Memory lapses: opportunities for adaptive behaviour

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.

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.

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.