Identification of the higher-order cognitive mechanisms by which prefrontal and anterior cingulate circuits regulate negative emotion
Lead Research Organisation:
University of Cambridge
Department Name: Physiology Development and Neuroscience
Abstract
As individuals we are faced with situations that provoke fear and anxiety on a daily basis, whether they be relatively mild, e.g. giving a talk to a group of people, or more serious, e.g. the prospect of losing one's job. Mild fear and anxiety are associated with changes in our behaviour and accompanying changes in our physiology, including increased heart rate, muscle tension and stress hormone levels. Such emotional responses allow us to adapt to a given situation and either prepare us for, or help us to avoid, a negative event. However, in excess, and unregulated, these responses lead to clinical anxiety, which is a core symptom of anxiety disorders (which have a lifetime prevalence of 16%), but can also be a prominent symptom of many other disorders, including Depression, Obsessive Compulsive disorder, Schizophrenia and Sociopathy. Unfortunately, the range of potential treatments is relatively restricted and the level of treatment success, highly variable. This is probably because there are varied reasons as to why someone may show clinical anxiety. For example, there are many factors that contribute to how well we cope with negative events, including how predictable they are, whether we have control over them, how much we let negative events dominate our thoughts and distract us from paying attention to other, more positive events in our environment. Impairments in brain circuits that are important for predicting events or learning how to control such events or controlling what we attend to, can lead to enhanced anxiety. For example, if an individual's ability to predict is disrupted and thus negative events seem more uncertain, this will generate anxiety. Alternatively, an impairment in attentional control will result in an individual failing to inhibit their attention towards negative stimuli, thus spend more time focussing on negative outcomes, resulting in heightened anxiety. However, whilst the anxiety is common in both cases, the underlying mechanisms are different.
The goal of this research proposal is to identify the different functions of distinct regions of the brain that help us to regulate our emotions. In particular, this proposal focuses on four main regions within areas of the brain called the prefrontal cortex and the anterior cingulate cortex. In order to identify the distinct contributions of each brain region we will investigate their functions in experimental animals performing behavioural tests. A critically important feature of our approach is that our behavioural analysis in experimental animals will be directly comparable with studies in human subjects and patients. This will facilitate the translatability of our findings into the clinic. We will use a methodology that will allow us to temporarily inactivate a given brain region for a short time period (approx. 30 minutes) and investigate the effects on emotional responses. We will also investigate the effects of these selective brain inactivations on activity elsewhere in the brain, allowing us to investigate not just single brain structures but brain circuits. Overall, this will provide insight into the distinct differentiable causes of anxiety and thus help us to refine our diagnoses. It will also help us to tailor existing treatments for individuals based on those different causes as well as develop novel treatment strategies.
The goal of this research proposal is to identify the different functions of distinct regions of the brain that help us to regulate our emotions. In particular, this proposal focuses on four main regions within areas of the brain called the prefrontal cortex and the anterior cingulate cortex. In order to identify the distinct contributions of each brain region we will investigate their functions in experimental animals performing behavioural tests. A critically important feature of our approach is that our behavioural analysis in experimental animals will be directly comparable with studies in human subjects and patients. This will facilitate the translatability of our findings into the clinic. We will use a methodology that will allow us to temporarily inactivate a given brain region for a short time period (approx. 30 minutes) and investigate the effects on emotional responses. We will also investigate the effects of these selective brain inactivations on activity elsewhere in the brain, allowing us to investigate not just single brain structures but brain circuits. Overall, this will provide insight into the distinct differentiable causes of anxiety and thus help us to refine our diagnoses. It will also help us to tailor existing treatments for individuals based on those different causes as well as develop novel treatment strategies.
Technical Summary
The dysregulation of negative emotions, in particular fear and anxiety, is a prominent symptom of a variety of neuropsychiatric disorders including Anxiety, Depression, Obsessive-Compulsive disorder and Schizophrenia. Unfortunately, the range of potential treatments is relatively restricted and the level of treatment success, highly variable. This is due in part to the diverse set of cognitive control processes including predictability, controllability, contextual control and selective attention that regulate our emotions. Fundamental understanding of the neural mechanisms that underlie these cognitive control processes and their interaction in regulating our emotions, is however, lacking. Clinical studies reveal altered activity within prefrontal and cingulate regions associated with emotion dysregulation. Thus, by fractionating and mapping the component control processes that constitute the top-down regulatory mechanisms of prefrontal and anterior cingulate cortices we will provide the necessary new insights into the varied causes of anxiety. This will allow for more precise diagnostics and hence therapeutic approaches. Thus this proposal will determine the specific involvement of primate subgenual and dorsal anterior cingulate cortex, anterior orbitofrontal cortex and ventrolateral prefrontal cortex in these control processes that regulate negative emotion. Specifically, we will investigate the effects of temporary inactivations of these regions on expression and extinction of conditioned fear, sustained anxiety and cost-benefit analysis of reward and punishment in decision-making. Interactions within the PFC and with downstream structures e.g. amygdala, BNST will be studied using crossed disconnections and viral vectors incorporating Designer Receptors Exclusively Activated by Designer Drugs into target brain pathways. Changes in activity of functional circuits following targeted prefrontal lesions will be investigated using 18F-Fluorodeoxyglucose microPET.
Planned Impact
The dysregulation of negative emotion is a major symptom of a wide variety of neuropsychiatric disorders including Anxiety, Depression, Obsessive Compulsive Disorder and Schizophrenia and neurodegenerative disorders such as Huntington's disease and Fronto-Temporal dementia. Clinical neuroimaging studies have implicated the prefrontal cortex (PFC) and anterior cingulate cortex in the underlying dysregulation but a fundamental understanding of the causal functions of these brain regions in regulating negative emotion is lacking. This limits our ability to refine the diagnoses of these disorders and also restricts our ability not only to target existing treatments effectively but also to develop novel treatments. By fractionating and anatomically mapping the component cognitive processes that constitute the top-down prefrontal regulation of negative emotion this proposal will inform immediately our understanding of the multi-varied nature of anxiety, leading to refined diagnoses of clinical anxiety, specifically, and emotional dysregulation, more generally. It will also provide the necessary neurocognitive framework for understanding the mechanisms underlying the efficacy of current treatments including drugs, cognitive-behavioural therapy (CBT) and brain stimulation and importantly, how they interact to modulate these associative neural networks. It will also stimulate the development of new treatment strategies. For example, a greater understanding of the different cognitive processes that, if dysregulated, lead to anxiety, will inform the development of alternative forms of CBT and in addition, highlight alternative neural pathways for targeting novel treatments. It will also provide the critical platform on which future neuropsychological and neurobehavioural studies combined with fMRI can be performed in humans and on which the next generation of studies to investigate the role of gene x environment interactions in the abnormal development of these brain circuits can be performed.
Thus, major beneficiaries in the short term will be scientists working in the fields of decision making/neuroeconomics and emotion regulation, as this research proposal will bridge these two largely non-interacting but highly related fields of cognitive neuroscience, thereby improving existing neurocognitive models of PFC function and stimulating theoretical development. It should also reveal important principles of behavioural control relevant to neural network applications.
In the short/intermediate term, clinically oriented researchers and clinicians will also be beneficiaries of our research, contributing to the nation's quality of life and health as the research will inform both diagnoses and treatment strategies. Thus, patients and their carers will also ultimately benefit from our research.
As this research will inform clinical diagnoses and treatment strategies it will indirectly contribute to the nation's wealth and economy, given the large costs involved in the long term care (many years) for many of these patient groups. In addition, the drug-based anxiety treatments developed by the UK Pharmaceutical industry may be further optimised and new strategies facilitated.
This research will also contribute to the nation's education. Research articles and research reviews are cited in textbooks and review articles are featured in several University courses.
Finally, the work from this lab has already had an impact on public policy via the Weatherall report which examined the scientific case for the use of primates in research into the prevention or treatment of disease (p113, ref 343), and may well do again.
Thus, major beneficiaries in the short term will be scientists working in the fields of decision making/neuroeconomics and emotion regulation, as this research proposal will bridge these two largely non-interacting but highly related fields of cognitive neuroscience, thereby improving existing neurocognitive models of PFC function and stimulating theoretical development. It should also reveal important principles of behavioural control relevant to neural network applications.
In the short/intermediate term, clinically oriented researchers and clinicians will also be beneficiaries of our research, contributing to the nation's quality of life and health as the research will inform both diagnoses and treatment strategies. Thus, patients and their carers will also ultimately benefit from our research.
As this research will inform clinical diagnoses and treatment strategies it will indirectly contribute to the nation's wealth and economy, given the large costs involved in the long term care (many years) for many of these patient groups. In addition, the drug-based anxiety treatments developed by the UK Pharmaceutical industry may be further optimised and new strategies facilitated.
This research will also contribute to the nation's education. Research articles and research reviews are cited in textbooks and review articles are featured in several University courses.
Finally, the work from this lab has already had an impact on public policy via the Weatherall report which examined the scientific case for the use of primates in research into the prevention or treatment of disease (p113, ref 343), and may well do again.
Publications
Alexander L
(2019)
A Focus on the Functions of Area 25.
Alexander L
(2023)
The ventromedial prefrontal cortex and emotion regulation: lost in translation?
in The Journal of physiology
Zeredo JL
(2019)
Glutamate Within the Marmoset Anterior Hippocampus Interacts with Area 25 to Regulate the Behavioral and Cardiovascular Correlates of High-Trait Anxiety.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Quah SKL
(2020)
Trait Anxiety Mediated by Amygdala Serotonin Transporter in the Common Marmoset.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Clarke HF
(2015)
Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making.
in Proceedings of the National Academy of Sciences of the United States of America
Stawicka ZM
(2020)
Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset.
in Proceedings of the National Academy of Sciences of the United States of America
Santangelo AM
(2019)
Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates.
in Proceedings of the National Academy of Sciences of the United States of America
Roberts A
(2019)
Why we need nonhuman primates to study the role of ventromedial prefrontal cortex in the regulation of threat- and reward-elicited responses
in Proceedings of the National Academy of Sciences
Pizzagalli DA
(2022)
Prefrontal cortex and depression.
in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Mikheenko Y
(2015)
Serotonergic, brain volume and attentional correlates of trait anxiety in primates.
in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Santangelo AM
(2016)
Novel Primate Model of Serotonin Transporter Genetic Polymorphisms Associated with Gene Expression, Anxiety and Sensitivity to Antidepressants.
in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Klink PC
(2021)
Combining brain perturbation and neuroimaging in non-human primates.
in NeuroImage
Wang X
(2021)
U-net model for brain extraction: Trained on humans for transfer to non-human primates.
in NeuroImage
Shiba Y
(2016)
Beyond the Medial Regions of Prefrontal Cortex in the Regulation of Fear and Anxiety.
in Frontiers in systems neuroscience
Quah SKL
(2020)
Avoidant Coping Style to High Imminence Threat Is Linked to Higher Anxiety-Like Behavior.
in Frontiers in behavioral neuroscience
Oikonomidis L
(2017)
A dimensional approach to modeling symptoms of neuropsychiatric disorders in the marmoset monkey.
in Developmental neurobiology
Lear A
(2022)
Understanding them to understand ourselves: The importance of NHP research for translational neuroscience
in Current Research in Neurobiology
Quah SKL
(2022)
Higher-order brain regions show shifts in structural covariance in adolescent marmosets.
in Cerebral cortex (New York, N.Y. : 1991)
Wallis CU
(2019)
Hippocampal Interaction With Area 25, but not Area 32, Regulates Marmoset Approach-Avoidance Behavior.
in Cerebral cortex (New York, N.Y. : 1991)
Sawiak SJ
(2018)
Trajectories and Milestones of Cortical and Subcortical Development of the Marmoset Brain From Infancy to Adulthood.
in Cerebral cortex (New York, N.Y. : 1991)
Rahman SS
(2021)
Differential Contribution of Anterior and Posterior Midcingulate Subregions to Distal and Proximal Threat Reactivity in Marmosets.
in Cerebral cortex (New York, N.Y. : 1991)
Stawicka ZM
(2022)
Differential Effects of the Inactivation of Anterior and Posterior Orbitofrontal Cortex on Affective Responses to Proximal and Distal Threat, and Reward Anticipation in the Common Marmoset.
in Cerebral cortex (New York, N.Y. : 1991)
Jackson SA
(2016)
Role of the Perigenual Anterior Cingulate and Orbitofrontal Cortex in Contingency Learning in the Marmoset.
in Cerebral cortex (New York, N.Y. : 1991)
Alexander L
(2019)
A Focus on the Functions of Area 25.
in Brain sciences
Shiba Y
(2017)
Converging Prefronto-Insula-Amygdala Pathways in Negative Emotion Regulation in Marmoset Monkeys.
in Biological psychiatry
Description | Member of Council of Understanding Animal Research |
Geographic Reach | National |
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Description | Opportunities and limitations of genetically modified nonhuman primate models for neuroscience research. White paper for the National Academies, USA |
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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 | Psychological, pharmacological and developmental insights into the prefrontal circuits underlying threat regulation and negative bias in marmosets |
Amount | £2,558,971 (GBP) |
Funding ID | MR/V033492/1 |
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Country | United Kingdom |
Start | 08/2021 |
End | 07/2026 |
Title | Measurement of anhedonia |
Description | To measure autonomic arousal in anticipation of rewarding stimuli |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | This will help us to understand the neuropathology associated with anhedonia, a prominent symptom of depression and schizophrenia. |
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 | 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. |
Title | Data related to PNAS article: 10.1073/pnas.2009657117. |
Description | Data related to PNAS article: 10.1073/pnas.2009657117. |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | None |
URL | https://doi.org/10.17632/76c2j7bbbd.1 |
Description | "Generation, Characterization, and Validation of Marmoset Models of Alzheimer's Disease". PI:Dr Peter Strick, Afonso Silva, Stacey Rizzo. |
Organisation | University of Pittsburgh |
Country | United States |
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PI Contribution | I have been advising on the training of cognitive testing in the aging marmosets |
Collaborator Contribution | They are studying aging on the cognitive and emotional functions in the common marmoset with an aim to develop a transgenic model of Alzheimers disease. |
Impact | None so far |
Start Year | 2019 |
Description | Collaboration with Dr Eduardo Gascon Gonzalo at Institut de Neurosciences, Marseille Univeristy, France |
Organisation | Aix-Marseille University |
Country | France |
Sector | Academic/University |
PI Contribution | We are providing punches of specific regions of brain tissue from a cohort of marmosets that have been genotyped for the serotonin transporter polymorphism that we have described in (Santangelo et al, Neuropsychopharm 41:2366-76) and for which we have behavioural phenotyping data related to their individual levels of threat reactviity to distal and proximal threat. |
Collaborator Contribution | Dr Gascon Gonzalo's Laboratory is using single cell sequencing to explore the potential regional selectivity of the underlying molecular mechanisms of this polymorphism. |
Impact | Popa N., Roberts, A.C., Santangelo, A.M., Gascon, E. Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior. BioRixv 2021. |
Start Year | 2020 |
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 |
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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 | The PRIMatE Data Exchange (PRIME-DE) global collaboration and consortium |
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Department | National Institute of Mental Health (NIMH) |
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PI Contribution | Dr Steve Sawiak shares our neuroimaging datasets to this on line resource. |
Collaborator Contribution | There are over 25 partners providing neuroimaging datasets to this on line resource. |
Impact | https://doi.org/10.1016/j.neuron.2018.08.039 https://doi.org/10.1016/j.neuron.2019.12.023 |
Start Year | 2018 |
Description | The PRIMatE Data Exchange (PRIME-DE) global collaboration and consortium |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Dr Steve Sawiak shares our neuroimaging datasets to this on line resource. |
Collaborator Contribution | There are over 25 partners providing neuroimaging datasets to this on line resource. |
Impact | https://doi.org/10.1016/j.neuron.2018.08.039 https://doi.org/10.1016/j.neuron.2019.12.023 |
Start Year | 2018 |
Description | The PRIMatE Data Exchange (PRIME-DE) global collaboration and consortium |
Organisation | University of Oxford |
Department | Oxford Neuroscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Dr Steve Sawiak shares our neuroimaging datasets to this on line resource. |
Collaborator Contribution | There are over 25 partners providing neuroimaging datasets to this on line resource. |
Impact | https://doi.org/10.1016/j.neuron.2018.08.039 https://doi.org/10.1016/j.neuron.2019.12.023 |
Start Year | 2018 |
Description | Invited talk to the National Insititute of Medicine Annual Meeting, Neurosci. Interest Group, Washington DC, USA |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | To inform the wider community about the importance of non human primate research in the study of psychiatric disorders. |
Year(s) Of Engagement Activity | 2022 |
URL | https://nam.edu/event/revolutionizing-the-biomedical-and-health-sciences-nam-annual-meeting/ |
Description | Use of animals in research display and stall at Cambridge Science Festival led by Dr Christian Wood |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
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Year(s) Of Engagement Activity | 2018 |
Description | Video on animal research on the neurobiologial mechanisms underlying compulsive behaviour presented at public neuroscience festival, BRAINFEST. |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | 30 minute video on Obsessive Compulsive disorder and the contribution of animal research, including primate research to our understanding. Not only on the open access part of our animal website and Cambridge University but also available to watch as part of a neuroscience public weekend festival we put on last June called BRAINFEST. |
Year(s) Of Engagement Activity | 2017 |