Dynamics of cell assemblies underlying adaptive and mal-adaptive memories

Lead Research Organisation: University of Oxford

Abstract

Learning and memory processes rely on the fine coordination of nerve cell activity in several brain regions including the hippocampus and the nucleus accumbens. In this programme we aim to explain how and why nerve activity is organised, not only for understanding normal brain function but also for explaining what goes wrong during memory disorders, including those associating an environment with drugs of abuse. We seek to explain how nerve cells in these brain regions produce accurate patterns of electrical activity that are essential for our memory representations of environments in which salient life events have been experienced. In this work we use cutting edge technologies, ranging from the combined use of rodent behavioural paradigms and brain recordings to light-based manipulation of nerve cell activity. In so doing we place special emphasis on explaining when, why and how special patterns of electrical activity, such as waves or rhythms in different types of nerve cell assist brain operations during normal behaviours. By using light-based tools to experimentally interact with different cell types in these brain circuits we identify patterns of electrical activity that might support abnormal behaviours. In conclusion, this programme of research will allow us to provide novel insights into how nerve cells in the brain coordinate their activity to guide so much of our daily behaviour in both health and disease.

Technical Summary

Memory is central to behaviour, enabling individuals to infer from past experience how to respond to their ever-changing environment. Nonetheless the recall of certain memory representations, such as those of environments where a drug of abuse was experienced, is undesirable as these can impair the individual’s ability to adapt to its environment and therefore put it at risk. In this programme our goal is to provide a mechanistic understanding of how temporally-structured neuronal activity in the brain underlies memory processes. To this end we seek to determine how pyramidal cell-interneuron dynamics underlie the temporal segregation of cell assemblies in the hippocampus for the coordination of the read-in/encoding of new information with the read-out/retrieval of old stored information. We further investigate how downstream network interactions with the nucleus accumbens mediate the guidance of purposeful behaviour by spatio-contextual memories. In this work, we use a number of complementary techniques to monitor and stimulate neuronal activity in the mouse brain during well-defined behaviour. In so doing, our programme will probe temporally patterned manipulations aimed at rebalancing brain dynamics by the selective enhancing, reprogramming or weakening of the cell assemblies providing brain representations of drug/fear-paired environments. This work is intended to provide principles of intervention of brain areas where network dynamics underlie pathophysiology of memories.

Publications

10 25 50
 
Title Sleep replay for memory consolidation 
Description A movie explaining how new memories are stabilised in the brain 
Type Of Art Film/Video/Animation 
Year Produced 2016 
Impact Increasing public knowledge about why sleep is a critical period for the consolidation of newly-acquired memories 
URL https://www.youtube.com/watch?v=USVDXlWQfRE
 
Description Animal Welfare and Ethics in Research
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Data management and sharing in research
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guideline committee
Impact Increase in best practice and knowledge related to the curing, sioring and sharing of scientific data
 
Description BBSRC research grant responsive mode
Amount £344,000 (GBP)
Funding ID BB/N0059TX/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2016 
End 04/2020
 
Description BBSRC research grant responsive mode
Amount £735,000 (GBP)
Funding ID BB/N002547/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 01/2020
 
Description Equipment Funds for Med-Career Researchers
Amount £95,000 (GBP)
Funding ID C0443 
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 04/2014
 
Description IBRO-PERC and The Brain Prize stipend to Mr Gido Van de ven
Amount £1,000 (GBP)
Organisation International Brain Research Organisation (IBRO) 
Sector Academic/University
Country Global
Start 04/2017 
End 04/2017
 
Description John Fell Fund to Dr Helen Barron
Amount £16,000 (GBP)
Funding ID 153/046 
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 03/2018
 
Description NASARD Young Investigator Grant to Dr Stephanie Trouche
Amount $70,000 (USD)
Funding ID 1602CJ001/VC2 
Organisation Brain & Behaviour Research Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2016 
End 06/2016
 
Description Oxford-McGill-ZNZ Partnership in Neuroscience
Amount £30,000 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 01/2018 
End 07/2018
 
Title Analytical framework for the identification of brain network states from electrophysiological data 
Description Development of a statistical framework to reveal hidden brain states featured by network oscillations 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2015 
Provided To Others? Yes  
Impact Identification of short-lived transient brain states with distinct power and functional connectivity (e.g., coherence). 
 
Title Closed-loop brain-machine interface for the in-vivo modulation of memory consolidation 
Description Development of an optogenetic closed-loop interface to manipulate in-vivo the neuronal activity during the short-lived sharp-wave/ripple oscillatory events 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2016 
Provided To Others? Yes  
Impact Identification of a brain circuit mechanism underpinning memory consolidation 
URL http://www.mrcbndu.ox.ac.uk/publications/hippocampal-offline-reactivation-consolidates-recently-form...
 
Title Optogenetic viral constructs to recode a memory representation 
Description Generation of adeno-associated viral tools that target specific subsets of neurons to manipulate them via in vivo-light delivery and thereby to dissect brain circuit mechanisms of memory processes 
Type Of Material Technology assay or reagent 
Year Produced 2016 
Provided To Others? Yes  
Impact Discovery that optogenetic silencing of neurons representing a spatial environment paired with drug abuse allows alleviating drug-seeking behaviour (Trouche et al, Nature Neuroscience 2016) 
URL http://www.mrcbndu.ox.ac.uk/publications/recoding-cocaine-place-memory-engram-neutral-engram-hippoca...
 
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 Large-scale recordings of brain network activity 
Description Electrophysiological dataset of parallel recordings of multiple neurons from the rodent brain 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Identification that neuronal activity in the rodent brain follow scale-free power-law dynamics 
 
Description Molecular tagging of memory-bearing neurons 
Organisation Tufts University
Department Department of Neuroscience
Country United States 
Sector Academic/University 
PI Contribution Using a tetTAG technology we labelled brain nece cells holding a memory representation of an environment paired with drug abuse. By controlling these tagged neurons, we have managed to alleviate the expression of a drug-place behaviour.
Collaborator Contribution Dr Reijmers provided the c-fos-tTA mouse line to implement the tetTAG technology.
Impact One peer-reviewed research article published: Nat Neurosci. 2016 Feb 22. doi: 10.1038/nn.4250. Recoding a cocaine-place memory engram to a neutral engram in the hippocampus. Trouche S, Perestenko PV, van de Ven GM, Bratley CT, McNamara CG, Campo-Urriza N, Black SL, Reijmers LG, Dupret D.
Start Year 2012
 
Description Role of SWR in memory consolidation 
Organisation Heidelberg University
Country Germany 
Sector Academic/University 
PI Contribution Interactive collaborative work to develop a closed loop interface to detect sharp wave/ripple events from the local field potential. This technology provides proof of principle for closed-loop manipulation of the neuronal representation of a memory trace.
Collaborator Contribution Interactive collaborative work to develop a closed loop interface to detect sharp wave/ripple events from the local field potential
Impact One peer-reviewed research article published: Hippocampal Offline Reactivation Consolidates Recently Formed Cell Assembly Patterns during Sharp Wave-Ripples. van de Ven GM, Trouche S, McNamara CG, Allen K, Dupret D. 2016. Neuron, 92(5): 968-974.
Start Year 2013
 
Description Study of neuronal cell assembly formation using information theory 
Organisation Imperial College London
Department Centre for Health Policy
Country United Kingdom 
Sector Academic/University 
PI Contribution To provide large-scale recordings of brain neuronal activity during memory tasks and expertise in brain network dynamics Our team will develop innovative analytical tool to estimate information content of neuronal assemblies
Collaborator Contribution To develop analytical tools from the field of information theory
Impact - Development of a innovative analytical framework to study the formation of mnemonic cell assemblies
Start Year 2016
 
Description Study of scale-free neuronal dynamics 
Organisation University of Helsinki
Department Institute of Behavioural Sciences
Country Finland 
Sector Academic/University 
PI Contribution The Dupret Lab is providing datasets of brain recordings of multi-neurons activity and expertise in network electrophysiology This work is revealing how the brain optimizes information processing capacities while avoiding chaotic instability
Collaborator Contribution The partner is providing analytical tools based on scale-free dynamics from the field of physics
Impact - Discovery that both brain neuronal activity and memory-guided behaviours are statistically governed by spatio-temporal power-laws (similar to those governing avalanches).
Start Year 2016
 
Title Closed-loop manipulation of memory representation during off-line epochs 
Description The research described how to implement a closed-loop neuronal silencing of memory representations from the on-the-fly-detection of sharp wave/ripples network events 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2016
Licensed Yes
Impact Has open new perspectives into ways to interfere with the neuronal underpinning of a memory trace
 
Title AAV genetic constructs 
Description DNA sequence allowing the expression of optogenetic silencer under the control of the tetracycline responsive element 
Type Of Technology New Material/Compound 
Year Produced 2016 
Impact Using this construct, our team has been able to silence the subset of neurons holding a representation of an environment paired with drug abuse in order to alleviate the expression of a drug-place behaviour 
URL http://www.mrcbndu.ox.ac.uk/publications/recoding-cocaine-place-memory-engram-neutral-engram-hippoca...
 
Title Real-time detection of memory consolidation events in sleep 
Description Brain-machine interface for the real-time detection of sharp-wave/ripples events during which memory consolidation occurs 
Type Of Technology Detection Devices 
Year Produced 2016 
Impact Identification of the brain state responsible for the consolidation of new memories 
 
Description Cheltenham Science Festival 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interactive displays about the brain works

During this festival many people ask questions about how to become a research scientist and how far from finding a treatment for Alzheimer's disease we are
Year(s) Of Engagement Activity 2014
URL http://www.mrc.ox.ac.uk/news/unit-engages-cheltenham-science-festival-2014
 
Description Generating Genius School Visit during MRC Festival Week (commencing week 20 June 2016) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Generating Genius, http://www.generatinggenius.org.uk/ a charity that works with high-achieving secondary school students from disadvantaged backgrounds to help them acquire the skills they need to win places on STEM courses at top universities. 22 Students from two schools attended the open day on 22 June 2016.

A group of bright GCSE students from the pre-16 strand of the programme called Junior Genius. A range of hands-on practical sessions, lab tours and talks will be run by Unit members at all levels to provide the children with an insight into the nature and benefits of medical/brain research, and inspire them to pursue a career in science.
Year(s) Of Engagement Activity 2016
URL http://www.generatinggenius.org.uk/
 
Description MRC Unit Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk sparked questions from A-level students

After the Open Day the lab received inquiries for summer placements
Year(s) Of Engagement Activity 2013,2015
URL http://www.mrc.ox.ac.uk/news/centenary-open-day
 
Description Participation to the Departmental Animal Welfare meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Promote best practice in scientific research
Year(s) Of Engagement Activity 2017
 
Description Primary School Science Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Explain how does the brain control our movements to Year 4 pupils

During the presentation many pupils asked about how nerve cells communicate to each other
Year(s) Of Engagement Activity 2014
 
Description School Open Day - 16 March 2017 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 120 GCSE/A level students from 8 local schools within Oxfordshire area attended the school open day. A range of hands-on practical sessions, lab tours and talks ran by Unit members at all levels to provide the children with an insight into the nature and benefits of medical/brain research, and inspire them to pursue a career in science. Also in attendance were local County Cllr Lorraine Lindsay-Gale , City Councillors Pat Kennedy and Louise Upton.
Year(s) Of Engagement Activity 2017
URL http://www.mrcbndu.ox.ac.uk/news
 
Description School Open Day - 17 March 2016 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 140 GCSE/A level students from 12 local schools within Oxfordshire area attended the school open day. A range of hands-on practical sessions, lab tours and talks ran by Unit members at all levels to provide the children with an insight into the nature and benefits of medical/brain research, and inspire them to pursue a career in science.

Also in attendance were local Oxfordshire MP (Rt. Hon Mr Andrew Smith) and Councillor (Mr Bob Price) attended the school open day.
Year(s) Of Engagement Activity 2016
URL http://www.mrcbndu.ox.ac.uk/outreach
 
Description School visit - Work experience 
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 A group of 5 students from local schools within Oxforsdshire area spent two weeks in the Unit to gain work experience. A range of activities was arranged for them. During this period, the students were able to observe, participate in and learn about research science; Gain insight into scientific techniques and methods; Get exposure to a University environment, scientists, PhD students, and professors; Develop self-confidence, verbal and written communication skills

In2Science, http://in2scienceuk.org/ partners with academic institutions to give sixth-form students from low income backgrounds the opportunity to work alongside STEM scientists, with a view to inspiring/coaching them to get into top universities.
Year(s) Of Engagement Activity 2016
URL http://in2scienceuk.org/
 
Description School visit - work experience 
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 A group of 5 students from local schools within the Oxfordshire area was enrolled on a 2-week programme (non-residential) during which they were given:
- Personalised mentoring from scientists
- Opportunities to gain a wide variety of practical experiences as well as exposure to key concepts and challenges in research
- Integrated workshops with in2scienceUK, where the pupils receive guidance on university applications, wider information about STEM careers, and training in transferable skills. In2science partners with academic institutions to give sixth-form students from low income backgrounds the opportunity to work alongside STEM scientists, with a view to inspiring/coaching them to get into top universities.
Year(s) Of Engagement Activity 2017
URL http://in2scienceuk.org
 
Description Science in Your world 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact various activities to discover how nerve cells in the brain communicate
Year(s) Of Engagement Activity 2015
 
Description The Research Expo 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Event organised to present current scientific research to university students from all disciplines
Year(s) Of Engagement Activity 2015
URL http://www.seh.ox.ac.uk/about-college/st-edmund-hall-research-expo-2015
 
Description Training Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Series of talks to present scientific careers
Year(s) Of Engagement Activity 2016
URL http://www.mrcbndu.ox.ac.uk/news/unit-holds-its-first-training-and-careers-development-event
 
Description Work Experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Hosted 5 pupils from 4 local schools in Oxford.

The placement scheme hosted at the Unit was a first for Oxford, and was tailored for pupils from local state-funded schools to support their progress into university degrees and careers in science, technology, engineering and mathematics (STEM).

During their time in the Unit, the pupils worked alongside Unit scientists and received personalised mentoring to gain a wide variety of practical experiences and learn more about key concepts and challenges in neuroscience and medical research. In a series of integrated workshops with in2scienceUK, the pupils also received guidance on university applications, wider information about STEM careers, and training in transferable skills. The pupils recorded their experiences and progress in blogs and images.
Year(s) Of Engagement Activity 2016
URL http://www.mrcbndu.ox.ac.uk/news