Abstract
Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKO × MS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.
Highlights
Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation
Few 5-HT positive cells in the raphe region remained, which may point to ineffective nuclear translocation of tryptophan hydroxylase-2 gene (Tph2)-CreERT2 probably due to reduced expression of Tph[2] in certain 5-HT immunoreactive neurons, we achieved similar recombination efficiencies as reported for other induced Tph[2] KO mice using CMV-CreERT2 transgenics as Cre driver line[41] or using AAV-Cre viral injection into the rostral raphe n uclei[42]
Efficient reduction of brain 5-HT and 5-hydroxyindolacetic acid (5-HIAA) within 4 weeks of TAM treatment has previously been reported[43], which indicates that the TAM-mediated induction approach requires a relatively long time period before a significant deficiency in brain 5-HT concentration is established
Summary
Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Genetic manipulation in mice, which results in embryonic inactivation of Tph[2] or other 5-HT neuron development-related genes (e.g. Pet[1], Lmx1b), provided insight into the behavioral and physiological consequences of 5-HT deficiency in the brain[14,15]. Several studies showed that neonates with a constitutive Tph[2] inactivation present viability and growth-related problems compared to wildtype counterparts[16,17] While these mice retain normal 5-HT neuron morphology and physiology, and are indistinguishable from controls in adulthood[18,19], several behavioral phenotypes have been reported[20,21,22]. Partly, dependent on 5-HT during brain m aturation[23,24] and may result in structural and functional differences of the networks involved in emotional processing of mice lacking T ph[225]
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