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Title: Serotonin and threat : from gene to behaviour
Author: Quah, Shaun Kit Lung
ISNI:       0000 0004 8501 2261
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Anxiety and fear are emotions provoked by threatening situations and shape adaptive behaviours, but excessive and uncontrollable anxiety and fear form core symptoms of anxiety disorders. High trait anxiety, an individual's disposition to feel anxious, is associated with greater risk of developing depression and anxiety disorders. This raises the question: why are some more vulnerable to experiencing negative emotions associated with threat than others? As serotonin has been implicated as a key neuromodulator of emotion, the thesis addresses this question by adopting a multi-systems approach to investigate the link between serotonin and both threat-driven behaviour and trait anxiety with the common marmoset as a model. Firstly, factors underlying threat-related behaviour modelled with an exploratory factor analysis revealed a relationship between a predominantly avoidant fear coping style and an increased propensity for anxiety, establishing a link between specific fear-driven behavioural patterns and anxiety. After characterising anxiety and fear-driven behaviours, mRNA quantification of brain regions implicated in anxiety revealed serotonergic gene expressions corresponding to anxiety and fear-driven behaviours. Most notably, amygdala serotonin transporter expression was positively associated with anxious behaviour and was differentiated by the serotonin transporter polymorphism. Based on this association, the hypothesis that increased amygdala serotonin transporter expression may contribute to the high trait anxious phenotype was tested. Consistent with this hypothesis, blockade of amygdala serotonin transporters via local infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram reduced key characteristics of the high trait anxious phenotype: high state anxiety, and both the behavioural and physiological expression of conditioned fear. Anatomically, high anxious animals showed reduced basolateral amygdala (BLA) volume in adulthood. Moreover, BLA volume in adulthood was differentiated by the serotonin transporter polymorphism. During development, high anxious animals showed a delayed BLA growth trajectory. These findings demonstrate morphological changes in the BLA across different developmental timepoints predictive of high anxiety in adulthood. Taken together, findings here provide evidence of amygdala serotonin's role in trait anxious expression, and propose behavioural, genetic, molecular and anatomical factors that may contribute to an individual's vulnerability to anxiety.
Supervisor: Roberts, Angela Sponsor: MRC ; Wellcome Trust ; Malaysian Public Service Department
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Threat ; Anxiety ; Fear ; Serotonin ; Serotonin Transporter ; Amygdala ; Nonhuman primate ; Coping ; Neuroscience ; Emotion ; Emotion Regulation