Understanding the hippocampal-perirhinal-prefrontal tripartite circuit in associative memory

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

Abstract

Visual recognition memory is knowing whether something that we see is new or whether it is familiar. This is a form of memory that is taken for granted but it is essential for all our normal daily activities. Decline of such memory can be devastating, as occurs in dementias including in Alzheimer's disease. Recognition memory relies on the integration of information from several different brain regions including the hippocampus, perirhinal cortex and the prefrontal cortex. While a lot is known about how the hippocampus and the perirhinal cortex process information essential for recognition memory very little is known about the role of the prefrontal cortex.

The work that we propose will answer questions about how the information between these three regions of the brain is integrated and how the different regions contribute to different aspects of recognition memory. An important chemical transmitter that is known to be important for memory is acetylcholine. Levels of this transmitter are known to decline in dementia. However, there is very little known about how acetylcholine affects the information flow between the three brain regions involved in recognition memory. Experiments in this proposal will investigate this question and therefore increase our understanding of the functions of this important transmitter.

Overall, this proposal will increase knowledge about how three different brain regions work together to produce a type of learning that is essential for normal every-day life.

Technical Summary

Object-in-place recognition memory, is essential for normal everyday life. For such memory, the perirhinal cortex (PRC) encodes the familiarity of objects and the hippocampus encodes spatial information. In theory therefore these two brain structures should be sufficient for processing associations between objects and places necessary for object-in-place memory. However, lesions of prefrontal cortex (PFC) demonstrate that it too is essential for such memory. The PFC together with PRC and hippocampus form a tripartite circuit that is essential for object-in-place memory and cholinergic transmission in hippocampus, PRC and PFC is also required for normal object-in place memory.

However, little is known about the physiology of the synaptic connections that make up the tripartite circuit, the direction of information transfer in the tripartite circuit during object-in-place memory, nor the mechanisms by which acetylcholine regulates the tripartite circuit and therefore object-in-place memory.

Understanding the physiology of the tripartite circuit has been hampered by the inability to selectively stimulate each of the monosynaptic connections of the circuit. Recent advances in slice methodology and the application of optogenetic techniques now make it possible to study the essential synaptic components of this complex circuit. This proposal will bring together electrophysiology, optogenetics, pharmacology and behavioural studies to investigate for the first time:

(1a) in vitro the synaptic and plastic properties of the monosynaptic connections (hippocampus-PFC, PRH-PFC and PFC-PRH) that make up the tripartite circuit

(1b) how each of the tripartitie circuit connections are regulated by acetylcholine

(2a) in vivo the role of each of the tripartite circuit connections in the processing of encoding and retrieval of object-in-place memory

(2b) the role of the cholinergic system in regulation of encoding and retrieval of object-in-place memory

Planned Impact

Who will benefit?

The research will be of benefit to

a) commercial companies seeking to develop treatments that facilitate learning and memory.
b) patients suffering from memory loss and their families.
c) charities and organisations seeking to support patients with memory disorders and their families.
d) the research staff employed on the grant will benefit from training in multidisciplinary approaches to understanding memory processes as well as training in transferable skills.
e) those in the field of educational neuroscience, wishing to understand how to maximise learning potential.
f) members of the general public with an interest in memory function.

How will they benefit?

The insights gained from this research will help ultimately in understanding memory loss that occurs with ageing, dementia and trauma. Thus the research could provide therapeutic targets of benefit to commercial companies seeking
to develop treatments that facilitate learning and memory. Progress in understanding memory requires a global perspective on brain function, i.e. it is not sufficient to study one brain region alone. A more global analysis will provide a more accurate picture of the neurobiology of memory, but also highlight the range of brain structures that when damaged contribute to memory loss in disease.

The impact of the research on patient groups and their families will be in terms of potential new therapies and also in being able to provide a better understanding of what is happening in these distressing conditions. Further by providing insights into memory function, the research will enable charities which support patients with memory dysfunction, to realise their mission of providing education and help to patients.

The findings from this project will prove applicable to understanding human memory. Such knowledge is of wide interest to the general public and thus be relevant to display and disseminate through science museums, to audiences of school-age children and interested adults.

Staff employed on the project will be trained to use the specific scientific techniques necessary for the successful completion of the project. Staff will also gain a number of transferable skills such as time/project management; communication skills training (oral & written presentations) to scientific and general audiences through public engagement opportunities; team working and networking.

What will be done to ensure that they have the opportunity to benefit from this research?

The research will be disseminated through peer reviewed journals within the standard timescale for this field. The research will be presented to the scientific community at national and international conferences. To realise the potential benefits of this research to private companies, Bashir has connections and collaborations with pharmaceutical companies with an interest in enhancing learning and memory and ameliorating memory impairments. Bashir is a member of the Physiological Society, British Neuroscience Association, Forum for European Neuroscience, which provide networking opportunities with members of the pharmaceutical companies and with other scientists. The impact of the research will be increased through Bashir's collaborative projects. These include collaborations within Bristol (and with other Universities (University of Cardiff). Bashir has extensive experience in presenting the research to the scientific community and wider public audiences including school children through public engagement seminars organised by Bristol Neuroscience.

Publications

10 25 50
 
Description The aims of this award are to understand how the connections between hippocampus, prefrontal cortex and perirhinal cortex are controlled and how this contributes to associative recognition memory. To date we have discovered that transmission between hippocampus and prefrontal cortex is regulated in a frequency depdendent manner by activation of the NMDA receptor and that the NMDA receptor itself is controlled by dopamine receptors.
Exploitation Route these findings may help the pharma industry to develop ligands that can target appropriate transmitter systems to reverse deficits in learning
Sectors Pharmaceuticals and Medical Biotechnology

 
Description BBSRC SWBio DTP studentship
Amount £90,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 09/2021
 
Description Wellcome Trust Investigator Award
Amount £2,040,736 (GBP)
Funding ID 206401/z/17/z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2017 
End 08/2022
 
Description Wellcome Trust PhD programme
Amount £150,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 09/2019
 
Description Public talk Bristol 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A talk and debate about brain imaging.
to spark discussion about brain function and disorders and how brain imaging can and cannot help.
There was a lively debate amongst the audience and the presenters about disorders, what is normal ageing, where do we draw the boundaries or normal/abnormal.
Year(s) Of Engagement Activity 2015