Physiopathology of brain-wide assemblies in adaptive memory
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
When making decisions, we often draw on previous experience. This ability to inform behaviour from memory relies on the fine-grained coordination of activity between nerve cells in the brain. The hippocampus is a region of the mammalian brain where the activity of such “cell assemblies” has been related to memory-guided behaviour. However, memories of important life events are expected to span multiple brain regions, with each region processing a particular dimension of information. This organisation of information representation could be at the heart of the complexity of the cognitive disabilities associated with natural ageing and certain neurological/psychiatric diseases. Here, we will first seek to provide a comprehensive mechanistic explanation of how cell activities distributed across multiple brain regions support complex, detail-rich memories. In this work, we will further consider unwanted memories related to drugs of abuse that underpin maladaptive responses, investigating how cross-brain-region communication drives the re-emergence of behaviourally-extinguished drug memory. We will finally identify brain mechanisms of inferential reasoning, a higher-order operation that allows individuals to deduce logical links between sets of information that have not been experienced together. This work is intended to provide principles of interventions to harness brain physiopathology of maladaptive memory.
Technical Summary
Memory is central to adaptation, enabling individuals to infer from past experience how to respond to ever-changing situations. The idea that groups of neurons transiently synchronize their spiking activity to organize information-representing cell assemblies has laid the foundation of scientific investigations carried at the nexus between brain, memory and behaviour. Notably, past work has established how neural dynamics of assemblies in the hippocampus circuit serve memory-guided behaviour. However, memories of important, salient events are expected to span multiple brain circuits, with each circuit processing a particular dimension of mnemonic information. This organisational principle of neurally-distributed memory items could be at the heart of the complexity of the cognitive disabilities associated with natural ageing and certain neurological/psychiatric diseases. Here, we seek to obtain a comprehensive mechanistic explanation of how neuronal activities distributed across brain regions allow the division of representational labour involved in complex, detail-rich memories. We will perform this work while keeping in mind that not all memories serve adaptive behaviour. This is notably the case of strong memories related to drugs of abuse that underpin the expression of maladaptive responses. Throughout this programme, we will deploy a number of cutting-edge strategies, including cell-type-selective and input-defined optogenetic interventions as well as real-time manipulation of brain circuit dynamics, to establish causal links with behavioural phenotypes. We will first determine how temporally-patterned cooperation of neuronal spiking distributed across memory circuits allows brain-wide operations to serve optimal behaviour in situations of uncertainty caused by multiple information streams. We will then investigate how cross-brain-region communication relates to the renewal of behaviourally-extinguished drug-paired memory and associated re-occurrence of drug seeking. We will finally provide a comprehensive description of the macrocircuit and microcircuit mechanisms of inferential reasoning, a higher-order operation that allows combining discrete memory items to infer logical associations between sets of information that have not been directly experienced together. In doing so, our research programme will identify neuronal motifs and pathways supporting memory-guided behaviour. This work is intended to provide principles of interventions to harness network physiopathology of maladaptive memory.
Publications
Barron HC
(2021)
Cross-species neuroscience: closing the explanatory gap.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Barron HC
(2020)
Neuronal Computation Underlying Inferential Reasoning in Humans and Mice.
in Cell
Barron HC
(2021)
Neural inhibition for continual learning and memory.
in Current opinion in neurobiology
Barron HC
(2020)
Prediction and memory: A predictive coding account.
in Progress in neurobiology
Clarke-Williams C
(2024)
Coordinating brain-distributed network activities in memory resistant to extinction
in Cell
Ekhtiari H
(2022)
A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.
in Nature protocols
El-Gaby M
(2021)
An emergent neural coactivity code for dynamic memory.
in Nature neuroscience
Fernandez-Ruiz A
(2023)
Over and above frequency: Gamma oscillations as units of neural circuit operations.
in Neuron
Gava GP
(2021)
Integrating new memories into the hippocampal network activity space.
in Nature neuroscience
Heinze K
(2020)
Impaired inhibitory processing: a new therapeutic target for autism and psychosis?
in The British Journal of Psychiatry
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00003/1 | 01/04/2020 | 31/03/2025 | £1,280,000 | ||
MC_UU_00003/2 | Transfer | MC_UU_00003/1 | 01/04/2020 | 31/03/2025 | £2,361,000 |
MC_UU_00003/3 | Transfer | MC_UU_00003/2 | 01/04/2020 | 31/03/2025 | £1,126,000 |
MC_UU_00003/4 | Transfer | MC_UU_00003/3 | 01/04/2020 | 31/03/2025 | £2,269,000 |
MC_UU_00003/5 | Transfer | MC_UU_00003/4 | 01/04/2020 | 31/03/2025 | £2,274,000 |
MC_UU_00003/6 | Transfer | MC_UU_00003/5 | 01/04/2020 | 31/03/2025 | £2,177,000 |
Description | Eco-friendly research |
Geographic Reach | Europe |
Policy Influence Type | Membership of a guideline committee |
Impact | We are assembling a European Network of research scientists from the field of Life sciences to assess ways to implement sustainable research. |
Description | Knowledge transfer about research practice with the scientific council of the French Embassy in London |
Geographic Reach | Europe |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Public Outreach Committee |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Research staff is being trained to share their knowledge to the general public, and notably to discuss animal related work in medical research. Notably, this allows changing public attitudes towards how scientific research is delivered and the use of animals in research. |
Description | Cross-Network Novelty Encoding along the VTA-Hippocampal Pathway |
Amount | £17,000 (GBP) |
Funding ID | 2445705 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2020 |
End | 09/2024 |
Description | Cross-regional coactivity for the formation of brain-wide neuronal assemblies |
Amount | SFr. 118,600 (CHF) |
Funding ID | P500PB_206885 / 1 |
Organisation | Swiss National Science Foundation |
Sector | Public |
Country | Switzerland |
Start | 03/2022 |
End | 03/2024 |
Description | Hippocampal-Hypothalamic Network Mechanisms of Maladaptive Contextual Eating |
Amount | £914,378 (GBP) |
Funding ID | MR/W004860/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2021 |
End | 09/2025 |
Description | UK DRI Grand Challenges Award Programme 2022 |
Amount | £1,690,295 (GBP) |
Funding ID | DRI-GCFA223 |
Organisation | UK Dementia Research Institute |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2023 |
End | 07/2026 |
Title | Genetic construct for Cre-dependent expression of Flp recombinase pAAV-EF1a-DIO-FLPo-Myc |
Description | This genetic construct generated in my laboratory allows users to express the recombinase Flp conditioned to the expression of the recombinase Cre. This construct is used for cell-type-selective optogenetic manipulation of nerve cells in the mammalian brain. |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | This construct has allowed to identify the neural pathway supporting the behavioral expression of appetitive memories in the adult mammalian brain (https://www.mrcbndu.ox.ac.uk/publications/hippocampus-accumbens-tripartite-neuronal-motif-guides-appetitive-memory-space). This construct is available at Addgene (see URL below). |
URL | https://www.addgene.org/124641/ |
Title | Genetic construct for Cre-dependent expression of optogenetic silence ArchT pAAV-EF1a-FDIO-ArchT-GFP |
Description | This genetic construct generated in my laboratory allows users to express the neuronal silencer ArchT conditioned to the expression of the recombinase Flp. This construct is used for cell-type-selective optogenetic silencing of selective nerve cells in the mammalian brain. |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | This construct has allowed to identify the neural pathway supporting the behavioral expression of appetitive memories in the adult mammalian brain (https://www.mrcbndu.ox.ac.uk/publications/hippocampus-accumbens-tripartite-neuronal-motif-guides-appetitive-memory-space). |
URL | https://www.addgene.org/124640/ |
Title | analytical tool for network oscillations using Empirical Mode Decomposition |
Description | A set of Python programs to extract frequency content of network oscillations |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This toolbox allows identifying non-linear and non-stationary oscillatory components of complex signals. |
URL | https://pypi.org/project/emd/ |
Title | Code used for analysis of task-relevant, time-resolved functional Magnetic Resonance Spectroscopy (fMRS) |
Description | This package contains code for Preprocessing of fMRS data (matlab), fsl_mrs code for simulations of fMRS data (python), Code for analysis of behavioural data (matlab), Code to assess relationship between fMRI and fMRS data (matlab) and Plotting functions |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This package allows scientists to study and analyse functional magnetic resonance spectroscopy |
URL | https://ora.ox.ac.uk/objects/uuid:4ff5cd17-a794-4f85-8666-b07de85d2301 |
Title | Code used for analysis of task-relevant, time-resolved functional Magnetic Resonance Spectroscopy (fMRS) |
Description | This package contains code for: Preprocessing of fMRS data (matlab), fsl_mrs code for simulations of fMRS data (python), Code for analysis of behavioural data (matlab), Code to assess relationship between fMRI and fMRS data (matlab) and Plotting functions. |
Type Of Material | Data analysis technique |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This research dataset and codes allow scientists to analyse functional Magnetic Resonance Spectroscopy acquired in humans. |
URL | https://data.mrc.ox.ac.uk/data-set/frms-code |
Title | Combined fMRI-fMRS dataset in an inference task in humans |
Description | This dataset consists of the following components: fMRI data showing group maps for contrasts of interest (nifti) raw fMRS data of 19 subjects (dicom) preprocessed fMRS data of 19 subjects, preprocessed in MRspa (mat) behavioural data from inference task during MRI scan (mat) behavioural data from associative test post MRI scan (mat) Participants performed a three-stage inference task across three days. On day 1 participants learned up to 80 auditory-visual associations. On day 2, each visual cue was paired with either a rewarding (set 1, monetary reward) or neutral outcome (set 2, woodchip). On day 3, auditory cues were presented in isolation ('inference test'), without visual cues or outcomes, and we measured evidence for inference from the auditory cues to the appropriate outcome. Participants performed the inference test in an MRI scanner where fMRI-fMRS data was acquired. After the MRI scan, participants completed a surprise associative test for auditory-visual associations learned on day 1. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This dataset allows studying neural mechanisms of inferential reasonning in humans |
URL | https://ora.ox.ac.uk/objects/uuid:6ce36198-7b7f-4cbf-9261-d18931ac460c |
Title | Detection of cell assemblies |
Description | Development and refinement of analytical tools to detect coordinated neuronal activity forming functional cell assemblies |
Type Of Material | Data analysis technique |
Provided To Others? | No |
Impact | Validation to the behavioural relevance of short time-scale hippocampal assembly-patterns |
Title | Instantaneous frequency profiles of theta cycles |
Description | This dataset contains the local field potentials recorded from 10 tetrodes located in the mouse dorsal CA1 hippocampus and the simultaneous movement tracking data for two recording sessions, from each of three mice. There are three subdirectories, each containing four datafiles: two raw 64-channel .eeg files (binary file; 1,250Hz sampling; hence, sample interval is 800 microsecs) and two .whl files (text file; 39.0625Hz sampling; an ordered list of X,Y locations of the animal; 2-column format). All data recordings are made during open field exploration. The data runs ending with *_2.eeg and *_2.whl correspond to exploration of a familiar environment and the runs ending with *_5.eeg/*_6.eeg and *_5.whl/*_6.whl correspond to exploration of a novel environment. Each subfolder contains two meta-data files. A .desel file that reports the location of each tetrode. In this dataset a value of '1' indicates CA1; 'cx' indicates cortex. A .par file that describes the acquisition parameters of the dataset, the correspondence between individual channels and tetrodes (max 4 channels per tetrode), and the list of whitelisted channels suitable for further analysis. A commented example of a par file is below (though the actual files do not contain comments) |
Type Of Material | Data analysis technique |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This package provides a novel technique to assess oscillatory dynamics in brain networks |
URL | https://data.mrc.ox.ac.uk/data-set/instantaneous-frequency-profiles-theta-cycles |
Title | Topological analysis of hippocampal CA1 co-firing graphs |
Description | This package allows applying a novel technique from graph-theory to neuronal networks. In the dataset provided, each matrix contains the hippocampal CA1 co-firing graphs computed using the spike trains of pyramidal cells recorded from mice during active exploratory behaviour (i.e., excluding immobility epochs and sharp-wave/ripples) in four different tasks: (i) conditioned place preference (CPP), (ii) exploration of a novel context (without reward), (iii) spontaneous place preference (SPP) for a novel context and (iv) rewarded exploration of an otherwise familiar context (without CPP). In these co firing graphs, each node represents one cell; the edge linking any two nodes represents the coactivity of that cell pair, with a weight computed as the Pearson correlation coefficient between their spike trains. Each co-firing graph is defined by its adjacency matrix, whose elements are the edges of the graph / co-firing relationships between pairs of neurons indexed by the rows and columns of the matrix. For each matrix, the code provided (python 3.6) analyses the co-firing relationships among pyramidal cells for the 6 sessions recorded on that task day. Graph-theoretical measures are obtained for each co-firing graph (one graph per task session) and their dynamics across the 6 task sessions are analysed. See the paper 'Integrating new memories into the hippocampal network activity space' for description of the task and detailed methods. Notably, these example co-firing graphs and codes relate to figures 1, 2 and extended data figure 2. |
Type Of Material | Data analysis technique |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This package allows applying a novel technique from graph-theory to neuronal networks. |
URL | https://data.mrc.ox.ac.uk/data-set/topological-analysis-hippocampal-ca1-co-firing-graphs |
Description | Brain and behavioral dynamics of social interaction |
Organisation | École Normale Supérieure, Paris |
Country | France |
Sector | Academic/University |
PI Contribution | My laboratory is providing expertise in brain network physiology linked to social behaviour |
Collaborator Contribution | My collaborator is providing expertise in theoretical modelling of social dynamics |
Impact | This collaboration is multidisplinary, including experts in statistical physics and brain network physiology |
Start Year | 2020 |
Description | circuit-level biomarker of AD pathology |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The UK DRI Grand Challenge Award will support a collaboration between the Dupret Group at the MRC Unit and researchers based at University College London, and will be led by UK DRI Group Leader Dr. Marc Aurel Busche. The team will work together to develop a biomarker for Alzheimer's that can be used to identify and monitor early signs of the disease. My laboratory will leverage its leading expertise in the electrophysiological interrogation of brain functions underlying memory, focusing on state-of-the-art mouse models of Alzheimer's. |
Collaborator Contribution | The Award will also support parallel studies in human research participants at the UK DRI, offering a valuable opportunity for cross-species translation of research discoveries. |
Impact | The collaboration is about to officially start. |
Start Year | 2023 |
Description | hippocampal network physiology in the human brain |
Organisation | National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) |
Country | France |
Sector | Academic/University |
PI Contribution | In this collaboration, my laboratory is deploying expertise in brain network dynamics to analyse neural dynamics in the human hippocampus. Notably, we use state-of-the-art spectral decomposition of the local field potentials recorded from the human brain during memory tasks where participants use their memory abilities to draw conclusions. |
Collaborator Contribution | My collaborators are collecting the data at the hospital, running the memory task and brain recordings with the human participants. |
Impact | This collaboration is multi-disciplinary and cross-species: this project combines in vivo brain electrophysiology and medicine; rodents and humans. |
Start Year | 2022 |
Description | neural dynamics in AD |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | In this collaboration, my laboratory is deploying expertise in brain networks to reveal dysfunctional neural dynamics in Alzheimer Disease. Notably, we use state-of-the-art spectral decomposition of the local field potentials recorded from the brain during memory tasks where participants use their ability to continually learn new information to adjust their behaviour on a moment-by-moment basis. |
Collaborator Contribution | My collaborators are providing expertise in the neurobiological basis of AD pathology. |
Impact | This collaboration is multi-disciplinary and cross-species, allowing to combine multiple techniques (molecular biology, electrophysiology, imaging, medicine) to assess early biomarkers of AD onset in humans and rodents. |
Start Year | 2021 |
Description | Featuring the brain in a museum exhibition |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Research staff contributed to a large and new exhibition held at the Banbury Museum & Gallery (Oxforshire) by providing microscopic images to illuminate in beautiful details the circuits and cells of the mammalian brain. The exhibition, entitled "Your Amazing Brain: A User's Guide", ran from 12th February to 5th June 2022 and was an interactive, family-friendly experience offering the public an opportunity to journey inside the brain and discover more about what makes the brain so special. The Unit's images formed the core of a gallery piece "Zoom into your brain" that showcases, at increasing magnification, the organisation of the brain into regions, different types of neurons, and specialised structures such as axons, dendrites, and synaptic connections. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.banburymuseum.org/events/your-amazing-brain/ |
Description | General public documentary: The Symphony of the Brain |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | This documentary explains to the general public the notion of brain waves, and how this processs supports memory and movements. This documentary is available to anyone on the Youtube channel. It is a producion made in partnership with Oxford Sparks. Video Summary: "We can think of singers in a choir as neurons in the brain. Like these singers, neurons have to work together to create harmony, and once they do, the results are magnificent!" When neurons, or nerve cells, in the brain communicate with each other, they generate synchronised electrical activities known as brain waves. But what is the function of these brain waves? Can we 'see' them? What happens if these collective activities go 'out of sync'? In this video, Demi Brizee, a PhD student in the Medical Research Council Brain Network Dynamics Unit at the University of Oxford, introduces us to the fascinating world of brain waves, and explains how a better understanding of them could lead to new therapies for neurological conditions. |
Year(s) Of Engagement Activity | 2022,2023 |
URL | https://youtu.be/2YFHVyl8l1I |
Description | General public seminar about brain and memory |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | I discussed recent advances in the field of memort to the general public, annswering all questions from the audience. This event has allowed to clarify to the general public recent advances in the field of memory. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.seh.ox.ac.uk/events/fellowship-lunchtime-lectures-professor-david-dupret |
Description | In2science 'virtual placement programme' |
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 | In July/August 2020, MRC BNDU continues to participate in the previously partnered with the charity In2science to host Year 12 school pupils enrolled on their STEM work-experience programme. Each summer, for the past 4 years, we have delivered personalised mentoring and rich STEM experiences for pupils from disadvantaged backgrounds. Charles Clarke-Williams from Dupret group together with some members of the Brown/Tan/Magill group took part in a research-based module "Interacting with the brain" that was jointly designed and delivered in support of In2scienceUK's Virtual Placement Programme. They organised webinars and research tasks (with real data!) for the students who took part. |
Year(s) Of Engagement Activity | 2020 |
URL | https://in2scienceuk.org/ |
Description | Internship with the Royal Institution |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | One of our PhD student has started a competitive three-month internship with the Royal Institution of Great Britain. The Ri is a charity that works to improve the relationship between scientists and the public, supporting open access and scientific discourse for all. During this internship, our stduent is working with their digital media team to create engaging content, including YouTube videos, livestreamed talks, written blogs, podcast episodes, TikToks, and more! |
Year(s) Of Engagement Activity | 2023 |
Description | Locked-in: science on screen |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | I joined a group of University of Oxford neuroscientists for a film screening and discussion about The Diving Bell and the Butterfly, the true story of a former Elle editor, Jean-Dominique Bauby. Briefly, a major stroke leaves Bauby almost entirely paralysed, with the exception of his left eye. Bauby uses the experience to redeem himself for his less than exemplary life. In this event, I discussed the film's premise that consciousness is at the core of humanity and discussed scientific knowledge about locked-in syndrome, stroke and brain plasticity. This event contributed to the 2021 Oxford Science+ideas Festival (9-26October 2021), which comprised of 36 online and 67 face-to-face events with covid measures in place; a total of 35,000 people engaged with on-demand or live contents including 6,500 who came to 20 Oxford venues with 1.4 million social media users. |
Year(s) Of Engagement Activity | 2021 |
URL | https://if-oxford.com/wp-content/uploads/2021/08/IF-2021-PROGRAMME.pdf |
Description | Special Forum at FENS-Kavli Network of Excellence |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | 14 July 2020, at the FENS-Kavli Network of Excellence (FKNE), Professor David Dupret took part in a Session on Environmentally friendly Science. This special forum discussed what we can do to adopt a more sustainable model for life-sciences. The organizers presented the results of a small survey performed among neuroscientists and their research institutes to trigger the discussion on the environmental footprint of our community and to start identifying solutions. A panel of academics, activists and life-science industry representatives, among others, shared their viewpoints and experiences implementing concrete actions towards an environmentally friendly life-science framework. In addition to raising awareness on the impact of life sciences on the environment, they highlighted the need to better measure and document this impact, including plastic and Co2 emissions in scientific events and research centers. they also aim to draw up a list of concrete actions that define gold-standards of sustainability for our scientific community. |
Year(s) Of Engagement Activity | 2020 |
URL | https://forum2020.fens.org/event/sie05-towards-an-environmentally-friendly-model-for-life-sciences-1... |