Co-operative interactions of identified neurons in hippocampal network activity

Lead Research Organisation: University of Oxford

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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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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Somogyi P (2014) Temporal redistribution of inhibition over neuronal subcellular domains underlies state-dependent rhythmic change of excitability in the hippocampus. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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Tukker JJ (2013) Distinct dendritic arborization and in vivo firing patterns of parvalbumin-expressing basket cells in the hippocampal area CA3. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Unal G (2015) Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Human Cell Types Advisory Council
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description MSc in Neuroscience Oxford
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
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. 
 
Title Interneuron library of the hippocampus 
Description The largest known sample of in vivo recorded, labelled and identified hippocampal neurons catalogued and also used by others. 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact The only known systematically characterised in vivo recorded neuron library that other scientists can consult for identifying their cell. 
 
Title Neuron identification protocol 
Description GABAergic cells in the hippocampus were characterised on the basis of molecular expression profile AND in vivo activity pattern. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2007 
Provided To Others? Yes  
Impact GABAergic cell types can be recognised and distinguished from other ones in the hippocampus 
 
Description A. Baude 
Organisation Aix-Marseille University
Country France 
Sector Academic/University 
PI Contribution In vivo recording of novel neurons in the brain. Identification of neurons. Design of experiments. Concept of quantitative estimation of defined neuron populations.
Collaborator Contribution Microscopic expertise and analysis, original observations and discovery.
Impact 17122364
Start Year 2006
 
Description D.Kullmann 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification of recorded cells, training of staff for project.
Collaborator Contribution Design and execution of experiments, pharmacological, histological and physiological analysis
Impact 17332410
Start Year 2006
 
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 L. Marton 
Organisation Sapientia Hungarian University of Transylvania
Country Romania 
Sector Academic/University 
PI Contribution Recording neuronal activity in the brain, labelling and discovering cell types
Collaborator Contribution Developing analysis tools and programmes. Training provided to Unit members.
Impact 18367092; 18829959; 18599766
Start Year 2006
 
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 M.Scanziani 
Organisation University of California
Country United States 
Sector Academic/University 
PI Contribution Design of experiments, identification of cell types recorded, microscopic analysis, training partners.
Collaborator Contribution Design of experiments, in vitro recordings, pharmacological analysis, innovative technology.
Impact 19029887
Start Year 2007
 
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 Sieghart W 
Organisation Medical University of Vienna
Country Austria 
Sector Academic/University 
PI Contribution Immunohistochemical localisation of GABA-A receptors
Collaborator Contribution Partner has developed, tested and modified specific antibodies for the project
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 W.Wisden 
Organisation Heidelberg University
Country Germany 
Sector Academic/University 
PI Contribution Proposing brain area to test proof of principle. Microscopic demonstration of Knock-in transmitter receptor location in new mouse. Development strategy and concept.
Collaborator Contribution Developing novel mouse line for cell type specific control of activity. Reagents. Know-how. Conceptual development.
Impact 17572671
 
Description Y. Dalezios 
Organisation University of Crete
Country Greece 
Sector Academic/University 
PI Contribution Access to data
Collaborator Contribution Advanced data analysis
Impact 18599766; 17122364; 18829959
 
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 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 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