Synaptic circuit mechanisms of rhythmic slow oscillatory dynamics in the rodent and human cerebral cortex

Lead Research Organisation: University of Oxford

Abstract

Co-ordinated neuronal activity in the brain is intrinsically linked with behaviour. Malfunction of neuronal coordination results in psychiatric and neurological disorders. Much of the brain activity is rhythmic, as rhythmicity facilitates local and global interactions and enables the representation of temporal sequences. Rhythmicity resets the parameters of neuronal population activity for encoding and delivering information in support of behavioural needs. Importantly, the action of single nerve cells as well as groups of neurons can change systematically relative to the population rhythm and is used by the brain for coding of information.
We explore a widespread rhythmicity in the cerebral cortex in the so-called theta frequency range (4-12 cycles per second) in rodents and the homologous brain areas in humans. Theta oscillations are linked to higher frequency oscillations associated with cognitive processes. Such linking of rhythmicity with different frequencies is a basic principle of the brain, as changes in the strength of links indicate behavioural performance, cognitive states such as navigation, decision-making and memory and are impaired by pathology such as dementia. We identify the nerve cells, the links between them, and sites where influencing the memory system with drugs, or changing the activity of selected pathways restores normal rhythmic activity and improves co-ordination by attenuating pathological activity.

Technical Summary

Co-ordinated neuronal activity is intrinsically linked with behaviour and malfunction of neuronal coordination results in psychiatric and neurological disorders. Timing is crucial for neuronal integration including events lasting from milliseconds up to several seconds. Much of the neuronal activity is rhythmic in the brain. Rhythmicity facilitates local and global interactions and enables the representation of temporal sequences. Rhythmicity provides flexibility by resetting the frequency, amplitude and phase of population activity for encoding and delivering information in support of behavioural needs. Importantly, firing of single neurons and that of groups of neurons can change systematically relative to the population rhythm and reflect temporal coding of information.
We study the mechanism of a widespread cortical oscillation, rhythmic slow activity in the theta frequency range, typically 4-12 Hz in the temporal cortex of rodents and humans. Theta oscillations modulate higher frequency gamma (30-120 Hz) oscillations associated with cognitive processes in humans. Such cross-frequency coupling is a basic principle of brain function as changes in coupling strength indicate dynamic changes in neuronal network activity underlying behaviour, cognitive states such as navigation, decision-making and memory performance.
Programme objectives
• To define how specific cell types contribute to the timing of neuronal population activity in the hippocampus and temporal cortex.
• To establish the identity of GABAergic neurons in the cerebral cortex and subcortical areas innervating it, and to determine their in vivo firing patterns relative to theta, gamma and high frequency 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 cortical network is a condition of the synchronous pyramidal cell discharge.
• To explain how behaviour specific changes emerge in interneuron firing and how these changes contribute to pyramidal cell activity.
• To define the cellular and synaptic mechanisms of subcortical influence on cortical network oscillations.
• To determine the identity and distribution of specific neuronal types in the medial septum and cortex of the human brain.
• To identify specific sites and links in the temporal lobe memory system for modulation by drugs and electrical activity in order to improve pathological memory processes.
We explore how distinct neuronal types contribute to behaviour, and how the network mechanisms governing neuronal activity relate to both normal and abnormal brain function in rodent disease models. We hypothesise that temporal coordination of neuronal assemblies is regulated by a temporal redistribution of inhibition over principal cell subcellular domains. We reveal how the firing patterns of different GABAergic, cholinergic and glutamatergic neurons relate to network oscillations during different behavioural states such as movement and sleep and how their connectivity to other cells explains the underlying network oscillations. By extracellular recording and single cell labelling, we can capture the temporal properties during different network and behavioural states and also determine the synaptic sites of interaction through cell type identification and axon target distribution. The rigorous definition of circuits, cells and molecules helps to define the chronocircuitry of the brain.

Publications

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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 Horizon 2020 ERC-ADG-2015
Amount £999,917 (GBP)
Funding ID Grant No 694988 - Project acronym INHIBITHUMAN 
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 12/2016 
End 11/2021
 
Description Wellcome Trust Strategic Award
Amount £333,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 12/2020
 
Description A Sen 
Organisation University of Oxford
Department Nuffield Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Data
Collaborator Contribution Data and analysis
Impact N/A
Start Year 2014
 
Description Dr David Duret 
Organisation Medical Research Council (MRC)
Department MRC Brain Network Dynamics Unit at the University of Oxford (BNDU)
Country United Kingdom 
Sector Public 
PI Contribution Data
Collaborator Contribution Data and analysis
Impact n/a
Start Year 2016
 
Description Dr Olaf Ansorge 
Organisation John Radcliffe Hospital
Department Department of Neuropathology and Ocular Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Data
Collaborator Contribution Data and analysis
Impact n/a
Start Year 2016
 
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 2014
 
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. Topolnik 
Organisation Mental Health University Institute of Quebec
Department Centre of Research
Country Canada 
Sector Academic/University 
PI Contribution Experimental data
Collaborator Contribution Experimental data and analysis
Impact n/a
Start Year 2013
 
Description Mr Richard Stacey 
Organisation Oxford University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Data
Collaborator Contribution Data and analysis
Impact N/A
Start Year 2016
 
Description Mr Richard Stacey 
Organisation Oxford University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Data
Collaborator Contribution Data and analysis
Impact N/A
Start Year 2016
 
Description Professor K D Harris 
Organisation University College London
Department Neuroscience, Physiology & Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Data
Collaborator Contribution Data and analysis
Impact N/A
Start Year 2017
 
Description Professor Marco Capogna 
Organisation Aarhus University
Department Department of Biomedicine
Country Denmark 
Sector Academic/University 
PI Contribution Aarhus University
Collaborator Contribution Data
Impact n/a
Start Year 2017
 
Description Puneet Plaha 
Organisation John Radcliffe Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Data
Collaborator Contribution Data and analysis
Impact N/A
Start Year 2017
 
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 T Klausberger 
Organisation Medical University of Vienna
Department Center for Brain Research
Country Austria 
Sector Academic/University 
PI Contribution Experimental data and analysis
Collaborator Contribution Data and analysis
Impact Katona, L., Lapray, D., Viney, T.J., Oulhaj, A., Borhegyi, Z., Micklem, B.R., Klausberger, T. & Somogyi, P. (2014) Sleep and movement differentiates actions of two types of somatostatin-expressing GABAergic interneuron in rat hippocampus. Neuron 82, 872-886. Somogyi, P., Katona, L., Klausberger, T., Lasztóczi, B. & Viney, T. (2014) Temporal redistribution of inhibition over neuronal subcellular domains underlies state-dependent rhythmic change of excitability in the hippocampus. Phil. Trans. R. Soc. B. 369, 20120518. Ciocchi, S., Passecker, J., Malagon-Vina, H., Mikus, N. & Klausberger, T. (2015) Selective information routing by ventral hippocampal CA1 projection neurons. Science 348, 560-563. Forro, F., Valenti, O., Lasztoczi, B. & Klausberger, T. (2015) Temporal organization of GABAergic interneurons in the intermediate CA1 hippocampus during network oscillations Cereb. Cortex.Cereb. Cortex. 25, 1228-1240.
Start Year 2014
 
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 2014
 
Description 9th Int mGlur Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk title: mGluR8 and the incredible beauty of subcortical GABAergic innervation of the cortex
Year(s) Of Engagement Activity 2017
 
Description Brain Prize Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Presentations at the Brain Prize Meeting, Copenhagen
Year(s) Of Engagement Activity 2016
 
Description Cell Advisory Council Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Member of Cell Advisory Council Meeting - Allen Institute
Year(s) Of Engagement Activity 2016
 
Description Cell Types & Connection Advisory Council Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Cell Types & Connectivity Advisory Council meeting
Location: Allen Institute for Brain Science, Seattle, USA
Year(s) Of Engagement Activity 2015
 
Description Cell Types & Connections Scientific Advisory Council 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Member of the Cel Types & Connections Scientidic Advisory Council,, Allen Institute for Brain Science
Year(s) Of Engagement Activity 2017
 
Description ENCODES 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Invited Pleanary Lecture: Title: Rhythmic co-operation of neuronal societies in time and space
Year(s) Of Engagement Activity 2017
 
Description East-West - cultural patterns - cognitive patters - a good life 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact An international meeting held at Nanyang Executive Centre, Nanyang Technological University, Singapore
Year(s) Of Engagement Activity 2016
 
Description Gordon Research Cenference 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Inhibiton in the CNS - Acted as Discussion Leader and chairman on Modeling Neurodevelopmental Disorders
Year(s) Of Engagement Activity 2017
 
Description Hungarian Student Council Lecture Series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Internationally recognised experts of various fields - diplomacy, politics, science and business - engage and ispire the youner generation. Q&A session with speakers
Year(s) Of Engagement Activity 2015
 
Description Multinational Congress on Microscopy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Microscopic exploration of time and space of neuronal circuits in the brain
Year(s) Of Engagement Activity 2015
 
Description Symposium in honour of Michael Fortscher 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk title: "The Hungarian (GABAergic) connection."
Year(s) Of Engagement Activity 2017