Control of neuronal networks and cognitive behaviour by deep brain, transcranial and optogenetic stimulation

Lead Research Organisation: University of Bristol
Department Name: Physiology and Pharmacology

Abstract

Your brain is constantly doing sums, weighing-up past experience and the current situation in order to decide how best to behave. Unfortunately, patients with brain diseases like schizophrenia have trouble coping with these decisions that most of us take for granted; electrical activity in different parts of their brains becomes subtly uncoordinated, making it difficult to see the wood for the trees. This project will use stimulation techniques designed to control the brain‘s electrical signalling (very carefully - you wouldn‘t notice if it was done to you) to see if we can re-coordinate brain activity at important times, such as during decisions.
Brain activity during sleep is also important, often mirroring previous events. This reflects the brain ‘sorting out‘ recent thoughts, preparing useful information for long term storage. A bad night‘s sleep is often followed by sluggish thoughts, and sleep is commonly impaired in brain disease. We will therefore also use brain stimulation during sleep to see if that can boost efficient decision-making.
It is difficult to design drugs to treat impaired thought processes. Our research will develop new techniques that - potentially in combination with future drugs - can be used to treat thought disorders in schizophrenia and related diseases.

Technical Summary

Learning, memory and decision-making arise through coordinated activity across networks of brain regions that encode, integrate and store information about behavioural parameters including location, reward and rules. The hippocampus and prefrontal cortex are central to such cognitive processes, and constitute an experimentally tractable model system in which to define the neuronal network bases of cognition, its experience-dependent modulation and its impairment in psychiatric diseases including schizophrenia. My own work has shown how coordination of rodent hippocampal-prefrontal activity underlies functional connectivity, selectively enabling information transfer during working memory and decision-making. An analogous framework translates to humans, and appears impaired in schizophrenic patients.

Despite this converging evidence regarding the nature of hippocampal-prefrontal interactions, little is known about control mechanisms: how does input to the two structures modulate their coordination according to current behavioural demands? Can exogenous control of their coordination be used to generate behavioural changes or treat disease symptoms? I will answer these questions using a novel combination of network recordings and neural stimulation techniques that mimic endogenous neurophysiological mechanisms, allowing the entrainment of neuronal activity at key behavioural timepoints and thus direct control of cognition.

Dopaminergic and cholinergic neuromodulatory systems are known to directly influence hippocampal and cortical activities. Using stimulation patterns informed by computational models and analyses, event-related deep-brain stimulation of dopaminergic and cholinergic projections will be used to influence encoding of reward and spatial information during decision-making behaviour.
Complementary optogenetic approaches - with which genetically-defined subsets of dopaminergic, cholinergic and GABAergic cells can be selectively activated with millisecond precision - will enable dissection of the distinct roles of dopaminergic and cholinergic projections and their interactions with inhibitory neurotransmission in hippocampal-cortical networks.
Coordinated neuronal activity during sleep is critical for cognition, and its disruption by abnormal sleep patterns generates or exacerbates cognitive symptoms in a wide range of diseases. Rhythmic deep-brain and transcranial stimulation - mimicking the oscillatory patterns seen during natural sleep - will be used to entrain hippocampal-cortical network activity believed to underlie memory consolidation. In collaboration with Eli Lilly & Co., this manipulation will be used to try and normalise disrupted sleep neurophysiology and behaviour in a rat model of schizophrenia.

This unique combination of state-of-the-art electrophysiological and genetic technologies with behavioural testing and psychiatric disease models will extend understanding of normal and pathological neuronal network activity, and rationalise stimulation protocols that may be used therapeutically to control brain activity and enhance or repair cognitive processing.

Publications

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Jones MW (2013) Sorting receptors at Down's syndrome synapses. in Nature medicine

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Gardner RJ (2013) Differential spike timing and phase dynamics of reticular thalamic and prefrontal cortical neuronal populations during sleep spindles. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Code Analysis Repository & Modelling for e-Neuroscience
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
 
Description Elizabeth Blackwell Institute Pilot Grant
Amount £50,000 (GBP)
Organisation University of Bristol 
Department Elizabeth Blackwell Institute for Health Research
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 12/2014
 
Description PhD Scholarship
Amount £50,000 (GBP)
Organisation The Needham Cooper Charitable Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2017
 
Description Senior Research Fellowship in Basic Biomedical Science
Amount £1,339,727 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2021
 
Description University of Bristol PhD Scholarship
Amount £20,000 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 09/2016
 
Description Wellcome Trust Strategic Award
Amount £5,500,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2013 
End 05/2018
 
Description Bazhenov Lab UCSD 
Organisation University of California, San Diego (UCSD)
Country United States 
Sector Academic/University 
PI Contribution The Bazhenov lab is a computational neuroscience group who have developed biologically realistic but computationally tractable models of thalamocortical activity during sleep.
Collaborator Contribution We have been testing predictions made by their models using our neurophysiological data, and have one manuscript in revision.
Impact Manuscript in revision at Journal of Computational Neuroscience
Start Year 2016
 
Description Patient Sleep EEG 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution Our custom analysis algorithms are being used to analyse clinical EEG data
Collaborator Contribution Professor Dara Manoach of HMS shared a patient EEG dataset.
Impact 2 peer-reviewed meeting abstracts (for Biological Psychiatry, 2013 and BNA Festival of Neuroscience, 2013)
Start Year 2012
 
Description Bristol Neuroscience Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 300 pupils and members of the public attended the talk during this celebration of 10 years of Bristol Neuroscience.

Increased contact with regional schools
Year(s) Of Engagement Activity 2013
 
Description Public lectures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public evening lectures arranged via university's public engagement office, plus 'Art of the Brain' evening at DANA Centre

Public interest and support
Year(s) Of Engagement Activity 2007,2008
 
Description School Talks 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Organised workshops with school pupils (15-18) to discuss neuroscience research in general, and the use of animals in biomedical research in particular.

Good public relations, overwhelming support for use of animals in research
Year(s) Of Engagement Activity 2008,2009
 
Description TEDMEDlive Bristol 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Seminar, available on YouTube

Contact with local patients and artists.
Year(s) Of Engagement Activity 2013
URL http://www.youtube.com/watch?v=QW2meB1rEaM