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Serotonin and Threat: from Gene to Behaviour


Type

Thesis

Change log

Authors

Quah, Shaun Kit Lung  ORCID logo  https://orcid.org/0000-0002-8857-1320

Abstract

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.

Description

Date

2019-03-22

Advisors

Roberts, Angela

Keywords

Threat, Anxiety, Fear, Serotonin, Serotonin Transporter, Amygdala, Nonhuman primate, Coping, Neuroscience, Emotion, Emotion Regulation

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Sponsorship
Work here was supported by an MRC Programme grant (ACR: MR/M023990/1) and performed within the Behavioural and Clinical Neuroscience Institute, University of Cambridge, funded jointly by the Wellcome Trust and MRC. SKLQ was supported by a scholarship by the Malaysian Public Service Department.