Co-operative interactions of identified neurons in hippocampal network activity

Lead Research Organisation: MRC Anatomical Neuropharmacology Unit

Abstract

All centres of the brain generate neuronal activity, which varies in time in a regular manner and is optimised for their roles. This temporal variability reflects and predicts interactions between neuronal centres and the environment. Simultaneous (synchronised) neuronal activity is widespread in the normal brain (e.g. electroencephalogram) and is altered by diseases, such as epilepsy, Parkinson’s disease, schizophrenia, bipolar disorder and severe depression, serving both as diagnostic tool and as a potential biological marker to discover the cause of diseases. Establishing how activity is synchronised and generated and how rhythmic activity assists information processing by the co-operation of diverse cell types are key steps in explaining the role of neuronal centres. This information will also help to explain the malfunctioning of the brain when the co-ordination of neuronal activity is abnormal. This programme defines how synchronous activity and the accompanying information processing emerges in the CA3 area of the rodent hippocampus, a brain area involved in learning, memory encoding and retrieval, where more than twenty distinct cell types may exist, but remain to be characterised. The definition of cell types and their interactions will explain the role of identified neurons in well-defined and behaviourally significant cortical network events.

Technical Summary

Neurons of the cerebral cortex generate temporally patterned neuronal activity, which assists and constrains interactions with other neuronal centres and the environment. Synchronous rhythmic cortical activity correlates with behaviour and performance, and also indicates malfunctions in diseases. Understanding how the co-operation of diverse cell types leads to synchronous rhythmic activity and how this activity supports performance will help to explain cortical function and disorders.
This programme defines how synchronous activity and embedded information processing emerges in the CA3 area of the hippocampus, a brain area involved in learning, memory encoding and retrieval, where more than twenty distinct cell types may exist in the rat. The cell types are identified by synaptic connections, in vivo firing patterns and cell type specific sets of signalling molecules. Building on our insights into the CA1 hippocampal region, we focus on how high-frequency gamma and sharp wave associated ripple oscillations are initiated and generated in the CA3 area. Gamma oscillations organise pyramidal cells into assemblies forming representation, whereas ripple oscillations may be involved in memory consolidation. We dissect the oscillations in time and space elucidating the contributions of different cell types. A central hypothesis is that sharp wave events in the CA1 area, a highly synchronous network state, are generated by phasic disinhibition of CA3 pyramidal cells, due to the inhibition of specific types of GABAergic neuron. We will establish the source of inhibitory inputs to these interneurons and monitor the contribution of each cell class to network and behavioural performance. The results will give a systems level explanation of how temporally defined and highly accurate neuronal activity emerges through the co-operation of identified neurons in a well-defined cortical network.
Aims:
To define how specific cell types contribute to the timing of neuronal population activity in the hippocampus.
To establish the identity of GABAergic neurons in the CA3 area and determine their in vivo firing patterns relative to network oscillations and pyramidal cell activity.
To test the hypothesis that disinhibition (i.e. the phasic inhibition, or deactivation of key GABAergic neurons in the CA3 area) is a condition of the synchronous pyramidal cell discharge in CA3 assembly activity that generates sharp waves in the CA1 area.
To discover what inputs might inhibit GABAergic neurons.
To test how sharp wave ripple events influence downstream targets of hippocampal output.
To explain how behaviour specific changes in interneuron firing contribute to pyramidal assembly activity.
To test if the cell types recognised on the basis of synaptic target specificity and molecular expression profiles in rodents can be identified in the human cortex.
The realisation of these aims will explain the role of identified neurons in well-defined and behaviourally significant cortical network events.

Publications

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Fuentealba P (2010) Expression of COUP-TFII nuclear receptor in restricted GABAergic neuronal populations in the adult rat hippocampus. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Gulyás B (2013) JÁNOS SZENTÁGOTHAI. 31 October 1912 - 8 September 1994: Elected ForMemRs 20 April 1978. in Biographical memoirs of fellows of the Royal Society. Royal Society (Great Britain)

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Lasztóczi B (2011) Terminal field and firing selectivity of cholecystokinin-expressing interneurons in the hippocampal CA3 area. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Massi L (2012) Temporal dynamics of parvalbumin-expressing axo-axonic and basket cells in the rat medial prefrontal cortex in vivo. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Nissen W (2010) Cell type-specific long-term plasticity at glutamatergic synapses onto hippocampal interneurons expressing either parvalbumin or CB1 cannabinoid receptor. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Oren I (2009) Role of ionotropic glutamate receptors in long-term potentiation in rat hippocampal CA1 oriens-lacunosum moleculare interneurons. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Neuroscience Strategic Oversight Committee, Oxford University
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Title Identification of in vivo recorded neruons in freely moving rats 
Description Nerurons are recorded in rats during behaviour and subsequently labelled for molecular analysis. The recording glass electrode is carried on the head of the rat and advanced with a novel hydraulic system. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2010 
Provided To Others? Yes  
Impact Two QQR research programmes, lead by Thomas Klausberger and the other one by myself employ this novel approach. 
 
Description Freund, T. F. 
Organisation Hungarian Academy of Sciences (MTA)
Department Institute of Experimental Medicine
Country Hungary 
Sector Academic/University 
PI Contribution Experimental data and design
Collaborator Contribution experimental data and analysis
Impact Ascoli (2008) Nature Re Neurosci 9, 557-568
Start Year 2008
 
Description G. Tamas 
Organisation University of Szeged
Department Department of Pharmacology and Pharmacotherapy
Country Hungary 
Sector Academic/University 
PI Contribution Experimental data
Collaborator Contribution Experimental data and analysis
Impact Varga C, Tamas G, Barzo P, Olah S and Somogyi P. (2015) Molecular and electrophysiological characterization of GABAergic interneurons expressing the transcription factor COUP-TFII in the adult human temporal cortex. Cereb. Cortex. 25, 4430-4449.
Start Year 2012
 
Description I Kacskovics 
Organisation ImmunoGenes
Country Switzerland 
Sector Private 
PI Contribution Experimental data
Collaborator Contribution Experimental data and analysis
Impact n/a
Start Year 2018
 
Description Klausberger T 
Organisation Medical University of Vienna
Department Center for Brain Research
Country Austria 
Sector Academic/University 
PI Contribution We have conducted joint experiments and analysis of data and helped with experimental design.
Collaborator Contribution Joint experiments and training of MRC personnel in advanced elecrophysiological methods. Design of research projects.
Impact Fuentealba, P., Klausberger, T., Karayannis, T., Suen, W.Y., Huck, J., Tomioka, R., Rockland, K., Capogna, M., Studer, M., Morales, M. & Somogyi, P. (2010) Expression of COUP-TFII nuclear receptor in restricted GABAergic neuronal populations in the adult rat hippocampus. J. Neurosci. 30:1595-1609.
 
Description Lamsa K 
Organisation University of Oxford
Department Department of Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification of recorded cells, design of experiments, antibodies and training of University staff. Award of a 5 year Wellcome Research Fellowship to Dr Lamsa
Collaborator Contribution Introducing innovative neuronal recording and pharmacological analysis of synaptic interactions in brain slices. Discoveries.
Impact Oren I (2009) J Neurosci 29, 939-950 Nissen (2010) J Neurosci 30, 1337-1247 Somogyi, J. (2012) Frontiers in Neural Circuits 6, 1-6
Start Year 2006
 
Description M. Goedert 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Experimental data
Collaborator Contribution Experimental data analysis
Impact n/a
Start Year 2012
 
Description M.Morales 
Organisation National Institutes of Health (NIH)
Department National Institute on Drug Abuse (NIDA)
Country United States 
Sector Public 
PI Contribution Experimental data
Collaborator Contribution Experimental data and analysis
Impact n/a
Start Year 2014
 
Description Shigemoto R 
Organisation National Institute for Physiological Sciences
Department Division of Cerebral Structure
Country Japan 
Sector Academic/University 
PI Contribution Experimental design, experimental work, data analysis
Collaborator Contribution Provided facilities in Japan, training, reagents and know-how
Impact Kasugai, Y., Swinny, J.D., Roberts, J.D.B., Dalezios, Y., Fukazawa, Y., Sieghart, W., Shigemoto, R. & Somogyi, P. (2010) Quantitative localisation of synaptic and extrasynaptic GABAA receptor subunits on hippocampal pyramidal cells by freeze-fracture replica immunolabelling. Eur. J. Neurosci. 30:Online:doi:10.1111/j.1460- 9568.2010.07473.x
 
Description Swinny J 
Organisation University of Portsmouth
Department School of Pharmacy and Biomedical Sciences Portsmouth
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided reagents, experimental design and know-how
Collaborator Contribution Experimental work
Impact Kasugai, Y., Swinny, J.D., Roberts, J.D.B., Dalezios, Y., Fukazawa, Y., Sieghart, W., Shigemoto, R. & Somogyi, P. (2010) Quantitative localisation of synaptic and extrasynaptic GABAA receptor subunits on hippocampal pyramidal cells by freeze-fracture replica immunolabelling. Eur. J. Neurosci. 30:Online:doi:10.1111/j.1460- 9568.2010.07473.x
Start Year 2006
 
Description Z. Magloczky 
Organisation Hungarian Academy of Sciences (MTA)
Department Institute of Experimental Medicine
Country Hungary 
Sector Academic/University 
PI Contribution Experimental data
Collaborator Contribution Experimental data and analysis
Impact n/a
Start Year 2018
 
Description 11th Oxford Spring Symposium on The Brain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The Oxford International Biomedical Centre and St Edward's School hed the 11th Spring Symposium jointly with the Oxford Univerfsitgy's Dept for Continuing Education on The Human Brain.
During the morning lectures were held followed by a debate session in the afternoon.
More than 100 pupils from other schools attended as well as pupils form St Edward's School.

Lecture title : Co-operation in neuronal "societies" through circuits of the brain
Year(s) Of Engagement Activity 2010
 
Description Arhus University Lecture 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk Title: Co-operation in science and neuronal societies of the brain

Public lecture as part of Brain Prize Winner 2011
Grete Lundbeck European Brain Research Foundation

Audience approx 430
Year(s) Of Engagement Activity 2012
 
Description Co-operation in science and neuronal societies of the brain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact n/a
Year(s) Of Engagement Activity 2013
 
Description EMBO 50th Anniversary Members Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk title: Co-operation in space and time by neuronal communities of the brain

n/a
Year(s) Of Engagement Activity 2014
 
Description Human Cell Types Advisory Council 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact n/a
Year(s) Of Engagement Activity 2014
 
Description Hungarian Physiological Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk title: Rhythmic re-distribution of inhibition on pyramidal cells in the hippocampus

n/a
Year(s) Of Engagement Activity 2014
 
Description Joint Meeting of the Japanese Soci Biol Psychiatry and the Japanese Soc Neurochem 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Tale title: Co-operation of distinct cell types in network state-dependent activity of the hippocampus

n/a
Year(s) Of Engagement Activity 2014
 
Description Unit Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact Six local schools attended and 110 students took part in lab activities/ They spent time getting hands-on experience with instruments, real specimens and experiments, providing a glimpse of what to expect in a working research laboratory

Student feedback indicated that the visit was very stimulating and that the research they were shown was interesting. Several students asked questions that indicated an interest in how to become a research scientist, how to do research and how well was it paid. Some students were inspired to make University applications for various bioscience degrees, including neuroscience and medicine.
Year(s) Of Engagement Activity 2012
 
Description Unit Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact Open Day for Schools held annually in March during Brain Awareness Week when invited local Secondary schools visit and learn at first hand how research is conducted and they are given explanations about the background f the Unit's work and are given hands on experience.

Each year approximately 120 pupils attend as well as 6-15 school staff , local MP's, Local Councillor's and administrative MRC personnel from outside the Unit. Positive feedback from schools and participants
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012
 
Description Unit Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact Seven local schools attended the day and 120 pupils and teachers took part in the activities. They spent time getting hands-on experience with instruments, real specimens and experiments, providing a glimpse of what to expect in a working research laboratory

Student feedback indicated that the visit was very stimulating and that the research they were shown was interesting. Several students asked questions that indicated an interest in how to become a research scientist, how to do research and how well was it paid. Some students were inspired to make University applications for various bioscience degrees, including neuroscience and medicine.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011,2012,2013,2014,2015,2016
 
Description University of Zurich 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact n/a
Year(s) Of Engagement Activity 2014