Serotoninergic modulation of hippocampal-prefrontal circuitry and the control of negative emotional regulation

Imagine walking down a dark street at night. Hearing unexpected footsteps behind you, you feel fear, your heart races, and you get ready to run - aspects of our complex emotional response. Abnormal emotional regulation causes major problems, and is seen in anxiety, depression, and schizophrenia. These disorders are treated with drugs influencing serotonin, but serotonin acts on many different brain regions and receptors. In disorders such as depression, specific brain regions are abnormal, including the amygdala (well known to influence emotional responses) but also the hippocampus and prefrontal cortex. How these structures contribute to normal emotional regulation, go wrong, and are influenced by serotonin is poorly understood. I will use tasks in monkeys that measure emotional biasing of perception (the glass half empty effect seen in depression), and how heart rate, blood pressure and behaviour alter in response to stimuli that unreliably predict emotional events. I will investigate the contribution of the hippocampus and prefrontal cortex to physiological and behavioural aspects of emotion by inactivating them, and altering their serotonin signalling using specific drugs. This will improve our understanding of how these regions control emotions and of the brain basis of disorders blighting the lives of millions.

The ability to regulate one‘s emotions appropriately in response to salient stimuli is crucial in our interaction with the environment. Emotional dysregulation features commonly in disorders such as depression and anxiety. It may result from cognition being abnormally biased by emotive stimuli, and from failure to integrate the behavioural and physiological aspects of emotional responses. However, the neural bases of emotional response integration and cognitive biases are poorly understood. Therapies for affective disorders primarily target serotonergic systems, while genetic polymorphisms affecting serotonin (5-HT) and alterations in 5-HT receptor levels are well documented within the affective disorders. Abnormal medial prefrontal cortex (mPFC) responses to affective feedback are seen in depressed patients and healthy humans following serotonergic manipulations, while hippocampal 5-HT is involved in the processing of some aversive cues. However, the roles of the hippocampus, mPFC, and their serotonergic innervation in the influence of emotional stimuli on cognitive processing and in emotional response integration are unknown. To investigate the negative interpretational bias seen in emotional responses to ambiguous stimuli in affective disorders (the ‘glass half empty‘ syndrome), a newly adapted behavioural paradigm will be applied to the marmoset, allowing discriminative performance and affective bias to be measured. Mood induction techniques will be used to produce an affective bias, and the effects of intra-hippocampal fluoxetine, intra-hippocampal 5-HT1A receptor antagonism, and intra-mPFC 5-HT2a receptor agonism and antagonism (in mPFC subregions of a priori interest) evaluated. This will identify the causal role of hippocampal and mPFC 5-HT in negative bias symptomatology. To investigate how these structures regulate the behavioural and physiological aspects of an emotional response, a remote telemetric procedure allowing simultaneous measurement of cardiovascular and behavioural responses to ambiguous emotive stimuli will be employed. Excitotoxic hippocampal and mPFC subregion lesions and inactivations will test hypotheses concerning the role of these structures in the acquisition, extinction and expression of autonomic and behavioural responses to ambiguously predictive cues, while focal administration of 5-HT1A/5HT2A agonists and antagonists will establish the serotonergic contribution to these behaviours. Together, these studies will identify how the hippocampus and mPFC contribute to abnormal emotive cognitive bias and dysregulation of the physiological and behavioural integration of an emotional response, and serotonin‘s contribution to such pathological processes. This information is critical to our understanding of the aetiology of specific symptom clusters within affective and other psychiatric disorders, and may eventually lead to developments in pharmacotherapy better targeted to dysfunctional regions of interest.