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

Psychopharmacology (Berl). 2015 Jul;232(14):2429-41. doi: 10.1007/s00213-015-3879-0. Epub 2015 Feb 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / psychology
  • Behavior, Animal
  • Body Weight
  • Brain Chemistry / genetics*
  • Chronic Disease
  • Depression / psychology
  • Emotions*
  • Fear
  • Female
  • Gene-Environment Interaction
  • Hypothalamo-Hypophyseal System
  • Male
  • Mice
  • Mice, Knockout
  • Motor Activity
  • Neurosecretory Systems / physiopathology
  • Pituitary-Adrenal System
  • Serotonin / biosynthesis*
  • Sex Characteristics
  • Stress, Psychological / metabolism*
  • Tryptophan Hydroxylase / genetics*


  • Serotonin
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase