Memory lapses: opportunities for adaptive behaviour

Lead Research Organisation: University of Sussex
Department Name: Sch of Life Sciences

Abstract

Associative conditioning is one of the most basic means by which animals learn to exploit the predictive value of particular sensations in a complex sensory environment. It provides a fundamental mechanism underlying the ability to respond adaptively to sensory signals that are associated with for example opportunity or threat. For instance, certain olfactory sensations may presage the presence of food. By learning such an association, an animal can more effectively locate and exploit food resources. Some sensations may become associated with threat, in which case the learned adaptive response might be withdrawal.

Following the initial formation of an associative memory there is a period of consolidation, during which the conditioned behaviour becomes progressively more permanent. Recently however, we found that during consolidation there are brief periods of amnesia during which the progression to long-term storage can be blocked by unanticipated changes in the sensory environment. The time-points of memory lapses and susceptibility correspond to transitions in the dependency on different underlying molecular and cellular mechanisms as consolidation proceeds. Our discovery of the susceptibility of memory formation to interference suggests that associative conditioning is a far more flexible process than hitherto appreciated.

The overarching aim of this proposal is to advance our understanding of the fundamental mechanisms underlying behavioural flexibility during the critical consolidation period. We will exploit the advantages offered by the relatively simple brain and behaviour of the mollusc Lymnaea. While having a CNS of only 20,000 neurons, this animal nevertheless shares all of the basic features of associative memory formation displayed by far more complex animals, including humans. This allows us to study a universal form of behavioural adaptation and flexibility at a level of cellular and molecular detail that would not be possible in more complex animals. Because we know that the process of memory formation and its underlying cellular and molecular mechanisms are evolutionarily highly conserved, this research is likely to reveal principles and mechanisms of behavioural flexibility that apply equally to both simple and complex animals. In the longer term this research may lead to the discovery of new drugs or procedures that can modify the flexibility of memory formation with the potential benefit that this may have for the treatment of memory disorders.

Technical Summary

Reports of temporary amnesia (or lapses) during memory consolidation are widespread, but it is not clear whether these lapses serve a functional role. Using a single-trial classical conditioning paradigm we have shown that in the conditioning of feeding behavior, lapses occur at critical time points during memory consolidation. These time-points correspond to when molecular mechanisms underlying different phases of memory are in transition. Our experiments have also shown that at these time-points consolidation can be interrupted by novel external stimuli. This suggests that during consolidation the trajectory of memory formation can be altered in response to unpredictable changes in the sensory environment. This flexible feature of memory systems may result in blocking of memories or their replacement by alternative learned behaviours in an on-going adaptation to the complexities of the natural world. Understanding this important aspect of memory flexibility is the overarching aim of this proposal.
We hypothesize that the lapses are a passive or inevitable consequence of transitions, when a memory is being transferred from its dependence on one underlying molecular mechanism to another. During the lapses however there is an opportunity for more active processes to alter the course of consolidation, introducing for example the flexible features of memory systems revealed by delivering novel stimuli during the molecular transitions. This is the general hypothesis that our research is designed to investigate.
We have developed a number of preparations, electrophysiological recording and intervention techniques and paradigms on the Lymnaea model system. These will allow us to investigate flexibility of memory formation during consolidation at behavioural, neuronal circuit, cellular and molecular levels. Deployed in conjunction with our computational model of the CNS, this exceptional capability will allow us to pursue an integrated systems biology approach.

Planned Impact

1 Beneficiaries
Outside the academic community our research benefits a) the public health sector, b) the commercial private sector, and c) the wider public - as indicated below:

1.1 Public Health Sector:
The benefit here will arise from the long-term impact of our work on understanding how memory consolidation works and can be altered at specific time points. There are a number of conditions such as depression, Parkinson's and dementia that affect our ability to learn and remember. The lapses of memory recall during consolidation provide periods when the progression of the memory trace can adapt to changing environmental influences and the fate of the memory can fundamentally be influenced. At the fundamental level of neural networks and neurotransmitters this is a very poorly understood area of significant clinical importance. Indeed considerable costs are associated with less than fully effective treatments for these conditions. Our research, using a model invertebrate system, will answer some of the most fundamental questions about the brain's control of actions - what neural architectures are involved, which neurotransmitter systems are involved and how? This research, carried out at a high level of neuronal resolution, will help the interpretation of much lower resolution information available to clinicians dealing with affected patients. Periods when lapses of memory occur after learning could be of targets to medical intervention providing windows of high sensitivity to treatments.

1.2 Commercial Private Sector:
Two distinctly different commercial areas have an interest in our research on simpler neural networks in Lymnaea - the pharmaceutical industry and the IT sector (including robotics). Eli Lilly have supported our work on the Lymnaea acetylcholine binding protein and we have initiated collaboration with Gedeon Richter Pharmaceuticals to use the Lymnaea system to screen memory enhancing drugs. In the IT sector a number of companies (NaturalMotion Ltd, NeuroRobotice Ltd, MultiChannelSystems MCS GmbH) have expressed an interest in our work on simple model nervous systems because an understanding of how neural networks generate adaptive behaviour can inspire new and more powerful artificial networks for a variety of applications in for example the entertainment (games and graphics) and robotic industries.

1.3 Wider Public and Issues of Public Concern:
Public understanding of science issues - we engage in school 6th form lectures, popular articles and books (e.g. O'Shea, The Brain; A Very Short Introduction, OUP) explaining neuroscience research, contribute to local Café Scientifique meetings and Brighton Science Festival. We will also continue to publish articles in the online journal Scholarpedia which is a refereed online medium for the general dissipation of knowledge (e.g. Benjamin & Kemenes 2010).
Animal welfare & issues of public concern: By conducting our experiments on an organism not covered by the A(SP)A 1986, our research will have a positive impact on the principles of the 3Rs - Replacement, Refinement and Reduction, principles adopted by all research councils and major charitable funding bodies.

2 Communications and Engagement
Effective links have already been established with the above mentioned companies. If funded, the proposed research will stimulate innovation at the neuroscience/artificial neural network interface, in particular by exploiting the insight into the inbuilt periods of flexibility in real neural networks that this research will reveal.

4 Capability
The impact will be undertaken primarily by the PI who is experienced with impact at the interface between neuroscience and the IT sector, with the support of the Co-Investigators.

5 Resource implications
There are no resource implications arising directly from the impact activities described above.
 
Description We have successfully established that there are brief periods after learning when there is a deficit in memory recall. Our experiments demonstrated that the timing and occurrence of these periods is independent of the type of training representing a general phenomenom during memory consolidation. We tested this by using different types of appetitive and aversive training paradigms and found that memory lapses occurred in all cases at around 30 min and 2 h after the acquisition. Our final experiments were aimed at discovering the function of these "lapses" and we made great progress of identifying "off line" processes underlying these periods. We also discovered that these periods are more sensitive to interference so they seem to be critical in the determination of the fate of memories in a real life situation where animals are bombarded with different environmental stimuli affecting the stabilization of a specific memory trace.
Exploitation Route In the health sector the understanding of how memory consolidation works and can be altered at specific time points is extremely important to deal with a number of conditions such as depression, Parkinson's and dementia that affect our ability to learn and remember. The lapses of memory recall during consolidation provide periods when the progression of the memory trace can adapt to changing environmental influences and the fate of the memory can fundamentally be influenced. At the fundamental level of neural networks and neurotransmitters this is a very poorly understood area of significant clinical importance. Our research, using a model invertebrate system, will answer some of the most fundamental questions about the brain's control of actions - what neural architectures are involved, which neurotransmitter systems are involved and how? This research, carried out at a high level of neuronal resolution, will help the interpretation of much lower resolution information available to clinicians dealing with affected patients. Periods when lapses of memory occur after learning could be of targets to medical intervention providing windows of high sensitivity to treatments.
The understanding of how neural networks generate adaptive behaviour can also inspire new and more powerful artificial networks for a variety of applications in for example the entertainment (games and graphics) and robotic industries.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description During the first two years of the grant some exciting new results emerged that increased a general interest in a new way of interpretation of memory consolidation. This was presented to groups of A-level students and also to the scientific community at several conferences where the PI was invited as key-note speaker. Our results were also communicated to teachers and demonstrations to school children, educators and families at Teachers' Conferences and at the events of the Brighton Science Festival.
First Year Of Impact 2017
Sector Education
Impact Types Societal,Policy & public services

 
Description Brighton - Sussex collaborative award
Amount £10,000 (GBP)
Organisation University of Sussex 
Sector Academic/University
Country United Kingdom
Start 05/2018 
End 04/2019
 
Description FP7 Marie Curie Actions COFUND
Amount € 174,130 (EUR)
Funding ID PCOFUND - GA - 2013 - 608765 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2014 
End 08/2017
 
Description Memory lapses: opportunities for adaptive behaviour
Amount £826,996 (GBP)
Funding ID BB/K018515/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2013 
End 05/2016
 
Description Research Development Fund
Amount £35,000 (GBP)
Organisation University of Sussex 
Sector Academic/University
Country United Kingdom
Start 05/2015 
End 04/2016
 
Description Updating of memories during memory consolidation
Amount £895,088 (GBP)
Funding ID BB/P00766X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2017 
End 06/2020
 
Description Alzheimer's Society Research Conference 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Most of the people on the conference visited our poster and approved the results.

Discussions with people in clinical research highlighted possible areas for collaboration.
Year(s) Of Engagement Activity 2014
 
Description BNA Conference Birmingham (2017) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact About 30 people attended our presentations and we had discussions about our research topic with several colleagues.
Year(s) Of Engagement Activity 2017
URL https://www.bna.org.uk/
 
Description Bright Sparks (Brighton Science Festival) 
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 did a demonstration aimed to attract school children as part of the Bright Sparks theme of the Brighton Festival. Lots of the parents and the visiting media were also very interested and children participated in the activities with great enthusiasm.
Year(s) Of Engagement Activity 2017
 
Description Brighton Festival 
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 Demonstrating the usefulness of invertebrate organisms in science.
Year(s) Of Engagement Activity 2018
 
Description Brighton Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I delivered a lecture on the topic of aging and memory decline to a wide general audience as part of the Science Festival. Together with postdocs and PhD students from my laboratory we also provided a demonstration showing how invertebrates can contribute to memory research.
Year(s) Of Engagement Activity 2016
 
Description COST Action (Berlin, Germany) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The COST Action meeting was set up to promote the development of welfare and breeding guidelines for invertebrate organisms.
Year(s) Of Engagement Activity 2015
URL http://www.cost.eu/COST_Actions
 
Description Demonstartion to A-level students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Around 70 students attended my demonstration. There were great interest in the simple experiment I set up and I discussed lots of general questions related to neuroscience at Sussex.

Due to the success of the demonstrations and talks on Open Days the school received a substantially increased number of applications for the Neuroscience Degree program.
Year(s) Of Engagement Activity 2014
 
Description Gordon Conference (Italy) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact More than 50 PG students were present on the meeting and lots of discussions were made after on and after the sessions.
Year(s) Of Engagement Activity 2015
URL https://www.grc.org/programs.aspx?id=14578
 
Description IBNS conference 2019 June 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact 150 under- and postgraduate students attended and several questions were discussed concerning memory research.
Year(s) Of Engagement Activity 2019
 
Description ISIN 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Around 100 researchers from Europe and the US attended the conference and my talk was followed by vivid discussions and raised interest in the research topic.
Year(s) Of Engagement Activity 2019
 
Description International Neuroethology Congress (Sapporo, Japan) 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact About 100 participants attended my talk and asked several questions.

I was invited to participate in other meetings and present our results.
Year(s) Of Engagement Activity 2014
 
Description Mediterranian Neuroscience Society (Sardinia, Italy) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The general aims and impact of research on model organisms were discussed and suggestions were made to increase impact of research.
Year(s) Of Engagement Activity 2015
URL http://www.mnsmeeting2015.it/
 
Description SONA conference, Uganda (2017) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Workshops and discussions to improve neuroscience education and research in Africa.
Year(s) Of Engagement Activity 2017
URL http://sonafrica.info/83-slidesdesc/100-sona-conferences
 
Description SfN Chicago (2019) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The research topic was discussed with other researchers and postgraduate students. New ideas for research and collaborations were formulated.
Year(s) Of Engagement Activity 2019
 
Description SfN Conference Washington 2017 Nov 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This is the largest international neuroscience meeting attended by ~ 30,000 participants including scientists, under and postgraduate students, business and industry. Our presentation was attended by ~50 people and we made contact with companies including "3Brain" that as a result coming to demonstrate their equipment in Sussex.
Year(s) Of Engagement Activity 2017
URL https://www.sfn.org/
 
Description Society for Neuroscience Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact More than 15 000 people attended the meeting from different fields of neuroscience. Connections were built with people in education and also in industry.
Year(s) Of Engagement Activity 2015
URL https://www.sfn.org/annual-meeting/neuroscience-2015
 
Description Teachers conference Sussex (2016) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk to secondary school teachers.
Year(s) Of Engagement Activity 2016
 
Description University of Third Age talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 80 mostly pension age people attended the talk and there was a lively discussion at the end, lots of questions were received especially concerning mental health and how research on invertebrates can complement to the field of neuroscience.
Year(s) Of Engagement Activity 2017