Intracellular signalling pathways essential to recognition memory

Lead Research Organisation: University of Bristol
Department Name: Anatomy

Abstract

Learning and memory are vital to normal everyday human existence. Memory relies on information storage in neurones of the brain. The purpose of this project is to understand the mechanisms of such storage in neurones that are responsible for visual recognition memory. Recognition memory allows us to know that we have seen something previously. We know that recognition memory depends upon the perirhinal cortex, part of the temporal lobe of the brain. Recognition memory mechanisms appear to be similar in rats and humans. Therefore by studying recognition memory mechanisms in rats we hope to better understand what happens in our own brains. We shall investigate how communication between neurones in perirhinal cortex is altered with recognition memory and learn about the cellular mechanisms that control these changes. We shall also investigate which genes are altered in perirhinal cortex as a consequence of recognition memory and allow information to be stored. The results from this study have the potential to impact on understanding mechanisms of learning and memory as well as to inform us about possible underlying causes of memory loss such as occurs in Alzheimer’s disease.

Technical Summary

The aim of the proposed experiments is to elucidate the intracellular signalling pathways essential to the familiarity discrimination component of long-term visual recognition memory. Previous work has established that the only known possible substrate for such memory is a reduction in the responses of perirhinal neurons and that this reduction is very probably contingent on synaptic weakening within perirhinal cortex. In contrast, there is a lack of information concerning: (i) the critical intracellular signalling processes that allow consolidation of information necessary for recognition memory, and (ii) the potentially parallel processes that follow the induction and underlie the maintenance of the synaptic weakening produced in perirhinal long-term depression (LTD). Hence, the proposed experiments will investigate the involvement of selected intracellular signalling pathways in: (i) behavioural measures of perirhinal-dependent recognition memory, (ii) perirhinal response decrements (measured by immunocytochemical imaging of Fos and CREB phosphorylation), and (iii) perirhinal LTD measured by electrophysiological recording in vitro. By determining whether or not effects are parallel across the behavioural, systems and cellular levels of analysis, critical tests will be made of the central hypotheses that plasticity mechanisms involved in LTD underlie the familiarity discrimination component of recognition memory and perirhinal response decrements. The intracellular signalling pathways to be tested will be based on: (i) existing evidence concerning their probable involvement in LTD and/or CREB phosphorylation, and (ii) new findings from preliminary and proposed gene array experiments. Thus the strategy will involve both selective and comprehensive components. First to be targeted will be selective pathways related to LTD mechanisms. Second will be pathways linked to CREB phosphorylation and c-fos activation. Further experiments will target pathways determined from the gene array results. Gene array analysis is important because current understanding of the cellular mechanisms underlying recognition memory is fragmentary and incomplete, while gene array technology now provides unprecedented opportunities to perform a genome-wide expression analysis. Interference with the intracellular signalling pathways chosen to be investigated will be regionally and temporally specific and experimental determinations will be made under very closely controlled conditions. The interference will be produced by: (i) localised infusion of selective inhibitors of, and/or (ii) viral delivery of genes to produce peptides that interfere with, or highly potent dominant-negative inhibitors of, specific cellular proteins. Overall, the findings will radically advance understanding of the cellular mechanisms underlying recognition memory, and reveal how these relate to mechanisms underlying other types of memory.

Publications

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Aggleton JP (2006) Interleaving brain systems for episodic and recognition memory. in Trends in cognitive sciences

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Androulidakis Z (2008) Computational models can replicate the capacity of human recognition memory. in Network (Bristol, England)

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Banks PJ (2014) Mechanisms of synaptic plasticity and recognition memory in the perirhinal cortex. in Progress in molecular biology and translational science

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Barker GR (2008) NMDA receptor plasticity in the perirhinal and prefrontal cortices is crucial for the acquisition of long-term object-in-place associative memory. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Barker GR (2009) Critical role of the cholinergic system for object-in-place associative recognition memory. in Learning & memory (Cold Spring Harbor, N.Y.)

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Barker GR (2006) The different effects on recognition memory of perirhinal kainate and NMDA glutamate receptor antagonism: implications for underlying plasticity mechanisms. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Wellcome Trust
Amount £1,569,000 (GBP)
Funding ID 087855/Z/08/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2009 
End 04/2014
 
Description JPA 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint research
Collaborator Contribution Joint research
Impact Many publications and a series of research grants
 
Description Blocking the expression of synaptic plasticity 
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 Local news item

None
Year(s) Of Engagement Activity 2008
 
Description Brain Awareness Week 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public interest engaged

None
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Cafe Scientifique 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public interest engaged

None
Year(s) Of Engagement Activity 2010
 
Description Summer schools 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact Pupils interest in studying science was enhanced.

Not recorded.
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Talks 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Talks in UK, Austria, Russia, USA. Audiences from 50 to several 100. Duration 20 min - 1 hour. Feedback always positive.

Further invitations
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Women in Science and Engineering 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Regional
Primary Audience Schools
Results and Impact 6th Form students learned more about career opportunities.

Not recorded.
Year(s) Of Engagement Activity 2010