Hippocampal circuit dynamics and memory processes

Lead Research Organisation: University of Oxford

Abstract

This research programme aims to determine how memory processes and goal-directed behaviours rely on the precise coordination of neuronal activity across three interconnected brain regions: the hippocampus (HPC), the ventral tegmental area (VTA) and the nucleus accumbens (NAc). These three brain regions are critical to process information related to spatial environments, rewards and action selection during purposeful behaviours. Our experiments will focus on investigating how the cooperative activities of neurons within this tripartite circuit subserve memory and adaptive behaviours. To achieve our goals, the electrical activity of many neurons in the HPC and related circuits in the basal ganglia (VTA, NAc) will be monitored simultaneously with a multi-channel extracellular recording technique in behaving rodents (mice, rats). These recordings are combined with optogenetic techniques to reveal the contribution of specific neuronal populations or specific network oscillations. This work will establish the principles by which temporally structured neuronal activity in the HPC-VTA-NAc brain system provides the spatial framework within which reward-related information are processed to guide behavioural actions. Such a cohesive understanding of neuronal communication in the HPC-VTA-NAc circuit in the normal brain is essential to identify pathological states underlying or leading to disease.

Technical Summary

The hippocampus (HPC) is a neural circuit that provides the brain with a representation of space used to guide our daily behaviour. Indeed, hippocampal pyramidal cells – known as place cells – discharge action potentials in relation to the subject’s location so that, at the population level, their joint activities map the entire environment. Numerous studies now clearly support the view that firing patterns of place cell assemblies underlie the formation and expression of spatial memory traces in the HPC. However a comprehensive explanation of memory processes requires an integrated investigation of brain circuits, with emphasis on revealing the contribution of inhibitory interneurons and well-defined network oscillatory patterns. Moreover the persistence of hippocampus-dependent memories is subject to extra-hippocampal neuromodulatory signals such as those coming from the dopaminergic neurons of the ventral tegmental area (VTA) involved in reward-information processing. Finally, once computed hippocampal mnemonic patterns propagate to several synaptically-connected circuits, including the nucleus accumbens (NAc) of the basal ganglia involved in action selection and goal-directed behaviours. Recent evidence indicates that the HPC-VTA-NAc system is a key tripartite circuit to establish place-reward associations used to guide behavioural actions according to the spatial context. The unmet research challenge of this programme is to determine how HPC-VTA-NAc neuronal dynamics operate during the encoding, storage and retrieval of spatial and reward information for the purpose of goal-directed behaviour. This programme contains 4 specific scientific objectives: 1: To describe hippocampal pyramidal cell-interneuron microcircuit dynamics during spatial learning 2: To identify the contribution of sleep-related hippocampal oscillations in memory consolidation 3: To test whether dopaminergic VTA neurons modulate mnemonic patterns of hippocampal assemblies 4: To investigate HPC-NAc network interactions during reward-seeking behaviour The main technique employed in this programme consists of performing large-scale electrophysiological recordings of neuronal activity from rodents during periods of waking behaviour and sleep. These recordings are combined with optogenetic techniques in order to investigate, with high temporal precision, the contribution of specific populations of neuron or specific network oscillatory patterns. These experiments are providing unique data on the behavioural significance of neurons in brain regions regulating memory processes and adaptive behaviours This work will establish the fundamental principles by which interrelated activity of neurons in the HPC-VTA-NAc system provides the spatial framework within which reward-related information are processed to guide behavioural actions. Such an understanding is a timely question not only for understanding normal brain function but also for explaining what goes wrong in neurological and psychiatric diseases and thus, how best to treat them.

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 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
 
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 depolarization-induced suppression of inhibition 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Public 
PI Contribution To provide in vivo firing patterns of hippocampal CA1 place cells to assess how self-tuning of inhibition by endocannabinoids shapes spike-time precision
Collaborator Contribution To perform in vitro experiments, collect and analyse the data
Impact One peer-reviewed research article published: Dubruc F, Dupret D and Caillard O. Self-tuning of inhibition by endocannabinoids shapes spike-time precision in CA1 pyramidal neurons. J Neurophysiol., 2013 Oct;110(8):1930-44.
Start Year 2012
 
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
 
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 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 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 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