title: Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice.
abstract: BACKGROUND
  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.
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Lise
authors.initials: L
authors.lastname: Gutknecht
authors.forename: Sandy
authors.initials: S
authors.lastname: Popp
authors.forename: Jonas
authors.initials: J
authors.lastname: Waider
authors.forename: Frank M J
authors.initials: FM
authors.lastname: Sommerlandt
authors.forename: Corinna
authors.initials: C
authors.lastname: Göppner
authors.forename: Antonia
authors.initials: A
authors.lastname: Post
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.forename: Daniel
authors.initials: D
authors.lastname: van den Hove
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
authors.forename: Angelika
authors.initials: A
authors.lastname: Schmitt
authors.forename: Maria B N
authors.initials: MB
authors.lastname: Colaςo
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.forename: Rupert
authors.initials: R
authors.lastname: Palme
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal; D001835:Body Weight; D001923:Brain Chemistry / Q000235:genetics*; D002908:Chronic Disease; D003863:Depression / Q000523:psychology; D004644:Emotions; D005239:Fear; D005260:Female; D059647:Gene-Environment Interaction; D007030:Hypothalamo-Hypophyseal System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009490:Neurosecretory Systems / Q000503:physiopathology; D010913:Pituitary-Adrenal System; D012701:Serotonin / Q000096:biosynthesis*; D012727:Sex Characteristics; D013315:Stress, Psychological / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000235:genetics*
chemical_list: D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase