Facilitate memory persistence through consolidation and reconsolidation in early, middle, and late adulthood in rats

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Clinical Brain Sciences

Abstract

Many daily functions require us to hold the information of events that happen for a sufficient period time (e.g. remember where the car is parked for a few hours). However, our ability of holding spatial memory declines with age. Cognitive ageing imposes negative impacts on the life quality in our later life. Facing a rapidly ageing population, such impacts extend from the individual to the families and the society as a whole. If we have a better understanding on how the memory decline occurs, we are in a stronger position to provide strategies to improve our memory retention, which will lead to a cognitively healthier society.
To understand how daily memory decays naturally over time, we propose to model this in rodents. This is because they provide invaluable opportunities to understand the brain mechanisms, to control the environmental factors, and to draw unconfounded causative conclusions. Indeed, using this model we know that memory formation and maintenance occurs in multi-phases. As we encounter an event in a place we 'encode' the experience. It undergoes a biological process in the brain to 'consolidate' it so we remember it later. As we 'retrieve' that information some time later, the memory undergoes another process in the brain to 'reconsolidate' and we can remember it for longer.
Importantly, we have identified a time window around the spatial memory encoding, during which we can introduce a novel event to make the memory last longer. This method of using novelty as a memory-facilitating event has so far only been proven to work in young animals. The first aim will determine whether the same strategy helps middle-aged and older animals. We will also explore more effective strategies to make memories last in older animals. It will also allow us to know whether the encoding and consolidation processes are differentially affected at different stages of ageing.
In real life, we do not always have the chance to target the encoding and consolidation process as the event happens. It therefore would be beneficial if we can target the reconsolidation process during the time window of memory retrieval to make the memory last. Hence, the second aim of the study is to establish whether introducing a novel event around memory retrieval can subsequently make the memory last longer. We will examine whether this is an effective approach to make memory last in older animals.
While the first 2 studies provide behavioural strategies to improve the longevity of memory at different ages, at present we do not know how the memory-encoding and memory-facilitating events interact at the cellular level in the brain. Previous research has pinpointed a key brain area, called the hippocampus that is crucial for linking events and place and form an episodic or associative memory. Previous theories also hypothesize that the cellular networks activated by the memory-encoding and memory-facilitating events are overlapping in the hippocampus that interactively contribute to longer-lasting memory. To visualise the cellular activities for these two events, we will mark the active cells with two fluorescence-labelled genes that can be detected by confocal microscopes. This technique has previously been established and will be carried out with our collaborator in Japan.
Together, this project will allow us to establish behavioural methods to improve memory so that they last longer in old animals and characterise the underpinning encoding or consolidation process that is affected by ageing. We will also understand the cellular mechanism for the facilitation of memory persistence to occur. The behavioural strategy that we use in this project is non-invasive and benign, and therefore can be translated to human studies in the near future through cross-discipline collaborations. Such knowledge can ultimately improve cognitive ageing in the society.

Technical Summary

Memory persistence declines with age. However, there are limited models to decipher whether this is primarily caused by encoding or consolidation failure and limited ways to facilitate memory persistence. We have developed a behavioural task in rats to address these issues and provide solutions. We have shown that short-lasting spatial memory after a weak encoding event can last longer if another novel (memory-facilitating) event occurs before or after the encoding. Using this paradigm, this project will first describe the decay of memory persistence over ageing. We will then introduce memory-facilitating events around encoding in the middle-aged and older aged animals to determine whether such events can enable the memory persistence and answer whether it is the consolidation process that is primarily affected by ageing. We will then investigate the older group to determine the effect of age on the encoding process and develop effective memory-facilitating strategies.
After the memory consolidation window is closed, a second window around memory retrieval may allow for memory modulation through reconsolidation. This project will target the retrieval and reconsolidation process to examine whether memory-facilitating events can contribute to memory persistence through reconsolidation in older animals. Finally, a potential cellular mechanism underlying the memory facilitation is through overlapping cell assemblies that represent both the encoding and facilitating events. To determine this, we will use double-labelling by fluorescence in situ hybridisation with two immediate early genes (Arc and Homer 1a) to mark the hippocampal neurones activated by these two events and examine how these changes with age. This will be done through international collaborations (RIKEN Brain Science). Together, this project will use multilevel approaches (behaviour, pharmacology, and cellular imaging) to provide novel strategies to facilitate healthy cognitive ageing.

Planned Impact

The long-term impact of the project will be to add knowledge and methods to improve cognitive wellbeing in the ageing population. It is widely reported that our society ages rapidly. For example, the number of people aged 60+ is expected to pass 20 millions (~28% of the population) in 15 years. That is one-in-four of us will be aged 60+ (Office for National Statistics, 2013). It is known that memory is a key determinant of our life quality and mental welling, and this ability declines with age. Hence, we need strategies to improve memory, which is the main objective of this project.
The direct and immediate impact of this project will be on the academia, which is described in the Academic Beneficiaries. The knowledge from this research can also lead to translation of novel ways to improve memories in humans. For example, collaboration with cognitive scientists can enable translation of novel events that improve spatial memory into equivalent human experiences. To do so, scientific discussions will be sought in seminars and conferences. We will also participate programs to facilitate cross-discipline collaborations such as 'virtual collaboration' organised by Aberdeen and other Scottish Universities.
Methodologically, the cellular imaging technique (double-labelling by fluorescence in situ hybridisation) can benefit researchers who wish to visualise active cellular networks. The images collected from this project can be displays in the public exhibition (e.g. outdoor exhibition organised by The Patrick Wild Centre and Mindroom charity in Edinburgh St Andrews Square) to raise the public's awareness of the brain functions. It can also lead to fusion of Art and Neuroscience collaboration through the College of Art and Edinburgh Neuroscience project.
Technologically, the 3D-confocal image acquisition and cell counting can lead to collaboration with Edinburgh Informatics to automate the procedures. This will allow systemisation and standardisation of the process and reduce the need of manual labour. The can be in the form of a novel program or a plug-in of existing image capture software (ImageJ). The commercial potential of such product will be discussed with Edinburgh Research and Innovation, which is specialised in commercialisation, technical transfer, and legal agreements.
Bilateral interactions with health professionals can also encourage the impact of this project. For example, it is often the first-line of caregivers that look after the elderly knows the best what they need. This is perhaps the hardest group to target. This will be planned through interactions with Age UK charity through our centre (Clinical Brain Sciences) and the Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE).
It is important to convey our findings in lay terms to the general pubic. There are three ways to achieve this. First, we will organise press release with the Press Office of the university to summarise our findings and impacts in future publications in scientific journals. We will also liaise with the neuroscience co-ordinator to publish such summaries on the Edinburgh Neuroscience website. Second, we will integrate new ideas and add new activities in the getBrainy and getRemembering workshops. These will engage a wide range of secondary school pupils in understanding brain and cognitive functions. Third, we will design a display or an interactive activity to participate the Science Festival to gain first-hand interaction with the general public. This can be done through liaising with the knowledge transfer office of CCACE. To improve the efficiency of communication, we will attend relevant workshops and training within the university and with the public engagement network Beltane.
 
Description We have developed a rodent behavioural paradigm that realistically mimics spatial memory in humans. This paradigm effectively resembles memory persistence at a short delay and memory decay over time in our daily experience. It also captures the decline of memory persistence over the neuroscience ageing process that is similar to the symptoms seen in human cognitive ageing. Some of the key findings are published in 2 papers online:
https://doi.org/10.1016/j.neurobiolaging.2018.02.023
https://doi.org/10.1016/j.neuropharm.2018.08.015
Exploitation Route The findings are made open-access and the paradigm can be used by other researchers to characterise memory changes in genetics, developmental or disease models.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

URL https://doi.org/10.1016/j.neurobiolaging.2018.02.023
 
Description We have regularly engaged with local and regional public to introduce brain awareness and memory-related activities. Detail in the section of engagement activities.
First Year Of Impact 2016
Sector Education
Impact Types Societal

 
Description Alzheimer's Research UK Masonic PhD Scholarship
Amount £107,581 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 08/2022
 
Description International Partnering Award
Amount £50,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2019
 
Description Senior research fellowship
Amount £420,000 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2019 
End 06/2023
 
Description Small Grant
Amount £2,000 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 03/2018
 
Description Characterise environmental factors in memory generalisation 
Organisation University of Tsukuba
Country Japan 
Sector Academic/University 
PI Contribution Experimental design, data analysis, manuscript discussion and revision, reply to the reviewers
Collaborator Contribution The collaborator's team conducted the experiment, collected the data and wrote and submitted the manuscript.
Impact An original research article was published in Molecular Brain in 2016: http://www.ncbi.nlm.nih.gov/pubmed/26745987
Start Year 2014
 
Description Determine the contribution of sleep in memory consolidation 
Organisation University of Tsukuba
Department International Institute for Integrative Sleep Medicine
Country Japan 
Sector Academic/University 
PI Contribution I have helped with the experimental design and data analysis and interpretation.
Collaborator Contribution The collaborator's group perform experiments deciphering the contribution of sleep on the subsequent memory consolidation and recall.
Impact This is an ongoing collaboration at the data collection stage. It involves electrophysiology and behavioural conditioning. It also allows training of postdocs and project students.
Start Year 2016
 
Description Develop behavioural and biological markers for cognitive ageing 
Organisation Chang Gung University
Country Taiwan, Province of China 
Sector Academic/University 
PI Contribution I initiated the collaboration and wrote a proposal for an international partnering award that was recently funded.
Collaborator Contribution Collaborators with CGU will provide Matlab codes for image analysis and training of PG students. Collaborators with NTU will provide chemical compounds and visiting internships.
Impact This is newly awarded collaboration that will start in the next month. It involves in vivo brain imaging and behavioural neuroscience.
Start Year 2017
 
Description Develop behavioural and biological markers for cognitive ageing 
Organisation National Taiwan University
Department Department of Psychology
Country Taiwan, Province of China 
Sector Academic/University 
PI Contribution I initiated the collaboration and wrote a proposal for an international partnering award that was recently funded.
Collaborator Contribution Collaborators with CGU will provide Matlab codes for image analysis and training of PG students. Collaborators with NTU will provide chemical compounds and visiting internships.
Impact This is newly awarded collaboration that will start in the next month. It involves in vivo brain imaging and behavioural neuroscience.
Start Year 2017
 
Description Develop methods of psycho-physiological interaction in rodent fMRI 
Organisation National Taiwan University
Department Department of Psychology
Country Taiwan, Province of China 
Sector Academic/University 
PI Contribution I designed and conducted awake rodent fMRI research and collected structural and functional brain images.
Collaborator Contribution Prof Chou's team provides methods and support for analysing psycho-physiological interaction.
Impact Neuroscience and Psychology
Start Year 2017
 
Description Validate automatic cell counting of fluorescent images 
Organisation University of Lethbridge
Country Canada 
Sector Academic/University 
PI Contribution We are collaborating with the Lethbridge Brain Dynamics lab to optimise automatic counting of foci fluorescent signals and validate the computer codes with our data. We aim to provide objective cell counting of brain cells that will bypass the shortcomings in subjective counting by experimenters. We provide the brain images.
Collaborator Contribution Our collaborator provides the computer codes that are compatible with NIH-funded open-access software.
Impact Neuroscience. Computer Science.
Start Year 2017
 
Description Community film screening and activities 
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 We will introduce Brain Awareness activities that are relevant to the 2016 Oscar-winning film 'Inside Out' at the Midlothian community cinema on 20 March 2016. We will lead hand-on activities with regional children to introduce the brain anatomy and emotion types. We will also run a Q&A session for adults related to the emotion and memory theme of the film.
Year(s) Of Engagement Activity 2016
URL http://www.moorflix.org.uk/season.html
 
Description French Neuroscience blog (Dr Gros) 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact BBSRC-funded postdoc in our group actively publishes her thoughts on Neuroscience research, written in generally accessible manner, in a French blog that received very positive feedback.
Year(s) Of Engagement Activity 2016
URL https://lejournal.cnrs.fr/nos-blogs/aux-frontieres-du-cerveau/limage-de-la-semaine-les-epines-dendri...
 
Description Midlothian Science Festival- Roslin legion 2016 
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 30 school-age children and their siblings and carers (total about 50) attended a brain and emotion workshop and film screening. We (with Hons student Victoria and MSc student Anish) helped them make paper dials/clocks with emotional facial stickers. They learned about the emotion brain circuits, watched the Oscar-winning film 'Inside-Out', and asked questions about memory and emotions. We discussed the complexity of the brain and the steps/habits for a healthy brain.
Year(s) Of Engagement Activity 2015,2016
URL http://midlothiansciencefestival.com/event/film-inside-out-with-brainy-fun-activites/
 
Description Moderating public talks on Mental Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact About 150-200 audience attended 2 TED-style talks and sparked questions and debate at the panel discussion
Year(s) Of Engagement Activity 2019
URL https://www.facebook.com/events/461385578058365/
 
Description Moderating public talks on Neurodegenerative disorders 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact About 150-200 audience attended 2 TED-style talks and sparked questions and debate at the panel discussion
Year(s) Of Engagement Activity 2019
URL https://www.facebook.com/events/3032613256813822/
 
Description Nursery visit (Edinburgh) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I planned and organised activities at the local Corner House nursery. About 20 pre-schoolers played with the brain puzzle, felt the weights of baby and adult brains, sang brain-themed nursery rhymes, coloured and made brain hats. They later recorded the activities and what they learned in an art book.
Year(s) Of Engagement Activity 2016
 
Description Penicuik Cinema outreach 
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 About 20 pre-school and school-age children and 20 adults (mainly parents) attended the pre-film workshop. We (BBSRC-funded postdoc Dr Alexandra Gros and I) showed them the brain model, explained the brain function, helped the children make and colour paper brains as we explained the 4 lobes. We discussed the truth and myth about brain functions involved in the film 'Inside-out' and answered the questions from the audience.
Year(s) Of Engagement Activity 2016
URL https://www.facebook.com/photo.php?fbid=10209168342388477&set=o.196007500461460&type=3
 
Description Poster presentation in Molecular Cellular Cognitive Society in Singapore 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The poster presentation attracted around 30-50 people and sparked discussion on the multi-faceted impact of ageing in learning and memory. The discussion contributed toward and enriched our recently accepted manuscript in Neurobiology of Aging and led to submission of a proposed symposium in an international conference in 2019.
Year(s) Of Engagement Activity 2017
URL http://medicine.nus.edu.sg/phys/MCCS/
 
Description Presentation at 9th Federation of Asian and Oceanian Physiological Societies Congress (FAOPS2019) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact An invited talk to ca. 100 audience (including professional researchers, PG and UG students) that spark questions and discussions
Year(s) Of Engagement Activity 2019
URL https://www.nips.ac.jp/faops2019/FAOPS_circular.pdf
 
Description Presentation at Edinburgh Neuroscience Day 2020 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Two poster presentations led to questions answered and new research direction discussed.
Year(s) Of Engagement Activity 2020
URL https://www.edinburghneuroscience.ed.ac.uk/events/neuroscience-day-2020
 
Description Presentation at the Alzheimer's research UK 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A poster presentation at the annual ARUK conference that attracted ca 40 researchers/students of viewing or discussion.
Year(s) Of Engagement Activity 2018
 
Description Presentation at the Edinburgh Neuroscience Day 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact An invited talk to ca. 300 audience (including professional researchers, PG and UG students) that spark questions and discussions
Year(s) Of Engagement Activity 2019
URL https://www.edinburghneuroscience.ed.ac.uk/neuroscience-day-2019-programme
 
Description Presentation at the Mediterranean Neuroscience Society 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact An invited talk at a symposium on Alzheimer's research, ca. 100 audience (including professional researchers, PG and UG students) that spark questions and discussions
Year(s) Of Engagement Activity 2019
URL https://mnsocietylive.files.wordpress.com/2019/05/programma-finale.pdf
 
Description Presentation at the Ministry of Science and Technology (Taiwan) symposium in Edinburgh 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Sharing our BBSRC UK-Taiwan collaboration experience with Taiwanese researchers and policy makers in Scotland
Year(s) Of Engagement Activity 2019
 
Description Presentation at the Society for Neuroscience 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation at the largest international Neuroscience Conference (>30k attended) what attracted c.a. 60 people viewing or discussing our research.
Year(s) Of Engagement Activity 2018
URL https://abstractsonline.com/pp8/#!/4649/presentation/29990
 
Description Science outreach (Pint of Science, Dr Gros) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact BBSRC-funded postdoc, Dr Alexandra Gros, in our group is one of the treasurers in the public outreach organisation 'Pint-of Science' to promote a wide range of science topics with the general public and students in a friendly and social environment.
Year(s) Of Engagement Activity 2016
URL https://pintofscience.co.uk/
 
Description Scottish Neuroscience Group Meeting (Glasgow) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact With BBSRC-funded postdoc, we presented a poster in the annual meeting at Scottish Neuroscience group. It sparked discussion with professionals and students from several disciplines, such as Psychology, Physiology, and Pharmacology.
Year(s) Of Engagement Activity 2016
 
Description Seminar in Neuroscience Summer Camp in National Taiwan University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact I gave a seminar talk in the Neuroscience summer training camp in National Taiwan University. Both senior researchers and students asked questions at the end of the seminar and reported learning new methods and findings in the field of memory research.
Year(s) Of Engagement Activity 2017
URL http://oiasystem.ntu.edu.tw/summer/course/index.detail/season/2/course_sn/111/intro/911
 
Description Society for Neuroscience Conference (San Diego) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact With an Honour undergraduate project student, we presented a poster at the Society for Neuroscience conference. It received a lot of interest and sparked a wide range of topics of discussion. It was also a very productive trip during which we identified new ways of data analysis, obtained oral agreements of reagent sharing from other research groups, strengthened on-going collaboration with Japan, and explored new collaboration opportunities with Taiwan.
Year(s) Of Engagement Activity 2016
URL http://www.abstractsonline.com/pp8/index.html#!/4071/presentation/18815
 
Description Symposium on Cognition and Ageing Brain 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I organised the mini-symposium that showcased brain research in our groups in University of Edinburgh and partnering groups in Department of Psychology of National Taiwan University. It provided a platform for facilitating UK-Taiwan bilateral collaboration.
Year(s) Of Engagement Activity 2017
URL https://www.edinburghneuroscience.ed.ac.uk/events/mini-symposium-cognition-and-ageing-brain
 
Description Workshop for widening participation for senior school students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact We (with another BBSRC-funded new investigator) participated the university's widening participation programme and organised a Kickstart workshop for senior school students. We gave a lecture and provided work stations where students could observe or try some of the neuroscience experiments we do. They rated highly positive and reported: The amount of content just right 88%, interested in looking further in the subject after the workshop 65%, Good chance to do practical's in the lab and on computers.
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/student-recruitment/widening-participation/projects/partnership-projects/kickst...