Understanding the dopamine signals triggered directly by striatal acetylcholine: The circuits, their timing and the actions of addictive drugs

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics

Abstract

Context of the research: The chemical transmitter in the brain dopamine is critically involved in our ability to select our everyday actions and movements. Drugs that are addictive, like nicotine and cocaine, release too much dopamine, promoting the actions that underlie more drug seeking, and hence the cycle of addiction. Conversely, loss of dopamine in Parkinson's disease (PD) causes problems selecting and starting movements. But, we still do not fully understand how the dopamine release is controlled. We need to grasp the underlying neural mechanisms if we are to understand the functions of dopamine better and how to treat dopamine disorders.
It has long been assumed that the only trigger for dopamine release is the electrical impulses generated in the cell soma, and that these travel along the long cables, or axons, to axon endings where dopamine is released. However, we have new evidence that radically revises this thinking. Using state-of-the-art methods to drive specific neural circuits in the brains of mice engineered to respond to flashes of light, we have identified that a different set of neurons can trigger dopamine to be released. These neurons release the chemical acetylcholine directly onto dopaminergic axons which triggers dopamine release, equally as powerfully as impulses in dopamine cells themselves. These findings cause a paradigm shift in our current thinking and place cholinergic neurons central to the functions of dopamine. Here in this research grant we propose to advance our understanding of how acetylcholine neurons and their inputs evoke DA signals. Excitingly, new technology allows us for the first time to address this highly timely question.
Aims and objectives of the research: The broad aim of this research is to promote our understanding of how acetylcholine-producing neurons drive brain dopamine signals, and to understand whether these mechanisms contribute to the neural actions of drugs of addiction. We will address this through three specific aims.
Aim 1. Acetylcholine neurons in striatum powerfully trigger the release of dopamine from axons, but when does this happen? Our data suggest that this might happen when cholinergic neurons are excited by their inputs. If we could identify which inputs were important, we would understand which circuits we could target in dopamine dysfunction, and begin to understand what kinds of functions we might expect this dopamine signal to have. Therefore, in Aim 1, we will address - what are the inputs to cholinergic neurons that can drive dopamine release?
Aim 2. We already know that electrical impulses generated in the dopamine cell bodies themselves can trigger dopamine release. So which of these two triggers is the most important one and how do they interact? We will address this in Aim 2. The answers to this question will tell us a huge amount about the best way to drive dopamine release.
Aim 3. Addictive drugs like nicotine and cocaine are able to boost dopamine signals in the brain. But is acetylcholine-evoked dopamine release a mechanism targeted by these drugs? Our pilot data suggest it might be. We will address this in Aim 3. The answer to this question would have significant impact on our understanding of drug addiction.
Potential applications and benefits of the research: Through this work, we will build a more complete picture of the neural circuits that drive dopamine transmission. In turn, we will shed light on fundamental mechanisms of normal brain function that might be disrupted, and then targeted for therapeutic benefit, in disorders of dopamine neuron function, including addiction disorders and PD. In addition, the technical infrastructure that we will establish will be cutting-edge and an excellent investment for future studies to investigate dopamine function further e.g. in disease. Therefore, whatever the outcome, our work will provide a fundamental advance in knowledge and be of direct benefit to future work.

Technical Summary

Striatal dopamine (DA) critically participates in the regulation of motivation and action selection. Dysregulation of DA signaling underlies a variety of psychomotor disorders, including addiction and Parkinson's disease. Surprisingly however, our grasp of the neuronal mechanisms that govern DA transmission remains incomplete. Activity in midbrain DA neurons has long been assumed to be its principal driver, but we have obtained new evidence for a radical shift to this paradigm, requiring us to rethink the mechanisms that govern DA release, and in turn, DA function and dysfunction.
Using an optogenetic strategy to light-activate striatal cholinergic interneurons (ChIs) that express channelrhodpsin2 (ChR2), and by detecting DA release at microelectrodes with subsecond resolution, we have identified that single action potentials in a population of ChIs triggers striatal DA release directly from DA axons by activating presynaptic nicotinic receptors (Threlfell et al, Neuron, in press). In addition, DA release was triggered by inputs to striatum from thalamus which coordinate ChI firing in vivo. Furthermore, ChI-evoked DA release overrode ascending activity in DA axons, suggesting that ChIs and their inputs might dominate as a trigger. These findings place ChIs central to our understanding of DA function and, potentially, dysfunction. It is imperative now to address key questions about how ChIs evoke DA release.
We will exploit optogenetic technologies to incorporate established and new light-activated channelrhodopsins (ChR2 and C1V1) in DA neurons, ChIs and/or their inputs to identify: (1) which inputs recruit ChIs to drive DA transmission?; (2) how do dynamic repertoires of activity in ChIs and DA neurons interact to govern DA transmission?; and (3) are these mechanisms targeted by addictive drugs? These studies are critical if we are to improve our knowledge of DA system function, and gain new insights about strategies for future therapies in DA dysfunction.

Planned Impact

The wider impact of this work to non-academic beneficiaries could be far reaching in the longer term. This work is likely to impact upon a variety of non-academic groups including clinicians, sufferers and carers of a diverse group of DA-centred psychomotor diseases, the general public and pharmaceutical companies seeking new targets for drug development. The timescales over which this work is likely to impact these different groups of people will vary. Short-term benefits will be felt by all these groups as a result of increased understanding of neurotransmission in the brain, and progression of research into psychomotor disorders resulting from our findings. Longer-term societal and economic benefits may be felt by disease sufferers and pharmaceutical companies should new therapeutic targets emerge as a result of our research.

Publications

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Brimblecombe KR (2015) Substance P Weights Striatal Dopamine Transmission Differently within the Striosome-Matrix Axis. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Dodson PD (2016) Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism. in Proceedings of the National Academy of Sciences of the United States of America

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Kosillo P (2016) Cortical Control of Striatal Dopamine Transmission via Striatal Cholinergic Interneurons. in Cerebral cortex (New York, N.Y. : 1991)

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Pristerà A (2015) Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice. in Proceedings of the National Academy of Sciences of the United States of America

 
Description DPhil Studentship BR
Amount £110,000 (GBP)
Organisation University of Oxford 
Department Clarendon Fund
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description MRC iCASE DPhil Studentship
Amount £120,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 09/2022
 
Description MRC-DTG Studentship 2014
Amount £79,546 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description MSD DPhil funding competition - Peter Kilfeather
Amount £85,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2020
 
Description Monument Trust Discovery Award Renewal 2015
Amount £5,800,000 (GBP)
Funding ID J-1403 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 02/2020
 
Description Parkinson's UK Project Grant 2015
Amount £297,158 (GBP)
Funding ID G-1504 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2016 
End 12/2018
 
Description Parkinson's UK Project Grant 2017 Magill PFFs
Amount £218,701 (GBP)
Funding ID G-1702 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 02/2021
 
Description Rhodes Scholarship 2013
Amount £70,000 (GBP)
Organisation Rhodes Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Cerevance 
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PI Contribution Study of new pipeline ligands
Collaborator Contribution Supply of new pipeline ligands
Impact New MRC iCASE studentship
Start Year 2017
 
Description Ewing lab mass spec 
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Country Sweden 
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Description John Lowry 
Organisation Maynooth University
Country Ireland 
Sector Academic/University 
PI Contribution Using new choline probes to explore striatal ACh function
Collaborator Contribution Manufacture and supply of choline probes
Impact New research effort and avenue
Start Year 2017
 
Description Optogenetic constructs 
Organisation Stanford University
Department Schools of Bioengineering and Medicine
Country United States 
Sector Academic/University 
PI Contribution Study of neural circuit function
Collaborator Contribution Provision of optogenetic gene constructs
Impact Publication PMID 22794260 Grant MR/K013866/1 Grant G-1305
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Description University of Copenhagen, Perrier, spinal cord 
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Department Department of Neuroscience and Pharmacology (DNP)
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Sector Academic/University 
PI Contribution Study of 5-HT transmission in spinal cord
Collaborator Contribution Study of 5-HT actions
Impact Published paper PMID 23487756
Start Year 2012
 
Description Discovery Award Participant Open Day' 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Sparked questions, discussion, interest in ongoing projects

DOnations
Year(s) Of Engagement Activity 2014
 
Description Discuss Parkinson's research with individual fundraisers (DB, EL, SB) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Engagement with small groups of charitable donors to promote fundraising into Parkinson's research
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Description Edinburgh International Science Festival 
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Results and Impact Talk sparked questions and debate

N/A
Year(s) Of Engagement Activity 2015
URL http://www.sciencefestival.co.uk/mediaLibrary/other/english/6285.pdf
 
Description Fundraising appeal for PUK 2014 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Supporters
Results and Impact Raised funds for research of £150k
Year(s) Of Engagement Activity 2014
 
Description Guest speaker at 25th Anniversary tea party, Newbury Parkinson's group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Guest speaker on disease research at anniversary tea party for Newbury Parkinson's group which sparked lively debate and questions and interest
Year(s) Of Engagement Activity 2017
 
Description Host lab visits for Chinese students for Oxford Prospects Programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Host lab visits for Chinese students for Oxford Prospects Programme
Year(s) Of Engagement Activity 2017
 
Description International Innovations article 2014 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/parliamentarians
Results and Impact Publication in internationally reaching magazine.
results not yet clear.

Not yet clear
Year(s) Of Engagement Activity 2014
URL http://www.internationalinnovation.com/hope-for-dopamine-disorders/
 
Description Keynote speaker on Career, DPAG Postdoc Day, Oxford 
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Part Of Official Scheme? No
Geographic Reach Local
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Results and Impact Invited to discuss career path as part of a postdoctoral scientist development day
Year(s) Of Engagement Activity 2017
 
Description Neuroscience exhibition in the Oxford museum of Science March 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Neuroscience exhibition in the Oxford museum of Science March 2014


Unknown
Year(s) Of Engagement Activity 2014
 
Description Parkinson's group talk Hereford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Share knowledge, stimulate interest

After the talk, audience asked to visit lab
Year(s) Of Engagement Activity 2015
 
Description School visit to lab - Akeley Wood 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 20 pupils attended for a school visit to the research organisation which sparked questions and discussions
Year(s) Of Engagement Activity 2017
 
Description Smarter UK 
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Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact KS3 talks about cognitive enhancing drugs

Not known
Year(s) Of Engagement Activity 2012
 
Description Speaker and Opening of fundraising walk for Parkinson's UK, Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Supporters
Results and Impact Speaker and Opening of fundraising walk for Parkinson's UK, Oxford
Year(s) Of Engagement Activity 2016
URL https://www.parkinsons.org.uk/content/walk-parkinsons
 
Description TV News interview ST 2013 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact TV description of PD work by ST

Not known
Year(s) Of Engagement Activity 2013
 
Description Talk at Stowe School to A-Level Medical Society on dopamine and careers in science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We attended a school to talk about science and careers in science which sparked questions and discussion
Year(s) Of Engagement Activity 2017
 
Description UNIQ summer school 2013 
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Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact 30 pupils attended a week-long course, I hosted a dinner and workshop with Q&A

Not yet known
Year(s) Of Engagement Activity 2013
URL http://www.uniq.ox.ac.uk/
 
Description Wow!How? Stall 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact science fair at the Oxford University of Museum of Natural History

Not known
Year(s) Of Engagement Activity 2012