Organisation of the Neuronal Networks of the Basal Ganglia

Lead Research Organisation: MRC Anatomical Neuropharmacology Unit

Abstract

Understanding how a particular region of the brain ‘works’, what it actually does and what goes wrong in disease requires detailed ‘wiring diagrams’ in which the roles and positions of individual nerve cells are characterised. Our aim is to characterise the ‘wiring diagram’ of a group of structures deep in the brain referred to as the basal ganglia. These structures are involved in a variety of motor and cognitive functions and their dysfunction is implicated in a variety of disorders, most notably, Parkinsons disease. We aim to understand how different connections of a sub-region of the basal ganglia interact in the selection of behaviours in both normal rodents and in models of Parkinsons disease and to understand the fundamental properties of those nerve cells that die in Parkinsons disease. Our studies, will thus provide basic and fundamental knowledge of the organisation of the basal ganglia thus providing insights into how they work and will also provide insights into what goes wrong in disease.

Technical Summary

The basal ganglia are involved in a variety of motor and cognitive functions and their dysfunction is implicated in a variety of disorders, most notably, Parkinsons disease. The aim of the proposed work is to elucidate the principles of operation of the neuronal networks of the basal ganglia in health and disease. Our previous findings have elucidated the critical role of the cortex and the so-called ‘indirect pathway’ in the expression of basal ganglia function. However, the basal ganglia is richly endowed with afferents from sub-cortical structures, including the thalamus, dorsal raphe, tuberomammillary nucleus and the pedunculopontine nucleus, that probably preceded, in evolutionary terms, the cortical afferents and are critical in the expression of basal ganglia function. One of the aims of the current proposal is define, using combined anatomical and physiological approaches, the roles of specific sub-cortical afferents of the basal ganglia, how they interact with the cortical and dopaminergic afferents in the ‘selection’ of populations of striatal spiny neurons and how they are altered in models of Parkinsons disease. We will also define the properties of the sub-populations of striatal projection neurons that give rise to the so-called direct and indirect pathways using transgenic animals and elucidate the properties of sub-populations of dopamine neurons that show differential susceptibility to degeneration in Parkinsons disease. The outcomes of this study will be a new level of understanding of the organisation of the basal ganglia in which both cortical and sub-cortical afferents are integrated, insights into what goes wrong in disease, and clues to possible new therapeutic targets in disease.

Specific aims
Define the organisation of sub-cortical inputs to the basal ganglia and define their relationship to other afferents.
Define the properties of identified striatal projection neurons that give rise to the direct and indirect pathways.
Define the topographical relationship between the dual striatal input to GPe and the complex microcircuitry of the GPe.
Define the properties of individual identified neurons of the pedunculopontine nucleus, define how their activity changes in models of Parkinsons disease and how any aberrant firing can be modified.
Define the properties of sub-populations of dopamine neurons that show a differential susceptibility to degeneration in Parkinson’s disease.
Assess the potential of olfactory stem cells as a source of dopamine neurons for transplantation therapies for Parkinsons disease.

Publications

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Anwar S (2011) Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Bolam JP (2016) Histamine and the striatum. in Neuropharmacology

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Bolam JP (2012) Living on the edge with too many mouths to feed: why dopamine neurons die. in Movement disorders : official journal of the Movement Disorder Society

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Boyes J (2007) Localization of GABA receptors in the basal ganglia. in Progress in brain research

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Boyes J (2007) Functional presynaptic HCN channels in the rat globus pallidus. in The European journal of neuroscience

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Brown MT (2009) Activity of neurochemically heterogeneous dopaminergic neurons in the substantia nigra during spontaneous and driven changes in brain state. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Coizet V (2009) Short-latency visual input to the subthalamic nucleus is provided by the midbrain superior colliculus. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Title A Nervous Encounter 
Description Art exhibition at 'The Old Fire Station' the product of interaction with scientists in the lab with MA art students from Central St Martin's School of Art, London 
Type Of Art Artwork 
Year Produced 2013 
Impact Art exhibition at 'The Old Fire Station' the product of interaction with scientists in the lab with MA art students from Central St Martin's School of Art, London Some of the work in now being exhibited in New York, USA 
 
Description EC FP7 funding
Amount £400,000 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 03/2008 
End 03/2012
 
Description Grant
Amount £180,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 04/2013 
End 10/2015
 
Description Parkinson's Disease UK Project Grants
Amount £165,210 (GBP)
Funding ID G-0601 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2006 
End 03/2009
 
Description Parkinson's UK Discovery Award
Amount £350,000 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2009 
End 02/2015
 
Description Parkinsons UK Innovation Grant
Amount £35,000 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2011 
End 02/2012
 
Title Beta oscillations in a rat model of Parkinson's Disease 
Description Exaggerated oscillations of activity in the basal ganglia at the beta frequency have been identified as a marker of Parkinson's Disease in humans. We have identified this same hallmark in rodent model of Parkinson's Disease and are now in the position to identify the origin and nature of these pathological oscillations 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Publications. New Senior Scientist/group in the Unit. 
 
Description Dopamine neurons and in situ 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution Discussion and planning of experiments in one paper (18355970). Most of the work for the second paper (19459217).
Collaborator Contribution Quantitative anatomical data on brain regions of interest to us. Help in carrying out in situ hybridization
Impact 18355970 19459217
Start Year 2006
 
Description GABA in GP 
Organisation Aston University
Department School of Life and Health Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Anatomical part of the analyses carried out by our group
Collaborator Contribution Named collaborator on grant to Dr. I Stanford. Aim is to characterize the GABAa receptor subunits at synapses in the globus pallidus
Impact Publication: 17439493
 
Description GABA in the BG Book 
Organisation Rutgers University
Country United States 
Sector Academic/University 
PI Contribution Joint editors
Collaborator Contribution Joint editorship of a book and one chapter
Impact Chapter 17499105 Tepper, Abercrombie & Bolam (eds) "GABA and the Basal Ganglia". Progress in Brain Research vol 160 (2007)
 
Description Oscillations in the BG 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution All experimental work carried out by our group
Collaborator Contribution Long-standing collaboration that has led to many publications
Impact 16709634 16763040 18448656 19109506
 
Description Oxford Parkinson's Disease Centre 
Organisation University of Oxford
Department Nuffield Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Co applicant. Co-Leader of one of the three themes of the project. The Whole project raised £5 million for 5 years
Collaborator Contribution Raised my awareness of Parkisnon's research
Impact No publications so far Multidisciplinary: systems neuroscience (our lab), genetics, clinical work, imaging
Start Year 2009
 
Description SC 
Organisation University of Sheffield
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Anatomical aspects of the study
Collaborator Contribution Collaboration on a paper
Impact 19403836
Start Year 2008
 
Title Methods of neural centre location and electrode placement in the central nervous system 
Description The newly patented technology (US Patent No. 7,582,062) stems from their original discoveries made in the Unit and published as a research paper in 2004, in which we demonstrated in rats how stimulation of superficial parts of the brain can be used to help target small structures deep within it. This approach has potential for improving the efficiency and accuracy of specialised brain surgery, such as that used in the implantation of electrodes for Deep Brain Stimulation to treat Parkinson's disease. 
IP Reference US7582062 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact The invention affords the possibility of effective and safe treatment using therapeutic electrodes through development of software for the manipulation of stereotactic robots in neurosurgery National phase
 
Description A nervous encounter 
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 Public/other audiences
Results and Impact Art exhibition at 'The Old Fire Station' the product of interaction with scientists in the lab with MA art students from Central St Martin's School of Art, London

Great deal of public understanding and public engagement with science
Year(s) Of Engagement Activity 2012
 
Description CAfe Scientifique: Phyllis Court Club, Henley 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Paul Bolam gave a lecture to the Computer Section of the Phyllis Court Club in Henley on the 10th August. The lecture was entitled 'Aged brain or diseased brain'. Paul talked about the ageing process in general and how ageing affects the brain. He then talked about the organisation of the brain and what might go wrong during ageing. He emphasised the difference between normal ageing, during which your brain is likely to fare much better than your body, and the diseased brain, illustrating this with reference to Alzheimer's disease and Parkinson's disease. His final point was to talk about how we can delay onset of ageing and possibly diseases of the brain. The lecture was followed by a lively discussion from the 120-strong audience.
Year(s) Of Engagement Activity 2015
 
Description Cafe Scientifique 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Sold out, people were turned away. Audience and organisors appreciative

Several other requests to give a presentation arose form this event
Year(s) Of Engagement Activity 2010,2013,2014,2015
 
Description Cheltenham Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Took part in a panel on 'The aging brain'

Session was 'sold out', 450 people in the audience
Year(s) Of Engagement Activity 2011
 
Description Cotswold school 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Ethics of the use of animals in medical research
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
 
Description Lay People visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Parkinson's and basal ganglia research in the Unit

Appreciative audience
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011,2012
 
Description Lecture "The Ageing brain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Lecture "The Ageing brain
Year(s) Of Engagement Activity 2016
 
Description Lecture by Paul Bolam "The ageing brain or diseased brain" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Lecture by Paul Bolam "The ageing brain or diseased brain"

I talked about the ageing brain, healthy ageing and age-related neurological disorders, in particular, Parkinson's disease and strategies for its treatment that are available now and new strategies that hopefully, will give benefit in the future.

Received a donation of £30 for PUK
Year(s) Of Engagement Activity 2017
 
Description Oxford Music Festival 
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 Gave a lecture at the May Oxford Music Festival on 'The aging brain'

Highest attendance at a 'science' talk
Audience very appreciative
Many people recruited to several different studies
Year(s) Of Engagement Activity 2012
 
Description Parkinson's UK Aylsebury Branch 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact People with Parkinson's and their carers

Good feedback
Year(s) Of Engagement Activity 2013
 
Description Parkinson's UK Newcastle Branch 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact People with Parkinson's and their carers

Good feedback
Year(s) Of Engagement Activity 2013
 
Description Parkinson's UK Oxford Branch 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact People with Parkinson's and their carers

Good feedback
Year(s) Of Engagement Activity 2013
 
Description Parkinson's UK South Region Fora 
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 Three talks given at different venues in Parkinson's UK South Region
Winchester, Newbury, Aylesbury, Buckingham, Fareham
Audience included Parkinson's UK staff, people with PD and carers

They loved it!
Year(s) Of Engagement Activity 2012,2013,2014,2015
 
Description People with Parkinson's and carers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Description of the Unit work on Parkinson's Disease and the basal ganglia

Participants appreciative
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2015
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk on 'The ageing brain'

Good feedback
Year(s) Of Engagement Activity 2013
 
Description Press 
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 Several press interviews, including contribution to a documentary on how our research involves the use of animals

Good feedback
Year(s) Of Engagement Activity 2006,2007,2008,2009,2014
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Lecture entitled 'The Ageing Brain'
Year(s) Of Engagement Activity 2015
 
Description School Teacher Visit 
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 School science teachers

Positive feedback and invited to a school to give talk in 2010
Year(s) Of Engagement Activity 2009
 
Description School Visit- Cotswolds School 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Parkinson's and basal ganglia research in the context of animal use in medical research

Good feedback. Invited back each year to include several sessions.
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013,2014,2015
 
Description School visit (Little Milton School/Grasmere Primary School) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Primary School visit. Talked about neuroscience and diseases of the brain

the feedback was that the kiids loved it
Year(s) Of Engagement Activity 2011,2014
 
Description School visit (Windsor School Science CLub) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact KIds enjoyed and were stimulated by the research discussion

Good feedback
Year(s) Of Engagement Activity 2014
 
Description Schools Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Groups of 6 th form pupils visit the laboratory and research explained

Students give good feedback
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013
 
Description Work exeprience 
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 Two work experience school pupils spent one week in the lab, one in August and one in Oct (2012). Other pupils in earlier years
2013: Four school students on different occasion for one week each.

Schools keep asking to send more students
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014