Neurophysiology

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

We study a small group of neurons, buried deep in the midbrain, that produce the neurochemical dopamine. Despite only numbering several hundred thousand, these neurons have a crucial influence on the normal functioning of the brain through their dense axonal projections to many other brain regions involved in memory, movement and attention. For example, the degeneration of one group of dopamine neurons underlies Parkinsons disease, a devastating neurological movement disorder. In addition, a neighbouring group of dopamine neurons play a key role in both drug addiction and schizophrenia. Under normal circumstances, dopamine neurons are activated by better-than-expected events, such as the surprising presentation of food, juice, or even money. This activation leads to a rapid and brief wave of dopamine release at projection sites, which in turn modulates attention, memory formation and controls behaviour. Many fundamental questions about dopamine neurons remain unanswered. This is in part because of the enormous complexity of the brain which makes examining cellular issues in the whole brain extremely challenging. The overall aim of our research is to provide a more detailed understanding of the anatomy and physiology of midbrain dopamine neurons and their associated neural networks. In addition, we examine the effects of drugs of abuse on the brain, in an attempt to gain insight into the molecular basis of addiction. We use a combination of high-resolution electrophysiological and neuroanatomical techniques in animal models. For example, in a recent study, my colleagues and I found that a group of these neurons, that were previously assumed to be dopaminergic, are actually not dopamine neurons. Although they represent a distinct group of non-dopaminergic neurons, little else is known about their anatomy and physiology. In the future, we will conduct experiments to examine issues such as how these non-dopamine neurons respond to environmental stimuli, where they project to and what neurotransmitters they release. Dopamine neurons exhibit considerable heterogeneity in terms of their activity, projection sites and neurochemistry. Some of these subgroups of dopamine neurons are less susceptible to Parkinsons disease. However, it has previously been difficult to relate these anatomical subgroups to in vivo physiology. We are carrying out studies to resolve these issues. These studies will provide us with crucial new information about how dopamine neurons (and non-dopamine neurons) function and how they integrate with the rest of the brain.

Technical Summary

The overall aim of our research is to provide a more detailed understanding of the anatomy and physiology of midbrain dopamine neurons and their associated neural networks. In addition, we examine the effects of drugs of abuse on the brain, in an attempt to gain insight into the molecular basis of addiction. We use a combination of high-resolution in vitro and in vivo electrophysiological and neuroanatomical techniques in rats and mice. Dopamine neurons play key roles in processing and learning about rewards. Dopamine neuron dysfunction is implicated in a range of disorders: for example, selective degeneration of substantia nigra pars compacta (SNpc) dopamine neurons underlies Parkinsons disease; classical anti-psychotics are dopamine receptor antagonists, implicating dopamine hyperfunction in schizophrenia; and drugs of abuse elevate dopamine levels and induce long-term molecular changes in the dopamine system that underlie compulsive addictive behaviour. We have recently shown that a sub-population of presumed dopamine neurons in the ventral tegmental area (VTA) are, in fact, not dopaminergic. Because these neurons were previously assumed to be dopaminergic, little is known about their anatomy and physiology and how that differs from dopamine neurons. One important difference concerns their responses to aversive stimuli. We found that dopamine neurons are uniformly inhibited by an aversive stimulus, which is consistent with reward theories of their function. In contrast, the non-dopamine neurons were typically excited by the aversive stimulus, which suggests that they may encode information about motivationally-important stimuli in a manner distinct from dopamine neurons. Part of our current research is focused on characterizing the in vivo physiology and anatomy of these non-dopamine neurons. In particular we wish to know which neurotransmitters they release, where they project to, what information they encode and whether a similar population exists in the SNpc. We are also carrying out quantitative anatomical studies of neuron distribution within the VTA and SNpc. In addition, we continue to address fundamental questions about dopamine neurons. For example, although there are distinct subgroups of dopamine neurons (e.g., those that co-release neuropeptides and express calcium binding proteins such as calbindin) it is not known if they have distinct in vivo physiology. This may be of clinical relevance because these subgroups of dopamine neurons show differential vulnerability to Parkinsons disease. In the near future, we will extend this combined physiological and anatomical approach to include dorsal raphe dopamine and serotonin neurons.

Publications

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Abdul Rahman NZ (2016) Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Impairs Synaptic Plasticity and Hippocampal-Dependent Memory. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Brischoux F (2009) Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Royal Society University Research Fellowship
Amount £198,788 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 09/2006 
End 08/2010
 
Description University Research Fellowship Renewal
Amount £313,031 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 09/2010 
End 08/2013
 
Description Wellcome Trust Project Grant
Amount £385,152 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2008 
End 08/2012
 
Description AB 
Organisation University of California, San Francisco
Country United States 
Sector Academic/University 
PI Contribution We co-wrote two review articles
Collaborator Contribution Initiated the writing of 2 review articles.
Impact 19891960 20438754
 
Description AF 
Organisation Imperial College London
Department Department of Bioengineering
Country United Kingdom 
Sector Academic/University 
PI Contribution Collected electrophysiological data for analysis and computational modelling. Co-supervised the project.
Collaborator Contribution Computational expertise and model. Co-supervised project.
Impact PMID: 28701749
Start Year 2010
 
Description AP 
Organisation Helmholtz Association of German Research Centres
Department The Max Delbrück Center for Molecular Medicine (MDC)
Country Germany 
Sector Academic/University 
PI Contribution We provided tissue as part of a collaborative project.
Collaborator Contribution Technical expertise.
Impact None yet.
Start Year 2018
 
Description CL 
Organisation University of Geneva
Country Switzerland 
Sector Academic/University 
PI Contribution We developed a theorectical view on the classification of addictive drugs and co-wrote a paper.
Collaborator Contribution He initiated the writing of this review article.
Impact 17105338
 
Description DEX 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Conducted electrophysiological recordings
Collaborator Contribution Bheavioural and anatomical experiments
Impact PMID: 23929547
Start Year 2006
 
Description DJW 
Organisation Medical Research Council (MRC)
Country United Kingdom 
Sector Academic/University 
PI Contribution We trained them in in vivo electrophysiology.
Collaborator Contribution They lead the project and conducted most of the research.
Impact PMID: 29262334
Start Year 2016
 
Description JCB 
Organisation University of Oxford
Department Oxford Centre for Functional MRI of the Brain (FMRIB)
Country United Kingdom 
Sector Academic/University 
PI Contribution We collected all the data.
Collaborator Contribution Help with physiological noise modelling for analysis of fMRI signal.
Impact 1 paper (PubMed ID): 21867762
Start Year 2010
 
Description JPB 
Organisation University of Oxford
Department MRC Anatomical Neuropharmacology Unit
Country United Kingdom 
Sector Public 
PI Contribution Conducted analysis of data.
Impact 1 paper (PubMed ID): 21375596
Start Year 2010
 
Description JPB 
Organisation University of Oxford
Department MRC Anatomical Neuropharmacology Unit
Country United Kingdom 
Sector Public 
PI Contribution We developed in situ hybridisation probes for use in the midbrain.
Collaborator Contribution Anatomical expertise helped with analysis.
Impact PMID: 19459217 18355970 22327472
 
Description JVH 
Organisation Medical Research Council (MRC)
Country United Kingdom 
Sector Academic/University 
PI Contribution My student collected all the data
Collaborator Contribution Helped established physiological monitoring during midbrain fMRI
Impact 1 paper (PubMed ID): 21867762
Start Year 2009
 
Description KT 
Organisation Massachusetts Institute of Technology
Country United States 
Sector Academic/University 
PI Contribution We contributed part of the data reported in the paper (http://www.ncbi.nlm.nih.gov/pubmed/26871628) which laid h efoundation for the subsequent work carried out by the collaborator.
Collaborator Contribution They contributed a large amount of data and together we wrote the paper.
Impact http://www.ncbi.nlm.nih.gov/pubmed/26871628
Start Year 2011
 
Description ML 
Organisation Medical Research Council (MRC)
Country United Kingdom 
Sector Academic/University 
PI Contribution We conducted electrophysiological recordings from ES cell-derived neurons
Collaborator Contribution Established recordings from ES-cell derived dopamine neurons
Impact (Pubmed IDs): 21880784, 21887381, 21761283, 22588303
Start Year 2010
 
Description NW 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution We lead the project, and conducted the experiments
Collaborator Contribution They provided genetically modified mice and discussions regarding the project.
Impact 20926611
Start Year 2007
 
Description NicoM 
Organisation University of Oxford
Department MRC Anatomical Neuropharmacology Unit
Country United Kingdom 
Sector Public 
PI Contribution We collected all the data
Collaborator Contribution Collection and analysis of ECoG data
Impact 1 paper (PubMed ID): 21925244
Start Year 2009
 
Description RF 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We lead the project and conducted the experiments
Collaborator Contribution They initiated the collaboration and provided conceptual input throughout.
Impact 20926611
Start Year 2006
 
Description RJW 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution My student collected all the data (co supervised by collaborator)
Collaborator Contribution fMRI experiments were conducted in his lab. Group provided support for analysis and interpretation of data.
Impact 1 paper (PubMed ID): 21867762
Start Year 2009
 
Description TG 
Organisation University of Pittsburgh
Department Department of Neuroscience
Country United States 
Sector Academic/University 
PI Contribution We wrote a review article together
Collaborator Contribution We wrote a review article together
Impact 22459161
Start Year 2011
 
Description TH-GFP 
Organisation Fukushima Medical University
Department Institute of Biomedical Sciences
Country Japan 
Sector Academic/University 
PI Contribution We conducted all the research and published paper.
Collaborator Contribution Donated TH-GFP mice
Impact 22925150 26871628
Start Year 2010
 
Description TrevB 
Organisation University of Strathclyde
Country United Kingdom 
Sector Academic/University 
PI Contribution We conducted some immunostaining which is part of a paper in press at Journal of Neuroscience.
Collaborator Contribution He lead the project and collected the rest of the data.
Impact Paper in press at Journal of Neuroscience
Start Year 2015
 
Description TrevS 
Organisation University of Oxford
Department Department of Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Collected all data
Collaborator Contribution Assistance with analysis, preparation of manuscript.
Impact 1 paper (PubMed ID): 21925244
Start Year 2010
 
Description BNA Core Concepts 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact In 2017, The British Neuroscience Association (BNA) mapped these 8 neuroscience Core Concepts onto every Biology syllabus in the UK, including GCSE, A-Level, National 5s, Highers and Advanced Highers. Therefore, teachers and educators can now explore where neuroscience-related syllabus content fits into these fundamental principles. Supporting these mappings, the BNA has curated a list of useful, relevant and free resources to aid in teaching this material.
Year(s) Of Engagement Activity 2017
URL https://www.bna.org.uk/about-neuroscience/neuroscience-in-schools/
 
Description Cafe Scientific 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I was one of two scientists who presented and took part in a discussion at The Royal Society.

none
Year(s) Of Engagement Activity 2013
 
Description Careers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact I have visited two schools for their careers day, via my membership of Inspiring the Future. A total of around 50 pupils heard me talk and asked me questions about careers in science.

Some students asked about summer placements. Teachers were extremely enthusiastic.
Year(s) Of Engagement Activity 2013
 
Description Emo Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact I gave an invited seminar at UCL

none
Year(s) Of Engagement Activity 2012
 
Description Gretschen Amphlet 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Supporters
Results and Impact Many questions afterwards. Video posted on youtube (viewed 724 times).

I was asked to visit a Parkinson's UK support group.
Year(s) Of Engagement Activity 2014
URL http://www.youtube.com/watch?v=5y_MjD63UjI
 
Description MP-Scientist Pairing Scheme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact I spent one week at the Houses of Parliament; Andrew Slaughter, our local MP, spent a day visiting the CSC.

Many memebers of the insititute had the opportunity to meet the MP and present their work. He was previously unaware of us but was impressed following the visit.
Year(s) Of Engagement Activity 2006
 
Description Matthews paper media 
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 We wrote a press release about our paper Matthews et al 2016 Cell. I also answered questions from a number of media sources.
Year(s) Of Engagement Activity 2016
 
Description PEN 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I wrote a short article about my research as part of a project between PEN (fiction writers) and the MRC.

http://www.englishpen.org/aboutenglishpen/partnerships/medicalresearchcouncil/theneurophysiologist/
Year(s) Of Engagement Activity 2007
URL http://www.englishpen.org/aboutenglishpen/partnerships/medicalresearchcouncil/theneurophysiologist/
 
Description School Visit (Beaconsfield) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Careers day at a primary school organised by Primary Futures.
Year(s) Of Engagement Activity 2017
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I visited a secondary school to discuss being a scientist and working on the brain. Around 40 pupils attended and my talk was followed by questions. I received the following feedback from the teacher:

Mark,

Thank you so much for coming to help with Breakfast club on Friday. It has thrown up some very interesting questions especially from our potential medics.

Kind Regards
Abigail

Abigail Waters
Teacher of Science
Holland Park School
Year(s) Of Engagement Activity 2015
 
Description Schools 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact I have attended 5 Primary, 1 secondary school, and 3 lay groups to discuss being a scientist and how the brain works.

None
Year(s) Of Engagement Activity 2011,2012
 
Description Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact I gave an invited talk at Institut du Fer a Moulin, Paris, France

None
Year(s) Of Engagement Activity 2011
 
Description video 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The video has been viewed 802 times on YouTube.

none
Year(s) Of Engagement Activity 2013
URL http://www.youtube.com/watch?v=lSE3_lL8xbs