Plasticity-related mechanisms involved in memory and pattern separation in the medial temporal lobe
Lead Research Organisation:
University of Cambridge
Department Name: Psychology
Abstract
One of the major concerns of older adults is the experience of memory loss, and with our currently aging population this is becoming more and more of an issue. The first step toward addressing this concern is to try to understand the basic systems underlying memory in the brain. A better understanding of memory systems will help us to develop treatments or strategies to deal better with age-related memory impairments. One critical aspect of memory systems that is poorly understood is the specific contribution of the different molecules involved. The proposed research will help us understand the molecular signals important for memory by testing the effects of drugs on tasks requiring different aspects of memory, eventually helping the large proportion of the population who will become more forgetful as they get older.
Technical Summary
Due to their established role during brain development, some of the most attractive molecular candidates for modulating synaptic plasticity related to learning and memory processes are members of the family of neurotrophins. These compounds are molecular signals, that allow an organism's nervous system to remain in an unbound plastic state. Among these proteins, brain-derived neurotrophic factor (BDNF) is of special interest. BDNF and its receptor TrkB are widely expressed in association with glutamatergic synapses, and BDNF is synthesized, stored and released in an activity-dependent manner from glutamatergic synapses. During the past few years, a mounting body of evidence has accumulated suggesting that BDNF plays a crucial role in learning and memory. In particular, BDNF is not only necessary but also sufficient for late protein synthesis-dependent phase of long term potentiation (LTP), and for persistence of long term memory storage in the hippocampus (HC). BDNF can induce LTP in HC slices in the absence of electrical stimulation and it has been shown to be a potent enhancer of both short and long-term memory. Given that BDNF is expressed in HC and also in the perirhinal cortex (PRh) and is associated with visual memory formation in monkey PRh, it becomes an excellent candidate to mediate plasticity required for the learning processes involved in memory and pattern separation in these structures. The aims of the proposed research are to: (1) determine the role of BDNF in PRh- and HC-dependent memory and pattern separation, (2) identify the upstream activators that trigger BDNF release in the PRh or the HC and that sustain pattern separation during acquisition, consolidation and storage of memory for objects and locations and (3) determine the potential role of BDNF as an enhancer of memory and pattern separation in PRh and HC and determine elements of the signalling pathways involved in this effect.
Publications
Bekinschtein P
(2014)
Brain-derived neurotrophic factor interacts with adult-born immature cells in the dentate gyrus during consolidation of overlapping memories.
in Hippocampus
Bekinschtein P
(2011)
Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable?
in Seminars in cell & developmental biology
Bekinschtein P
(2013)
BDNF in the Dentate Gyrus Is Required for Consolidation of "Pattern-Separated" Memories
in Cell Reports
Kent B
(2015)
Cognitive enhancing effects of voluntary exercise, caloric restriction and environmental enrichment: a role for adult hippocampal neurogenesis and pattern separation?
in Current Opinion in Behavioral Sciences
Kent BA
(2016)
The representational-hierarchical view of pattern separation: Not just hippocampus, not just space, not just memory?
in Neurobiology of learning and memory
Kent BA
(2015)
The orexigenic hormone acyl-ghrelin increases adult hippocampal neurogenesis and enhances pattern separation.
in Psychoneuroendocrinology
Oomen CA
(2014)
Adult hippocampal neurogenesis and its role in cognition.
in Wiley interdisciplinary reviews. Cognitive science
Pedro Bekinschtein (Author)
(2010)
Making memories unique: BDNF in the dentate gyrus is required for storage of separate representations of similar spatial locations
Pedro Bekinschtein (Author)
(2011)
Molecular mechanisms associated with non-spatial pattern separation
| Description | For most people, memory is about time. It is easier to remember a set of items in a memory test if they are presented a few seconds before memory retrieval, than if they are presented several hours before. When memory fails, as it does normally in old age, or under pathological conditions such as Alzheimer's disease, this failure is reflected in the inability to remember over an extended period of time - although the ability to remember over a few seconds may remain intact. Increasingly, however, memory researchers are becoming interested in the ability not to remember over time, but to keep memories distinct and resistant to confusion. If asked to remember where you parked your car this morning, yesterday morning and the day before, the task is difficult not because you need to remember over a long period - you can easily remember many things that happened three days ago - but because the similar memories of your car in that same parking lot are so easily confused. The ability to separate the components of memories into distinct complex memory representations that are unique and less easily confused has been simulated by computational models of memory and has been referred to as 'pattern separation'. These computational models and subsequent experimental work have suggested that this crucial memory function may be localized to the dentate gyrus (DG) of the hippocampus. The hippocampus has been known to be involved in memory for a long time. The DG is a region within the hippocampus and one of the two areas in the whole brain where new neurons are still produced in the adult. This process has been called adult neurogenesis. The rest of the brain has to function with neurons that were born during development. It has recently been shown that immature neurons from the DG are required for pattern separation. Thus, our project was aimed to understand the neurobiological mechanisms involved in this process. In particular, we were interested in understanding how pattern separation was related to memory processing. Increasing the strength of neuronal connections and the creation of new ones is essential for information to get stabilized or consolidated in the brain. This process of memory consolidation requires the activation of genes and proteins such as growth factors. One of them is named Brain-derived neurotrophic factor (BDNF). BDNF has been shown to generate neuronal plasticity, a phenomenon by which neurons are more responsive than usual by increasing the strength between neuronal connections. We thus analysed the relationship between pattern separation, memory consolidation, BDNF and adult neurogenesis. We developed a novel and very simple memory test in rats and mice to answer our questions. We found that, as for other behavioural pattern separation memory tests, ours was susceptible to a decrease in adult neurogenesis. We also discovered that BDNF was required in the DG for the process of memory consolidation, but only when memories were similar to each other and confusable, but not when they were different. In addition, recombinant human BDNF was able to increase the ability to perform pattern separation when injected into the DG. We also noticed that BDNF was increased in the DG when the animals spontaneously perform pattern separation. Interestingly, we were able to demonstrate that BDNF exerts its effect on 'pattern separated' memories though its action on newly born immature neurons. These experiments were performed in the context of spatial memories. However, we were also interested in pattern separation of non-spatial memories. Previous studies suggested that another brain region, the perirhinal cortex (Prh) was involved in this process. Thus we studied the neurobiological substrates of non-spatial pattern separation in Prh. We found that another gene related to brain plasticity, named Arc, was increased in Prh when the animals spontaneously did pattern separation and that Arc was required for consolidation of pattern separated non-spatial memories. An interesting study from the late nineties suggested that learning itself was able to induce adult neurogenesis in the hippocampus. Since them, many laboratories tried to reproduce those findings yielding variable results, but mostly negative ones. The finding that adult neurogenesis was necessary for pattern separation lead to our idea that learning might actually induce neurogenesis, but only if the learning experience had a high load of pattern separation. Bearing that in mind, we designed a set of experiments to answer that question. We found that performing pattern separation increases both adult neurogenesis and the capacity to perform pattern separation. If learning was experienced, but the load for pattern separation was low, no increase in neurogenesis was found and there was no enhancement of pattern separation ability. In conclusion, we found that an essential part of the process of storage of pattern separated less confusable memories was the action of BDNF on adult immature neurons in the DG. This process was no uniquely performed by the hippocampus, but also by Prh, although the biological mechanisms seem to be different. Finally, we found that performing pattern separation while learning increases neurogenesis in the hippocampus and also the ability to perform pattern separation. |
| Exploitation Route | Understanding the process by which memories for similar events become separated in the brain to prevent confusion is essential to understand normal memory storage and also memory loss as it happens with age or in the face of neurodegenerative diseases such as Alzheimer's. Our findings are important because it has been shown that there are simple ways of increasing both neurogenesis and BDNF in the brain, like voluntary exercise or caloric restriction. Our findings might lead to better ways of treating and preventing memory loss while improving general health as well. In addition there are drugs like antidepressants that alter neurogenesis and BDNF levels. Our findings might help to find other ways to use these drugs and insight into their mechanisms of action. The role of adult neurogenesis is a subject of intense study. It has been shown that many brain pathologies are associated with a decrease in adult neurogenesis and that many treatments that enhance cognition and ameliorate psychiatric symptoms are linked to increases in adult neurogenesis. We have developed a behavioural task that is particularly sensitive to changes in the levels of adult neurogenesis in the DG. In fact, many laboratories that are interested in studying the DG and neurogenesis have shown interest in our task and some are even starting to use it. This tool could potentially aid to move the field a step forward. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | No impact beyond academia as yet. We have applied for a Sparking Impact award to allow us to achieve further impact. |
| Title | Spontaneous Location Recognition |
| Description | This is a behavioural test of the psychological construct of pattern separation. |
| Type Of Material | Physiological assessment or outcome measure |
| Year Produced | 2013 |
| Provided To Others? | Yes |
| Impact | Unlike other tests of pattern separation that use discrete trial procedures, SLR uses a continuous variable as a measure of performance, which yields sufficient data within a single trial to allow manipulations at different stages of memory. Our modified paradigm, enables us to manipulate the similarity of locations at the time of encoding/consolidation, when pattern separation is thought to occur, rather than at retrieval like others tasks used to assess pattern separation (Clelland et al., 2009). |
| Description | Collaboration with Jeff Davies |
| Organisation | Swansea University |
| Department | College of Human and Health Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Behavioural/functional analysis |
| Collaborator Contribution | Ghrelin and histology |
| Impact | Kent, B.A., Beynon, A.L., Hornsby, A.K.E., Bekinschtein, P., Bussey, T.J., Davies, J.S., Saksida, L.M. (2014) The orexigenic hormone acyl-ghrelin increases adult hippocampal neurogenesis and enhances pattern separation. Psychoneuroendocrinology, in press. |
| Start Year | 2012 |
| Description | Collaboration with the Salk Institute |
| Organisation | Salk Institute for Biological Studies |
| Country | United States |
| Sector | Charity/Non Profit |
| PI Contribution | We are collaborating with the Salk Institute to investigate the effects of BDNF (brain derived neurotrophic factor) in neurogenesis and pattern separation. We conducted behavioural experiments using the animals with reduced neurogenesis from the Salk. |
| Collaborator Contribution | The Salk shipped us rats injected with LVdnWnt/Ires/GFP and LV/GFP, which significantly reduces neurogenesis in the dentate gyrus. |
| Impact | Bekinschtein, P., Kent, B.A., Oomen, C.A., Clemenson, G.D., Gage, F.H., Saksida, L.M., & Bussey, T.J. (2014) BDNF interacts with adult-born immature cells in the dentate gyrus during consolidation of overlapping memories. Hippocampus, in press. Bekinschtein, P., Kent, B.A., Oomen, C.A., Clemenson, G.D., Gage, F.H., Saksida, L.M. & Bussey, T.J. (2013) BDNF in the dentate gyrus is required for consolidation of "pattern-separated" memories. Cell Reports, 5: 759-768. |
| Start Year | 2012 |
| Description | Appearance in national newspaper |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Newspaper interview about our work on memory and pattern separation after the piblication of ine of the papers. Media and general public interest in our work. |
| Year(s) Of Engagement Activity | 2013 |
| URL | http://www.lanacion.com.ar/1635197-como-guarda-el-cerebro-recuerdos-similares-sin-confundirlos |
| Description | Cambridge 105 Radio: Monday Morning Show |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Not aware of results Not aware of impacts |
| Year(s) Of Engagement Activity | 2014 |
| Description | Cambridge 105 Radio: The Science Show |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Not aware of the results Not aware of the impacts |
| Year(s) Of Engagement Activity | 2012 |
| Description | Cambridge Science Festival |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Children learned about perception and memory Children asked many questions and were curious about how the brain works |
| Year(s) Of Engagement Activity | 2012 |
| Description | Cambridge Science Festival |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Children and general audience asked many questions Children and general audience learned about perception and memory |
| Year(s) Of Engagement Activity | 2013 |
| Description | Huffington Post Article How to grow your brain |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | I received comments and questions after the article was posted online Gates Cambridge publicized the article |
| Year(s) Of Engagement Activity | 2013 |
| Description | Neuroscience segment on TV show from Argentina on memory, neurogenesis and pattern separation |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | The youtube video had almost 900 views, thousands probably saw it on TV. Media became interested. |
| Year(s) Of Engagement Activity | 2014 |
| URL | http://www.youtube.com/watch?v=PnXG6cmyQRI |
| Description | Presentation at Pecha Kucha Nights in Buenos Aires |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Talked sparked questions and discussions from the audience. People from different disciplines such as music and architecture approached to discuss about memory. Also, the organizers contacted me to participate in the organization of a series of science talks for general public. |
| Year(s) Of Engagement Activity | 2014 |
| URL | https://www.youtube.com/watch?v=40gO13QID2Q&index=3&list=PLj9HqMpbqEy0yIFjanQdiWIJjNdyAQyMC |
| Description | Presentation for Brain Awareness Week in Buenos Aires, Argentina |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | talkes sparked questions and discussion from the audience of more than 200 people. The media was interested and I got interviewed some months after it. |
| Year(s) Of Engagement Activity | 2014 |
| URL | http://www.tiempopatagonico.com/medio-ambiente/2014/3/6/semana-cerebro-realizara-bariloche-marzo-302... |
| Description | Presentation for Brain Awareness Week in Buenos Aires, Argentina |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | talkes sparked questions and discussion from the audience of more than 200 people. The media was interested and I got interviewed some months after it. |
| Year(s) Of Engagement Activity | 2014 |
| URL | http://www.tiempopatagonico.com/medio-ambiente/2014/3/6/semana-cerebro-realizara-bariloche-marzo-302... |
| Description | Primary School Visit |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | The primary school children learned about how scientists study memory Children seemed more interested in the type of research happening at the University of Cambridge |
| Year(s) Of Engagement Activity | 2012 |
| Description | Science Poster for General Public: The role of adult-born brain cells for episodic memory and pattern separation |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Poster presentation sparked questions and discussion Members of the general audience learned and the role of new brain cells in their memories for their life events |
| Year(s) Of Engagement Activity | 2014 |
| Description | Talk to interdisciplinary group of University of Cambridge PhD students (Gates Cambridge Research Talk) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Talk sparked questions and discussion after the talk Several scholars asked for further information |
| Year(s) Of Engagement Activity | 2012 |
| Description | Talk to postgraduates students at St. John's College |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Students were clearly fascinated by the modifiable lifestyle choices that can affect neurogenesis and memory Several students came up to me after the talk to ask more about what behaviours they could modify to promote neurogenesis and improve their memory |
| Year(s) Of Engagement Activity | 2012 |