Positive affective states:a behavioural,autonomic and neural analysis.

Lead Research Organisation: University of Cambridge
Department Name: Anatomy

Abstract

Emotional disturbance is found in a number of psychiatric disorders including depression, autism, schizophrenia, obsessive compulsive disorder and frontal lobe dementia. However, the specific psychological nature of these deficits is poorly understood as is the nature of the brain damage causing such disturbances. To address these issues it is important that we have an understanding of the basic psychological processes that contribute to an emotional response and the neural structures and chemicals in the brain that control these processes. This application considers these questions with respect to positive emotional responses in a new world primate. To do this we have devised tests that will enable us to study different aspects of positive emotion. Thus, positive emotional responses may be elicited by the pleasure of eating a particularly tasty meal but also in wandering around Tesco?s selecting what foods you?re going to buy for a dinner party. The former is thought of as a primary reward while the latter are stimuli that evoke the thought of reward (called conditioned stimuli) and that can be rewarding in their own right. Indeed, learning about stimuli in the environment that predict reward and that take on reinforcing value in their own right is highly advantageous as it allows us to be able to anticipate and prepare for that reward and also to be motivated enough to go out and find the reward. This is equally true for negative situations in which hearing the bark of a neighbours vicious dog is enough to keep you out of harms way. We therefore propose to present marmosets with intrinsically neutral stimuli such as a light or tone that predict highly tasty food reward and under certain circumstances require the animal to learn a response to gain access to the primary reward or the conditioned stimulus in order to study what parts of the brain and chemicals in the brain allow an animal to learn about these stimuli and to show positive emotional reactions to these stimuli including changes in bodily responses that accompany such reactions. We will investigate the contribution made by two specific brain structures, the prefrontal cortex and amygdala in positive emotion as well as how they are modulated by particular chemicals. The benefits provided by this Programme lie in understanding the neuropsychological and neurochemical basis of emotion, information that can contribute to the development of pharmacological treatment strategies for various neuropsychiatric disorders.

Technical Summary

Emotional disturbance is a major component of a variety of neuropsychiatric and neurodegenerative disorders including depression, schizophrenia, autism, sociopathy and dementia of the frontal lobe type. In all of these disorders there is neuropathology or neurochemical imbalances in the neural circuitry that includes the amygdala, orbitofrontal cortex (OFC) and ventral regions of medial prefrontal cortex (vMPFC). Therefore defining the differential contribution of these neural structures and their neurochemical modulation to distinct aspects of affective processing will help us to understand the underlying behavioural and social deficits in these disorders and help us to target treatments more effectively and develop new treatments.
Emotion is a highly adaptive and complex response incorporating psychological, physiological and behavioural components. An important function of emotion is to produce appropriate anticipatory responses to improve chances of survival. Thus, when stimuli in the environment predict pain, a negative state of fear is induced, accompanied by peripheral and central arousal, along with behavioural arousal that promotes avoidance. A similar scenario occurs when stimuli in the environment predict reward but in this case, a positive state of anticipation is induced that also leads to heightened peripheral and central arousal, with the accompanying behavioural arousal facilitating approach. However our knowledge of the neural mechanisms underlying peripheral arousal and the significance of the visceral feedback on the development and maintenance of affective states is poor and therefore, so is our understanding of the neural mechanisms that together produce these integrated responses.
This research programme proposes to study positive affective states in a New World primate, the common marmoset, using a novel procedure by which autonomic activity can be measured in a freely moving, behaving, marmoset. Thus we intend to define autonomic arousal in a variety of affective contexts including the development of anticipatory affective states triggered not only by environmental stimuli but also ones own actions; the maintenance of such states and their flexibility in response to changing environmental circumstances. The complementary but separable roles of the OFC, vMPFC and amygdala to these distinct affective contexts will then be explored using bilateral excitotoxic lesions of individual structures as well as the disconnection of structures using crossed lesion techniques along with multiple measures of the affective response including different types of behaviour and a variety of cardiovascular measures. An additional goal is to investigate the relationship between autonomic feedback, the affective response and its underlying neural substrate including the central role of noradrenaline.

Publications

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Braesicke K (2005) Autonomic arousal in an appetitive context in primates: a behavioural and neural analysis. in The European journal of neuroscience

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Parkinson JA (2005) Acquisition of instrumental conditioned reinforcement is resistant to the devaluation of the unconditioned stimulus. in The Quarterly journal of experimental psychology. B, Comparative and physiological psychology

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Reekie YL (2008) Uncoupling of behavioral and autonomic responses after lesions of the primate orbitofrontal cortex. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Post Weatherall Review meeting including government advisors, Wellcome Trust and MRC
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact To maintain a body of information about the benefits of animal research and to continue to work together to maintain good practice for primate research and to influence european policy
URL https://royalsociety.org/policy/publications/2006/weatherall-report/
 
Description MRC Programme grant
Amount £1,278,456 (GBP)
Funding ID G0901884 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2010 
End 03/2015
 
Title model of anxiety in animals 
Description We have recently developed a model of anxiety in animals using a fear discrimination paradigm and the human intruder test. These tests differentiate individual differences in anxiety and initial analysis shows a correspondence between the anxiety measures on the two tests. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2014 
Provided To Others? Yes  
Impact This model will enable this animal model to be used to investigate the neural circuitry underlying anxiety and to investigate novel treatments 
URL http://www.ncbi.nlm.nih.gov/pubmed/24795587
 
Description McDonnell Foundation 
Organisation James S. McDonnell Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution We have been developing genotyping methods in the marmoset to investigate the relationship between polymorphisms in the genes that regulate serotonin and behavioural traits, including anxiety. In addition we have been investigating the effects of serotonin manipulations in the orbitofrontal cortex on sensitivity to negative feedback.
Collaborator Contribution The partners (E Phelps, TW Robbins, J LeDoux) have had meetings with my lab and have disseminated their work and discussed their ideas openly.
Impact We have successfully identified a functional polymorphism in the regulatory region of the serotonin transporter gene. Presented at Society for Neuroscience conference 2010
Start Year 2008
 
Description Newspaper article:Guardian 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I accepted a Guardian Science correspondent and his photographer into the marmoset unit to discuss the nature of our research and why using primates was essential for that research. The article was subsequently printed as a double page spread in the Guardian but for security reasons we remained anonymous.

Overall, the article appeared to be received favorably which is a good thing for primate research in this country.
Year(s) Of Engagement Activity 2008
URL http://www.guardian.co.uk/science/2008/may/31/ethicsofscience.animalwelfare
 
Description Radio broadcast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We allowed a BBC radio 4 science correspondent into our marmoset facility to see for himself how the marmosets were kept. His visit was recorded and played out on 'PM News', BBC Radio 4 (July, 2007).

None, but the more information appears in the Media discussing what really happens in primate laboratories, the better.
Year(s) Of Engagement Activity 2007