The Regulatory Mechanism Of Serotonin On Emotional Processing

The neurotransmitter serotonin(5-hydroxytryptamine,5-HT)is synthesized in the raphe nuclei and dense serotonergic projections from these nuclei enervate limbic and frontal brain regions.Serotonin plays a key role in structural and functional brain development and neuroplasticity by modulating neural progenitor cell proliferation,migration and differentiation,maturation of postmitotic neurons and apoptosis during the development of brain.Moreover,serotonin regulates a number of emotional and social cognitive processes,including anxiety,emotion regulation and social interactions.Together this has made the serotonin system a potential treatment target for mental disorders with emotional and social dysfunctions,particularly anxiety disorders,depression and autism spectrum disorders.Although initial animal studies suggest that the regulatory role of the serotonin system on social-emotional brain systems is influenced by environmental factors(e.g.early developmental environment)and interactions with other neurotransmitter systems such as oxytocin the influence of these individual factors has not been examined in humans.To address the interactions of the serotonin system with early life stress and the oxytocin system in humans three studies were designed.These studies combined behavioral and neuroimaging assessments with pharmacological and genetic methods to explore the effects of serotonin on emotional processing in interaction with early life stress and oxytocin,and the underlying cognitive and neural mechanisms.These findings may provide a more detailed understanding of the complex role of the serotonin system.Study 1 investigated interaction effects between early life stress(ELS)and serotonin on the structural and functional organization of the brain and an anxious-avoidant phenotype in humans.To this end the present study combined a dimensional imaging approach with genetics and phenotype trait assessments in a large sample of healthy young adult subjects(252 healthy subjects,129 males).Before the MRI scanning,early life and current stress and anxious avoidant behavior were assessed via self-report questionnaires(e.g.childhood trauma questionnaire,perceived stress scale and sensitivity to punishment scale).Buccal cells were collected for genotyping of the tryptophan hydroxylase 2(TPH2)polymorphism which regulates central serotonin biosynthesis rates.Next structural and resting state(f)MRI data were acquired.The current study found that TPH2 rs4570625 genotype and early life stress interact to affect the structural and functional architecture of thalamic-limbic-prefrontal circuits.Specifically,we observed that in TT homozygotes higher early life stress exposure was associated with increased volumes of hippocampal-amygdala,thalamic and frontal regions and decreased functional connectivity between left dorsal anterior cingulate gyrus and left amygdala.In TT homozygotes,higher levels of sensitivity to punishment on the phenotype level were associated with both higher exposure to early life stress and increased limbic and frontal brain volumes.No associations were observed in the G-carrier groups.In an independent replication sample(51 healthy males),associations between higher early life stress and increased frontal volumes in TT carriers were confirmed.Furthermore,the results showed that TPH2 genotype significantly moderated the impact of ELS on punishment sensitivity.An additional mediation analysis furthermore suggests that increased brain volumes in this circuitry critically mediate the impact of adverse childhood experiences on sensitivity to punishment solely in TT carriers.The findings suggest that early life stress shapes the structural and functional architecture of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance,thus promoting early adaptation to an adverse environment.Study 1 found evidence that serotonin levels can modulate the complex associations between threat-related behavior and limbic emotion processing regions while recent animal models demonstrated that interactions of the serotonin system with the oxytocin system modulate social emotional behavior and limbic brain activity.Therefore study 2 aimed at examining interactive effects of serotonin and oxytocin on amygdala threat processing.The study combined therefore an acute tryptophan depletion protocol which induces a robust decrease in central serotonergic signaling with the intranasal administration of oxytocin in 121 healthy male subjects to investigate how the interaction between serotonin and oxytocin may modulate threat-related amygdala processing as measured by task-f MRI.We found that oxytocin switched bilateral amygdala threat sensitization to desensitization and that this effect of oxytocin was significantly attenuated-yet not fully abolished-during decreased central serotonergic signaling following acute tryptophan depletion.Together,these findings suggest that serotonin and oxytocin interact to modulate amygdala threat desensitization,and that serotonin plays an important role in the complex social-emotional effects observed after oxytocin administration.Based on the results from Study 2,study 3 examined the interaction of serotonin and oxytocin on the amygdala networks during the resting state.121 healthy males,same with the sample in study 2,underwent the acute tryptophan depletion and intranasal oxytocin administration before resting state f MRI.We found significant interaction effects on the functional connectivity between the amygdala and the hippocampus.Oxytocin significantly increased the strength of functional connectivity between the left amygdala and left hippocampus relative to the placebo-reference group,whereas this effect of oxytocin was significantly attenuated during decreased central serotonergic signaling following acute tryptophan depletion.Together,the present findings provide the first evidence that the interaction between serotonin and oxytocin modulates the functional connectivity between the amygdala and hippocampus,which play important roles in anxiety,stress and emotional memory formation.Taken together,the current study combined MRI neuroimaging with genetic and pharmacological methods to explore the complex effects of serotonin on brain regions related to emotional processing.We found that serotonin interacts with early life stress to shape the structure and function of limbic-frontal systems and that serotonin interacts with oxytocin to modulate limbic brain activity and connectivity.The current study moreover may have important information for the application of serotonin research,for example by providing important hints for the optimization of treatment plans and personalized treatment.