Hippocampal circuit dynamics and memory processes

Lead Research Organisation: MRC Anatomical Neuropharmacology Unit

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

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Allen K (2012) Hippocampal place cells can encode multiple trial-dependent features through rate remapping. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Csicsvari J (2014) Sharp wave/ripple network oscillations and learning-associated hippocampal maps. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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Dupret D (2012) The medial entorhinal cortex keeps Up. in Nature neuroscience

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Jiruska P (2010) High-frequency network activity, global increase in neuronal activity, and synchrony expansion precede epileptic seizures in vitro. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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O'Neill J (2010) Play it again: reactivation of waking experience and memory. in Trends in neurosciences

 
Title Spike data 
Description We have collected data and assembled a large database in which the activity of hippocampal CA1 neurons (pyramidal cells and interneurons) was recorded both in behaviour and anaesthesia. This work forms the D.Phil. thesis of one of my students. The database is not public yet as we have not published it. 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact We have collected data and assembled a large database in which the activity of hippocampal CA1 neurons (pyramidal cells and interneurons) was recorded both in behaviour and anaesthesia. This work forms the D.Phil. thesis of one of my students. The database has not released in public databases yet as we have not published it. 
 
Description Dedritic spike patterns using real data 
Organisation University of Bonn
Country Germany 
Sector Academic/University 
PI Contribution Provided spike data to test how action potetials propagate to dendrites of in vitro cells.
Collaborator Contribution Paper in Neuron
Impact PMID: 19323999
Start Year 2008
 
Description Neuronal activity during epilepsy 
Organisation University of Birmingham
Department College of Medical and Dental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Helped with data analysis and provided advice in recording methodology
Impact Publication: pubmed id 20410121
Start Year 2008
 
Description Press release about publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Press release was issued with the help of MRC press officers

The publication was highlighted at the British Neuroscience Association web site
Year(s) Of Engagement Activity 2010
 
Description Science day at the MRC unit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact 50-100 pupils attended event

feedback from schools indicated that several of their students decided to choose biology related subjects at university
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010