - chronic stress
KW  - gene-by-environment interaction
KW  - anxiety
KW  - fear
KW  - depression
KW  - aggression
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154586
VL  - 232
SP  - 2429
EP  - 2441
ER  -