Abnormal interactions between the hippocampus and prefrontal cortex in rodent models of schizophrenia

Lead Research Organisation: University of Bristol
Department Name: Anatomy

Abstract

Brains are like orchestras. Both are subdivided into numerous, specialized sections with individual roles, yet the activity of all sections must be coordinated in order for the whole to function properly. Musicians in an orchestra keep time by following the lead of their conductor; by analogy, how do neurons of different brain regions coordinate their activity during the complex repertoire of behaviour?

Electrophysiology allows us to record the electrical impulses through which neurons communicate. We find that many groups of neurons, like the sections of an orchestra, show rhythmic activity. Rhythms in connected neural networks are coordinated with one another, but only during behaviour that requires communication between the brain regions that contain them. Thus rhythmic activity can act as the brain?s conductor, allowing different groups of neurons to communicate with one another at different times. This study will use recordings from three brain regions involved in learning and memory and decision-making to see how they interact during behaviour. All three of the regions in question show signs of damage in schizophrenic patients. We suspect that the brain behaves like a ?cacophonous orchestra? during schizophrenia: a breakdown of coordinated timing leads to cognitive and behavioural abnormalities because different brain regions do not keep time with one another.

We can model schizophrenia in rats and mice. For example, if we give animals drugs like ketamine (?Special K?), they develop behavioural problems like those in psychotic patients. By recording from the neurons of these animals, we can characterize the breakdown in coordinated neural activity that accompanies their breakdown in behaviour. Then, by comparing electrophysiology from these animal models with electrophysiology from the clinic (the impulses of human neurons can be recorded through the scalp as EEG, or ?brain waves?), we can begin to understand what goes wrong in the schizophrenic brain and, most importantly, begin to test therapies that will eventually put it right.

Technical Summary

I will use tetrode recordings in freely-behaving rats to examine simultaneous hippocampal and prefrontal (PFC) activities during spatial working memory (WM). Hippocampal and PFC activities are coupled in the 4-12 Hz theta frequency range. This coupling is selectively enhanced during maze-based spatial WM tasks, allowing the PFC to direct behaviour appropriately by integrating hippocampal, spatial information into a broader, decision-making network. Thus coordination of theta rhythms constitutes a mechanism through which the relative timing of these disparate neural activities can be synchronized. Dysfunctional neural synchrony and WM are implicated in schizophrenia; I will quantify disruption of hippocampal-PFC coordination in rat models of schizophrenia, allowing characterisation and refinement of animal models of the disease. The hippocampus and PFC both receive mesolimbocortical dopaminergic projections from the VTA, where dopaminergic activity relates to associative learning and reward prediction. I will use lesions and pharmacological tools to define the roles of dopaminergic projections from VTA in modulating and coordinating hippocampal-prefrontal interactions selectively according to current behavioral demands.

Publications

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Jones MW (2010) Errant ensembles: dysfunctional neuronal network dynamics in schizophrenia. in Biochemical Society transactions

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Jones MW (2011) Updating hippocampal representations: CA2 joins the circuit. in Trends in neurosciences

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Kucewicz MT (2011) Dysfunctional prefrontal cortical network activity and interactions following cannabinoid receptor activation. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Moran RJ (2015) Losing control under ketamine: suppressed cortico-hippocampal drive following acute ketamine in rats. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Onslow AC (2011) Quantifying phase-amplitude coupling in neuronal network oscillations. in Progress in biophysics and molecular biology

 
Description BBSRC CASE Studentship
Amount £100,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2014
 
Description BBSRC Project Grant
Amount £400,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2009 
End 02/2013
 
Description MRC CASE Studentship
Amount £100,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2008 
End 09/2012
 
Description MRC Senior Non-clinical Fellowship
Amount £1,500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2011 
End 04/2016
 
Title MAM sleep model 
Description Neurodevelopmental rat model of disrupted slow-wave sleep associated with schizophrenia 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2007 
Provided To Others? Yes  
Impact Manuscripts in preparation. First model of fragmented sleep as relevant to schizophrenia and related disorders. 
 
Title Staionary wavelet coherence 
Description Analytical method for quantification of covariant activity in electrophysiological recordings 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2008 
Provided To Others? Yes  
Impact Biometrika paper 
 
Description Centre for Cognitive Neuroscience 
Organisation Eli Lilly & Company Ltd
Country United Kingdom 
Sector Private 
PI Contribution We are applying our high-density, system neurophysiology recordings to characterise hippocampal and prefrontal cortical network abnormalities in translational rodent models of psychiatric disease in parallel with histopathological, behavioural and neurochemical assays run at Lilly UK.
Collaborator Contribution Lilly's CCN was conceived around the same time as this grant started, and is centred on directly related projects. A Lilly-funded postdoc spent 6 months in my lab, and the CCN provides a structured network through which to collaborate.
Impact The CCN constitutes a powerful and innovative model for academic-industrial collaborations. Outputs have included meeting abstracts: 1. Kucewicz M.T., Tricklebank M. and Jones M.W. (SfN San Diego 2010) Disruption of state-dependent hippocampal and prefrontal cortical network oscillations and interactions by a cannabinoid receptor agonist; 2. Phillips K.G., Jones M.W., Edgar D. and Wafford K. (SfN Chicago 2009) Sleep fragmentation and attenuated slow-wave synchrony in the MAM neurodevelopmental model of schizophrenia). 2 manuscripts are currently in preparation. The CCN agreement also formed the basis of an MRC Industrial Collaborative Studentship (started October 2008), and BBSRC-CASE studentship (started October 2010).
Start Year 2007
 
Description Janssen Pharmaceutica 
Organisation Johnson & Johnson
Department Neuroscience Johnson and Johnson
Country United States 
Sector Private 
PI Contribution Electrophysiological and optogenetic expertise
Collaborator Contribution Pending legal agreements, J&J have agreed to fund a 2 year postdoctoral position in my lab and a 3 year PhD studentship beginning in Spring 2011
Impact NA
Start Year 2010
 
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