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

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.

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.

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.