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

Abstract

RationaleWhile 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.ObjectiveHere, 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.ResultsLocomotor 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-015-3879-0) contains supplementary material, which is available to authorized users.

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

“…37 More specifically, we did not observe any effect in the anxiety levels of the VMAT2 SERTcre -HET mice. We could have seen such an effect, in the light of the increased anxiety observed in SERT-KO mice 38 as well as to the decreased anxiety observed in both the VMAT2 SERTcre -KO mice 17 (decreased latency to eat in the NSFT) and in the Tph2-KO mice 39 (decreased time spent in the closed arms of the EPM). These later studies indicate a fairly straightforward association between anxiety state and extracellular 5-HT levels, both of which were lowered in VMAT2 SERTcre -KO and Tph2-KO mice and increased in SERT-KO mice.…”

Reward processing by the dorsal raphe nucleus: 5-HT and beyond

“…SERT knockout rats are unable to change behaviors based on expected reward values in a Pavlovian reinforcer devaluation paradigm (Nonkes et al 2010), and respond excessively to the conditioned stimuli in an operant conditioning task (Nonkes and Homberg 2013). Knocking out Tph2 results in impulsivity, hyper-aggression, and abnormal sociosexual behaviors (Savelieva et al 2008;Liu et al 2011;Angoa-Perez et al 2012;Kane et al 2012;Zhang et al 2013;Gutknecht et al 2015).…”

Outside the brain: an inside view on transgenic animal and stem cell-based models to examine neuronal serotonin-dependent regulation of HPA axis-controlled events during development and adult stages

“…As for the female mice, constitutive TPH2 −/− mothers are characterized by low maternal care. Stress-naïve TPH2 −/− females displayed low corticosterone metabolites levels in their feces, suggesting hypoactivity of the HPA system under basal conditions due to the lack of 5-HT (38). However, in case of chronic mild stress (CMS), the HPA axis seems to be over activated but adapted to the chronic stress exposure after 3 weeks (38,39).…”

“…Stress-naïve TPH2 −/− females displayed low corticosterone metabolites levels in their feces, suggesting hypoactivity of the HPA system under basal conditions due to the lack of 5-HT (38). However, in case of chronic mild stress (CMS), the HPA axis seems to be over activated but adapted to the chronic stress exposure after 3 weeks (38,39). While TPH2 −/− females reacted to CMS with an increased corticosterone synthesis, TPH2 −/− males remained insensitive to chronic and acute stress.…”

“…While TPH2 −/− females reacted to CMS with an increased corticosterone synthesis, TPH2 −/− males remained insensitive to chronic and acute stress. Due to CMS, the expression patterns of the glucocorticoid receptor and mineralocorticoid receptor were differentially, gender-dependently affected in constitutive TPH-2 −/− mice in multiple brain regions, including frontal cortex, hippocampus, raphé nuclei and septum [see supplemental data (38)]. Interestingly, serotonin transporter-deficient mice also showed stressinduced alterations in the adrenocortical stress response as measured by corticosterone metabolites excretion levels (40).…”