Differential anxiety-related behaviours and brain activation in Tph2-deficient female mice exposed to adverse early environment

Eur Neuropsychopharmacol. 2018 Nov;28(11):1270-1283. doi: 10.1016/j.euroneuro.2018.07.103. Epub 2018 Aug 23.


Anxiety disorders represent one of the most prevalent mental disorders in today's society and early adversity has been identified as major contributor to anxiety-related pathologies. Serotonin (5-hydroxytryptamine, 5-HT) is implicated in mediating the effects of early-life events on anxiety-like behaviours. In order to further elucidate the interaction of genetic predisposition and adversity in early, developmental stages on anxiety-related behaviours, the current study employed tryptophan hydroxylase 2 (Tph2)-deficient female mice, as a model for lifelong brain 5-HT synthesis deficiency. Offspring of this line were exposed to maternal separation (MS) and tested, in the open-field (OF) or the dark-light box (DLB). Subsequently, neural activity was assessed, using c-Fos immunohistochemistry. In the DLB, MS rescued the observed decrease in activity in the light compartment of homozygous Tph2-deficient mice and furthermore increased the incidence of escape-related jumps in animals of the same genotype. In the OF, MS increased escape-related behaviours in homo- and heterozygous Tph2-deficient offspring. On the neural level, both behavioural tests evoked a distinct activation pattern, as shown by c-Fos immunohistochemistry. Exposure to the DLB resulted in Tph2-dependent activation of paraventricular nucleus and basolateral amygdala, while OF exposure led to a specific activation in lateral amygdala of maternally separated animals and a Tph2 genotype- and MS-dependent activation of the ventrolateral and dorsolateral periaqueductal grey. Taken together, our findings suggest that MS promotes active responses to aversive stimuli, dependent on the availability of brain 5-HT. These effects might be mediated by the distinct activation of anxiety-relevant brain regions, due to the behavioural testing.

Keywords: Anxiety; Behaviour; Maternal separation; Mouse; Serotonin; c-Fos.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / physiology
  • Animals
  • Anxiety / physiopathology*
  • Behavior, Animal / physiology
  • Brain / metabolism
  • Female
  • Maternal Deprivation*
  • Mice
  • Mice, Knockout
  • Paraventricular Hypothalamic Nucleus / physiology
  • Periaqueductal Gray / physiology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Serotonin / deficiency
  • Serotonin / physiology
  • Tryptophan Hydroxylase / genetics
  • Tryptophan Hydroxylase / physiology*


  • Proto-Oncogene Proteins c-fos
  • Serotonin
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase