Neurobiological and Neurochemical mechanisms underlying emotional regulation

Lead Research Organisation: University of Cambridge
Department Name: Physiology Development and Neuroscience

Abstract

Emotions are highly adaptive and complex states, which include our internal feelings, e.g. happiness or fear, our physiological reactions, e.g. sweaty palms, racing heart, and our behavioural responses e.g. approaching something nice and avoiding something harmful. They are triggered by stimuli in the environment, that through past experience, have gained emotional significance. However, our immediate reactions to such emotive stimuli are not always beneficial, and we need to be able to adapt and rapidly modify our emotional responses on a moment-by-moment basis, whether it?s in the workplace, or at home. The ability to regulate our emotions is essential for our physiological, psychological and social well-being and when this ability is impaired it can have a profound, deleterious impact on us. This is illustrated by the range of neuropsychiatric disorders in which emotional disturbance is a core feature, including anxiety, depression, schizophrenia, autism and sociopathy. Anxiety disorders alone have a lifetime prevalence of 16%. It has been shown that in many of these neuropsychiatric disorders there is pathology in various regions of the brain, including the orbitofrontal cortex and amygdala. In addition, there are also imbalances in a number of chemical messengers in the brain, including serotonin. Indeed, many drugs used to treat these neuropsychiatric disorders, target serotonin. However, exactly how these brain regions contribute to emotional regulation, and the role played by serotonin, is poorly understood. We will investigate this by modelling their effects in the brains of experimental animals performing behavioural tests that measure their ability to regulate their emotions. The benefits provided by this Programme lie eventually in understanding how these different regions of the brain control our emotions and how serotonin modulates these brain regions. This information is critical for our ability to develop novel therapies, as well as target current therapies more effectively, for a range of neuropsychiatric

Technical Summary

Emotions are highly adaptive and complex states, simultaneously engaging psychological, physiological and behavioral responses that are triggered by the appraisal of external events. However, our immediate reactions to emotive stimuli are not always beneficial, and therefore, an important element of emotion is the ability to appropriately adapt and rapidly modify emotional responses on a moment-by-moment basis. That such regulation is essential for the physiological, psychological and social health of the individual is clearly illustrated by the range of neuropsychiatric disorders in which emotional dysregulation is a core feature, including anxiety, depression, schizophrenia, autism and sociopathy. In all of these disorders there is neuropathology or neurochemical imbalances in neural circuitry that includes the amygdala and orbitofrontal cortex (OFC). Defining the underlying mechanisms by which this orbitofrontal-amygdala circuit contributes to distinct aspects of affective processing will help us to understand the underlying behavioural and social deficits in these disorders. It will also help us to develop new treatments and target current treatments more effectively.
This Programme will investigate the neural and neurochemical substrates of emotional regulation focussing on the OFC and the amygdala and their modulation by the neurotransmitter, serotonin. Major components of emotions are the physiological responses that accompany behaviour including autonomic, neuroendocrine and somatic. These changes in the internal state of the body anticipate, facilitate and accommodate the consequences of our actions. Thus, key cardiovascular variables, namely heart rate and blood pressure will be monitored alongside behaviour. We hypothesise that distinct elements of the orbitofrontal-amygdala circuit are involved in regulating our emotional reactions to cues in the environment that predict appetitive and aversive stimuli, as well as in regulating our instrumental actions, guided by those cues, to obtain or avoid such stimuli. We will assess the role of distinct sub-regions of the OFC in these different aspects of regulation and determine whether such processing is independent, or not, of affective valence. We will also identify the key role played by serotonin, both at the level of the OFC and at the level of the amygdala, in modulating these different aspects of regulation in both the appetitive and the aversive domain. Particular attention will be paid to how dysfunction within the orbitofrontal-amygdala circuit contributes to anxiety and whether changes in serotonergic modulation of this circuit underlie individual differences in anxiety.
 
Description Member of Council of Understanding Animal Research
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Understanding Animal Research provides information and educational materials based on thorough research and understanding of the facts, historical and scientific. Understanding Animal Research seeks to engage with and inform many sectors to bring about its vision. Key stakeholders include members of the public, the media, policy makers, schools and the scientific research community.
URL http://www.understandinganimalresearch.org.uk/
 
Description Investigator award
Amount £2,021,861 (GBP)
Funding ID 108089/Z/15/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Senior Investigator Award
Sector Charity/Non Profit
Country United Kingdom
Start 06/2016 
End 05/2021
 
Description Programme grant
Amount £1,560,000 (GBP)
Funding ID 089589/Z/09/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2010 
End 11/2014
 
Title Cortisol from saliva 
Description Measure of emotional function using a non invasive procedure. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2011 
Provided To Others? Yes  
Impact Provide more in depth analysis of emotional function. 
 
Title Dexamethasone suppression test 
Description A method for measuring the reactivity of the hypothalamic-pituitary axis, highly relevant to our understanding of human mood and anxiety disorders. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2011 
Provided To Others? Yes  
Impact A more thorough analysis of emotionality in marmosets. 
 
Title Measurement of anxiety 
Description Characterisation of behavioural responses related to anxiety using Principle Components analysis 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2012 
Provided To Others? Yes  
Impact A more robust measure of anxiety 
URL http://www.ncbi.nlm.nih.gov/pubmed/22502990
 
Title MicroPET to measure functional activity 
Description MicroPET imaging using 18FDG to measure functional activity across brain regions related to behavioural processes 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact This new approach will open up a whole new set of questions that we can address in our research 
 
Title Serotonin transporter polymorphism in animals 
Description A functional polymorphism has been identified in animals relevant to our understanding of trait anxiety and mood and anxiety disorders. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2012 
Provided To Others? Yes  
Impact This opens up a whole new approach to studying the genetic and neurobiological underpinnings of mood and anxiety disorders. 
 
Title microPET measurement of D2 and 5-HT2a receptors 
Description microPET imaging to measure dopamine D2 receptors and serotonin 5-HT2a receptors in anaethetised animals. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2014 
Provided To Others? Yes  
Impact Expansion of experimental research approaches for addressing scientific questions into the regulation of emotion and its neural underpinnings. 
URL http://www.ncbi.nlm.nih.gov/pubmed/24872570
 
Title port implant 
Description We have developed a method to infuse radioactive ligand directly into the jugular vein of marmosets but using a subcutaneous port implant so the marmoset receives minimal discomfort. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact It allows us to perform microPET imaging measuring FluoroDexoxyGlucose uptake as a measure of brain activity in freely moving marmosets. 
 
Description Brasilia 
Organisation University of Brasilia
Country Brazil 
Sector Academic/University 
PI Contribution Expertise and intellectual input
Collaborator Contribution Access to data, equipment and facilities
Impact Exchange of techniques
Start Year 2014
 
Description Contributing to a large marmoset programme between the Riken Institute in Japan and Cold Spring Harbour in the USA to map connectivity of brain networks in marmosets 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution I spent a week in October 2017 performing tracer injections in prefrontal regions of the marmoset prefrontal cortex
Collaborator Contribution They co-ordinated the surgery and are performing the analysis
Impact None so far
Start Year 2017
 
Description MRC neurochemist training Programme II 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution We will be investigating the relationship of mgluR5 receptor binding in target brain regions including orbitofrontal cortex, insula and ventral striatum, with trait anxiety.
Collaborator Contribution My partners will be developing and providing the mgluR5 ligand, 18F[FPEB] and will also be performing all the analyses.
Impact not yet started
Start Year 2013
 
Description MRC neurochemist training programme 
Organisation University of Cambridge
Department Wolfson Brain Imaging Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution We investigated 5-HT2a receptor binding distribution in the brains of marmosets with different alleles of the serotonin transporter gene and related this to trait anxiety.
Collaborator Contribution They provided the 5-HT2a receptor ligand, 18F altanserin, and performed the analyses of the dataset.
Impact Society for Neuroscience poster 2012
Start Year 2010