Synaptic circuit mechanisms of rhythmic oscillatory dynamics in the cerebral cortex

Lead Research Organisation: University of Oxford
Department Name: Pharmacology

Abstract

Rhythmic brain activity governs behaviour through the coordination of large numbers of nerve cells within and amongst specialised brain regions. Of particular importance is the formation or recall of everyday memories, which requires the synchronised action of millions of nerve cells of the temporal lobe within about a tenth of a second. In mammals, including humans, such synchronisation is observed as a 'slow' oscillating electrical rhythm measured by electroencephalography (EEG). Embedded within each cycle of the slow EEG signal, higher frequency oscillations emerge in relation to cognitive processes. Brain disorders including dementia and age-related memory impairments are accompanied by perturbation of these brain rhythms, thus highlighting their biological importance. The mechanisms for establishing and maintaining such rhythmic brain activity at various time scales, and the specific roles of the hundreds of nerve cell varieties that cooperate to deliver such a feat of function, remain to be defined. Brain rhythmicity creates sequential "windows" of increased and decreased activity levels of large groups of nerve cells, which enables the cerebral cortex to encode and link actual sequences of real-life events that are represented on distinct oscillatory cycles. In the proposed project, we will exploit our discovery of three novel varieties of nerve cells for establishing their roles in rhythmic oscillatory neuronal activity and memory processing. The novel types of nerve cell are found in a subcortical area deep within the brain called the medial septum, and each type sends parallel projections to a select area or areas of the cerebral cortex that each plays a distinct role in the formation and recall of memories. These cooperative brain areas, including the hippocampus and entorhinal cortex, are the ones first affected by neurodegeneration in Alzheimer's disease. Using a novel technology for the molecular dissection of gene expression profiles of these and other nerve cells in the medial septum, we will provide a comprehensive definition of cell types in both the mouse and the human brain. Building on our recent discoveries, we will establish how the function of these types of nerve cells changes in a mouse model of Alzheimer's disease. We will then use external modulation of the activity of some of these specific pathways to test how to improve memory processing. This project will thus advance our understanding of the functional organisation of the mammalian brain in relation to memory processing.

Technical Summary

Neuronal rhythmic synchronous activity in the theta frequency range (4-10 Hz) modulates the frequency and amplitude of gamma frequency (30-120 Hz) synchronisation, reflecting cognitive processes in the cerebral cortex. Theta oscillations are generated in a network of brain stem and midbrain structures and are transmitted to the cortex by the medial septum and diagonal band nuclei (MS/DB), but the principles of organisation of this pathway remain undefined. To identify the cell types in the MS/DB, I propose to provide a comprehensive gene expression profile of neurons using a pioneering technique, in situ RNA sequencing, and compare cell types in the murine and human MS/DB. In the ongoing MRC programme, we discovered that individual neurons in the MS/DB are highly specialised in time and space. We have defined four groups of strongly rhythmic GABAergic neuronal types in vivo. Three of these novel cell types are characterised: the Orchid cells, the Teevra cells and the dentate gyrus-targeting cells. They differ in their cortical target regions and brain state dependent firing in awake mice. We propose to establish their functional roles and contributions to behavioural states in normal and in the THY-Tau22 mouse model of Alzheimer's disease, by analysing their activity and synaptic connections. Using pharmaco- and opto-genetic modulation of their activity, first we focus on Teevra cells that selectively innervate specific GABAergic neurons via GABAergic synapses in hippocampal CA3 area, which provides context-dependent drive to the CA1 area during memory representation. We will test the hypothesis that the disinhibitory temporal windows assisted by Teevra cells increase hippocampal pyramidal cell excitability, providing temporal windows of context dependent read-out of hippocampus-dependent memory traces to the cerebral cortex and subcortical systems. This project will advance understanding of the functional organisation of the brain in relation to memory processing.

Planned Impact

The results of the project and the training provided in it will have benefits to a wide range of stakeholders:
(1) Researchers: neuroscientists engaging in basic brain research, both experimentalists and theoretical, clinicians working with patients suffering from dementia, neuroimaging specialists researching the human brain (e.g. functional MRI, connectomics), engineers and technologists (e.g. those working on brain-machine interfaces), molecular biologists, biochemists.
(2) Private sector: pharmaceutical companies undertaking drug discovery and clinical trials relating to Alzheimer's disease.
(3) Organisations, Institutes and government: national policy makers assessing the medium and long-term impact of basic neuroscience on society, European brain science initiatives such as the Human Brain Project, international Institutes (e.g. Allen Institute, Peter Somogyi serves on the Advisory Council of the theme "Human cortical cell types").
(4) Public sector: Alzheimer's Research UK charity, schools and other educational establishments, care homes.
Each group will benefit from the research in different ways:
The short-term benefits will be the impact on the research carried out by other neuroscientists and clinicians within the same field. Once our data are disseminated (e.g. through peer-review publication), other laboratories will immediately be able to use the results to design, modify or further support their experiments or re-evaluate their previous findings. For example, for researchers using Alzheimer's disease mouse models, they will directly be able to determine whether our findings on cell types within the basal forebrain projecting to cortical areas that degenerate in Alzheimer's disease may explain their results. Since our research output includes both neuroanatomical (e.g. projections from subcortical regions to the cortex) and neurophysiological data (e.g. role of network oscillations), studies on the human brain (e.g. neuroimaging) will gain a deeper understanding of the link between neuronal communication across cortical areas and 'functional' connectivity. Within the first 6 months of the project, as it is a continuation of current research, we expect to have published significant progress explaining cellular and synaptic mechanisms of setting up and maintaining rhythmic synchronised brain activity in the cerebral cortex.
In the medium to long-term, our research will benefit human health, as our results will be incorporated into understanding and explaining information processing in the brain.

Publications

10 25 50
 
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 Belgium
Start 12/2016 
End 11/2021
 
Description Wellcome Trust Strategic Award
Amount £333,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Charity/Non Profit
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 2018
 
Description Dr David Dupret 
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 2018
 
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 Bocchio M, Lukacs IP, Stacey R, Plaha P, Apostolopoulos V, Livermore L, Argue S, Ansorge O, Gillies MJ, Somogyi P and Capogna, M. (2019) Group II metabotropic glutamate receptors mediate presynaptic inhibition of excitatory transmission in pyramidal neurons of the human cerebral cortex. Front Cell Neurosci. 12, 508.
Start Year 2019
 
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. 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 Francavilla, R, Villette V, Luo X, Chamberland S, Muñoz-Pino E, Camiré O, Wagner K, Viktor K, Somogyi P and Topolnik L. (2018) Connectivity and network state-dependent recruitment of long-range VIP-GABAergic neurons in the mouse hippocampus. Nature Commun.,9, 5043.
Start Year 2018
 
Description Mr Richard Stacey 
Organisation Oxford University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution Data
Collaborator Contribution Acute human cortical surgeries for in vito slice physiology
Impact Bocchio M, Lukacs IP, Stacey R, Plaha P, Apostolopoulos V, Livermore L, Argue S, Ansorge O, Gillies MJ, Somogyi P and Capogna, M. (2019) Group II metabotropic glutamate receptors mediate presynaptic inhibition of excitatory transmission in pyramidal neurons of the human cerebral cortex. Front Cell Neurosci. 12, 508.
Start Year 2018
 
Description Mr Richard Stacey 
Organisation Oxford University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution Data
Collaborator Contribution Acute human cortical surgeries for in vito slice physiology
Impact Bocchio M, Lukacs IP, Stacey R, Plaha P, Apostolopoulos V, Livermore L, Argue S, Ansorge O, Gillies MJ, Somogyi P and Capogna, M. (2019) Group II metabotropic glutamate receptors mediate presynaptic inhibition of excitatory transmission in pyramidal neurons of the human cerebral cortex. Front Cell Neurosci. 12, 508.
Start Year 2018
 
Description Prof Jens Hjerling-Leffler 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Data
Collaborator Contribution In situ transcriptomic dissection of neuronal diversity
Impact Harris KD, Hochgerner H, Skene NG, Magno L, Katona L, Bengtsson Gonzales C, Somogyi P, Kessaris N, Linnarsson S and HjerlingLeffler, J. (2018) Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics. PLoS Biology, 16, e2006387.
Start Year 2018
 
Description Professor Angus Silver 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-supervisotr of the thesis of Istvan Lukacs
Collaborator Contribution n/a
Impact n/a
Start Year 2018
 
Description Professor K D Harris 
Organisation University College London
Department Neuroscience, Physiology & Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Harris KD, Hochgerner H, Skene NG, Magno L, Katona L, Bengtsson Gonzales C, Somogyi P, Kessaris N, Linnarsson S and HjerlingLeffler, J. (2018) Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics. PLoS Biology, 16, e2006387. Harris KD, Hochgerner H, Skene NG, Magno L, Katona L, Bengtsson Gonzales C, Somogyi P, Kessaris N, Linnarsson S and HjerlingLeffler, J. (2018) Classes and continua of hippocampal CA1
Collaborator Contribution Data and analysis
Impact N/A
Start Year 2019
 
Description Professor Marco Capogna 
Organisation Aarhus University
Department Department of Biomedicine
Country Denmark 
Sector Academic/University 
PI Contribution Aarhus University
Collaborator Contribution Data
Impact Bocchio M, Lukacs IP, Stacey R, Plaha P, Apostolopoulos V, Livermore L, Argue S, Ansorge O, Gillies MJ, Somogyi P and Capogna, M. (2019) Group II metabotropic glutamate receptors mediate presynaptic inhibition of excitatory transmission in pyramidal neurons of the human cerebral cortex. Front Cell Neurosci. 12, 508.
Start Year 2018
 
Description Professor Mats Nilsson 
Organisation Stockholm University
Department Department of Biochemistry and Biophysics
Country Sweden 
Sector Academic/University 
PI Contribution data
Collaborator Contribution In situ transcriptomic dissection of neuronal diversity
Impact n/a
Start Year 2018
 
Description Professor Nicoletta Kessaris 
Organisation National Institute for Health Research
Department UCLH/UCL Biomedical Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Data
Collaborator Contribution Molecular diversity of neurons in situ hybridisation
Impact Harris KD, Hochgerner H, Skene NG, Magno L, Katona L, Bengtsson Gonzales C, Somogyi P, Kessaris N, Linnarsson S and Hjerling-Leffler, J. (2018) Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics. PLoS Biology, 16, e2006387.
Start Year 2019
 
Description Puneet Plaha 
Organisation John Radcliffe Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Data
Collaborator Contribution Acute human cortical surgeries for in vitro slice phyiology
Impact Bocchio M, Lukacs IP, Stacey R, Plaha P, Apostolopoulos V, Livermore L, Argue S, Ansorge O, Gillies MJ, Somogyi P and Capogna, M. (2019) Group II metabotropic glutamate receptors mediate presynaptic inhibition of excitatory transmission in pyramidal neurons of the human cerebral cortex. Front Cell Neurosci. 12, 508.
Start Year 2019
 
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 Somogyi P and Klausberger T (2018) Handbook of Brain Microcircuits (2nd Ed) Hippocampus: Intrinsic Organisation, Oxford University Press
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 2018
 
Description 2018 Brain Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk at the 2018 Brain Confeence - The Necesity of Cell Tupes for Brain Research
"Brain Space and Time defines Neuron Types"
Year(s) Of Engagement Activity 2018
 
Description Axons in the Hills 
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 Cortical axo-axonic cells in brain time and space
Year(s) Of Engagement Activity 2018
 
Description Gordon Research Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion leader at the Inhibition in the CNS conference
Year(s) Of Engagement Activity 2019
 
Description IBRO-UM5, Rabat 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Module I: Neural substrates of cognitive functions
Titles: Hippocampus - place and roles in brain networks
(2) Hippocampus - intrinsic organization of time and space
Year(s) Of Engagement Activity 2019