Causal assessment of bilateral CA3-CA1 communication in hippocampal content representation

Lead Research Organisation: University of Oxford
Department Name: Pharmacology

Abstract

"You see at this moment, everything looks clear to me. But what happened just before? That's what worries me. It's like waking from a dream; I just don't remember."
The quote above is from Henry Molaison (H.M.), a patient who had part of his brain surgically removed to cure his epilepsy. H.M., and others like him, taught us that a region of the brain called the hippocampus, and surrounding regions, are crucial for the formation of memories of events and places. In order to understand how the hippocampus and surrounding regions process memories, researchers have turned to animals, particularly rodents. Nerve cells in both the human and rodent hippocampus behave as 'place cells'; that is nerve cells that are preferentially active when the subject is at a particular location. These cells, acting together as a population, might provide the brain with a representation of the surrounding environment used to guide behaviour in space. Hippocampal place cells can also change their activity in response to particular items, odours or sounds experienced at a particular location. These changes may allow the brain to associate discrete locations with a particular piece of information, such as a reward or punishment.

The aim of our project is to understand how place cells can acquire information about where a reward is. We will record from the hippocampus in both hemispheres while mice learn to locate reward in different enclosures. Furthermore, we will interfere with learning by temporarily silencing communication between two parts of the hippocampus circuit during learning. This will allow us to determine exactly where within the hippocampus learning-related changes happen.

In the final part of the project, we will look at the role of sleep in stabilizing memories. Certain neuronal activity patterns observed during active waking behaviour are reactivated during sleep, possibly for the purpose of stabilizing related memories. We will test this hypothesis by interfering with the communication between hippocampal neurons during sleep and testing the effect of this interference on memory stabilization.
Our work should further our understanding of how the hippocampus binds information together to form memories, and how these memories are stabilized during sleep. This will in turn aid efforts to enhance learning and memory in both healthy individuals and those with memory related disorders. In particular, sleep malfunctions have been linked to memory impairments and sleep related interventions seem to help. Understanding exactly how sleep promotes memory stabilization will allow us to refine and optimize sleep-related interventions. Moreover, this work should reveal strategies used by brain circuits to optimize learning, which could inform efforts to mimic what the brain does to achieve efficient machine learning.

Technical Summary

The hippocampus processes information about the spatial environment an animal is in ('context') and the items, odours and sounds ('content') present within this environment. This project aims to assess the neuronal circuit mechanisms underlying context-content binding in the hippocampus.
We have recently demonstrated a central contribution for the left CA3 neurons in a hippocampus-dependent associative learning task in mice. In the first phase of our project we will therefore record extracellular field potentials and multiple single-unit activities bilaterally from the mouse CA3 and CA1 subfields during learning. Mice will learn to associate either a location or an item with reward in two separate contexts. This will reveal whether learning modulation of place cell firing (e.g., changes in firing rate, place cell numbers or population synchrony) is distinct across the CA3 and CA1 subfields, whether it occurs preferentially in the left compared to right CA3, and whether any cross-hippocampi asymmetry observed is task dependent.

In phase 2 of the project we will address the causal relationship between the CA3 and CA1 during learning using optogenetic projection silencing informed by findings from phase 1. Such an analysis will allow us to understand the routing of information across hippocampal subfields and hence the types of computations task relevant 'content' information has to go through before reaching the CA1 subfield, the major output of the hippocampus.
Phase 3 will look at the reactivation of hippocampal cell assemblies during sleep-associated sharp wave-ripple (SWR) network events following learning. We will furthermore assess the necessity of SWRs arising in left and/or right CA3 in memory consolidation using an optogenetic feedback loop silencing system.

Planned Impact

The proposed project deals with the network-level mechanisms underlying learning and memory processes during complex behaviour. It is thus well positioned to have a broad impact, particularly on the educational front. This will involve both communicating the broad aspects of memory research in general and more project specific information. On the broad front, we will communicate some of the basics of neuronal network function during learning to schools and during science festivals and departmental open days. On the project specific front, we will emphasize the impact of learning and sleep on neural activity associated with the persistence of memory and education to teachers and students. In particular, we will communicate our findings regarding the causal contribution of certain activity states to memory stability and emphasize how this may impact on sleep related interventions in an educational setting. We also envisage that our analysis of cell assembly dynamics during learning will reveal novel insights into learning computations that can be used in the machine learning field to optimize learning algorithms. We intend to work closely with researchers in the machine learning field in both Oxford and Cambridge University. In all of these interactions, we will ensure communication is bidirectional, making use of feedback gained from the educational and machine learning fields to inform our own research activities.
 
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
 
Title tSC cover 
Description Front cover of issue in Neuron. 2018 Nov 21;100(4):940-952.e7 
Type Of Art Artwork 
Year Produced 2018 
Impact Increase the visibility of scientific discovery 
URL https://www.cell.com/neuron/issue?pii=S0896-6273(17)X0023-8
 
Description Groups of coactive neurons are thought to provide fundamental building blocks for encoding information in the brain. Short timescale coactivity can indeed bind together neurons with similar or contiguous tuning to external variables, giving rise to robust, distributed representations congruent with those of the participating neurons. Alternatively, coactivity may encode variables not represented by the individual neurons. This type of emergent coactivity-based coding has been described for physically well-defined variables, such as specific sensory inputs and actions, but its possible role in encoding abstract cognitive variables has not been explored. In this project we revealed that coactivity-based representations provide a flexible code in dynamic environments, where individuals must regularly learn short-lived behavioural contingencies. To do so, we trained mice to discriminate two new behavioural contingencies each day, while monitoring and manipulating neural ensembles in the hippocampal CA1. We found that, while neurons with congruent place fields formed coactivity patterns representing discrete locations during unsupervised exploration of the learning enclosure, the activity of additional neurons was organised into spatially discontiguous patterns that discriminated opposing learning contingencies. This contingency discrimination was an emergent property of millisecond timescale coactivity rather than the tuning of individual neurons, and predicted trial-by-trial memory performance. Moreover, optogenetic suppression of plastic inputs from the upstream left CA3 region during learning selectively impaired the expression of contingency-discriminating, but not space-representing CA1 coactivity patterns. This manipulation, but not suppressing the more stable right CA3 inputs, impaired memory of the contingency discrimination. The findings obtained in this project allow to propose that synaptic plasticity organises the firing of task-untuned neurons to discriminate task-relevant variables as an emergent property of their coactivity, with such coactivity-based code supporting the flexible computation of dynamic memories.
Exploitation Route Our findings reveal a cross-hippocampus communication that needs to be taken into consideration to understand how the hippocampus supports memory
Sectors Education,Pharmaceuticals and Medical Biotechnology

URL https://www.biorxiv.org/content/10.1101/776195v1
 
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 £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 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 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 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 theta-nested spectral components 
Description A software and associated data-set to provide an analytical framework to reveal spectral components of theta-band brain waves 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2018 
Provided To Others? Yes  
Impact Analytical tool to identify transient spectral components nested in theta cycles 
URL https://data.mrc.ox.ac.uk/data-set/tsc
 
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 
 
Title hippocampal theta oscillations 
Description Codes and electrophysiological data-set to reveal transient spectral components of hippocampal theta oscillations 
Type Of Material Data analysis technique 
Year Produced 2018 
Provided To Others? Yes  
Impact Changes the way the community analyse brain waves associated with memory functions 
URL https://data.mrc.ox.ac.uk/data-set/tsc
 
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 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 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 Festival School Visit to St Ebbes Primary School (15 June 2018) 
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 Myself and Stephen McHugh from my group together with other group members from Magill group - Paul Dodson, Ben Micklem, Julien Carponcy, Luke Bryden, from Sharott group - Abbey Becker, Brown Group - Petra Fishcer, Jean DeBarros and Unit members - Savita Anderson and Hayriye Cagnan returned to St Ebbe's C. of E. (Aided) Primary School in central Oxford, where they visited Year 6 pupils (~50 students) and their teachers to help them learn more about science, scientists, and how the brain works to control memory and movement.

Pupils were first given a brief introduction to the work of the Medical Research Council and the MRC Brain Network Dynamics Unit. Pupils, teachers and Unit members then engaged in a range of hands-on activities that included looking at nerve cells under a microscope, reporting on observations by making model cells, measuring electrical activity from muscles to control a robotic claw, comparing the brains of different vertebrates, discovering different types of memories, and using a game version of a brain-machine interface.

The Unit's visit to the school was one of many public engagement events led by the Medical Research Council and held across the country from 17th-24th June 2018 as part of the MRC Festival of Medical Research.
Year(s) Of Engagement Activity 2018
URL http://www.mrcbndu.ox.ac.uk/news
 
Description MRC Festival School Visit to St Ebbes Primary School (22 June 2017) 
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 On 22nd June 2017, I led a team of Unit members to visit Year 4 pupils and their teachers at St Ebbe's C. of E. (Aided) Primary School. Attended from my group were Stephen McHugh, Vadim Koren and Helen Barron including members from Brown and Magill groups. The purpose of the visit was to help students to learn more about science, scientists, and how the brain works to control memory and movement.

Pupils were first given a brief introduction to the work of the Medical Research Council and the MRC Brain Network Dynamics Unit. Pupils, teachers and Unit members then engaged in a range of hands-on activities that included looking at nerve cells under a microscope, reporting on observations by making model cells, measuring electrical activity from muscles to control a robotic claw, comparing the brains of different vertebrates, discovering different types of memories, and using a game version of a brain-machine interface. In all these activities, the guiding motto was "See - Do - Report", an approach devised by the Unit to mirror the "Concrete - Pictorial - Abstract" method that the pupils use in their maths classes.

The Unit's visit to the school was one of many public engagement events led by the Medical Research Council and held across the country from 17th-25th June 2017 as part of the MRC Festival of Medical Research.
Year(s) Of Engagement Activity 2017
URL https://www.mrcbndu.ox.ac.uk/news?page=7
 
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 STEM placements for local school pupils (in2science) - August 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 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
 
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 open day or visit at my research institution
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 Schools Open Day - 15 March 2018 
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 70 GCSE/A level students from 6 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 the Mrs Jean Fooks - Lord Mayor of Oxford, Cllr Chris Wright - Chair of Garsington Parish Council and Cllr Elizabeth Gillespie - South Oxfordshire District Council.
Year(s) Of Engagement Activity 2018
URL http://www.mrcbndu.ox.ac.uk/news
 
Description Workshop entitled "Getting Started in Academia" - March 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact On 5th April 2018, my Postdoctoral Researcher Dr. Mohamady El-Gaby recently extended the Unit's work in widening access and participation (WAP) through taking part in the inaugural National Muslim Student Research Conference, organized by the Federation of Student Islamic Societies, and held at St Anthony's College, Oxford. The conference aimed to promote Muslim engagement in academic research, through showcasing research across multiple disciplines and promoting interactions between students and professional academics.

Mohamady led a workshop entitled "Getting Started in Academia", which covered routes into academic research, admission to graduate courses (including Ph.D.), and early career development. Mohamady also contributed to a panel discussion on the experiences of Muslims early in their academic careers. This event also saw the launch of a Muslim Graduate Network, which has already resulted in cross-disciplinary collaborations such as those bringing together neuroscience, artificial intelligence and philosophy.
Year(s) Of Engagement Activity 2018
URL https://www.mrcbndu.ox.ac.uk/news?page=3