Memory consolidation and sleep

The project will elucidate molecular mechanisms of memory, of sleep and of the relationship between them by studying the intermediate and medial mesopallium (IMM), a forebrain region of the domestic chick strongly implicated in the learning process of imprinting. The available evidence strongly indicates that the IMM is a region in which information about the imprinting stimulus is stored as a result of learning. Recent research supported by the BBSRC has shown that sleep during a period shortly after training is required for stabilization of neuronal responsiveness in the IMM to an imprinting stimulus, and also for consolidation of memory for the imprinting stimulus. The project will determine which phases of sleep are important for the memory consolidation and enquire whether mild, non-invasive electrical stimulation of the brain can reverse the effects of sleep disruption on memory and neuronal tuning in the IMM to the imprinting stimulus. The project seeks to extend our understanding of memory mechanisms and in consequence may provide a rational basis for potential treatments of memory disorders. Memory and sleep are of paramount importance to human life, and research at both the behavioural and the neurobiological level is essential if these phenomena are to be understood satisfactorily. This understanding is particularly important if the many clinical neurological disorders that involve memory impairment are to be treated effectively. It is sometimes desirable to enhance memory and at other times to reduce it, as in the case of persistent aversive memories that may be associated with certain psychiatric disorders. A possible outcome of this work is the identification of sleep phases, the modification of which may therapeutically enhance or reduce memory, and a sound understanding of the neurobiological basis of such therapies.

The proposal investigates molecular mechanisms of memory, sleep and the relationship between them by studying the IMM, a forebrain region of the domestic chick strongly implicated in the learning process of imprinting. The evidence indicates that information about the imprinting stimulus (IS) is stored in the IMM. Sleep shortly after training is required for stabilization of neuronal responsiveness in the IMM to an IS, and for consolidation of memory of the IS. The objectives are: 1. Measurement of the effects of reduction of paradoxical sleep, slow wave sleep and sleep rich in 5-6 Hz EEG activity, on memory (retention of a preference acquired through imprinting). Specific phases of sleep will be disturbed during the six-hour period shortly after training (Session 1), when memory consolidation is vulnerable to random sleep disturbance. As a control, the specific disturbance will be applied during a later six-hour period (Session 2), when consolidation has been found to be insensitive to random sleep disturbance. 2. Selection of the specific sleep disturbance protocol that is most effective on memory consolidation (see Objective 1). Measurement of the effect of this protocol on neuronal responsiveness to the IS in the IMM following imprinting training. 3. Disturbance of sleep (thus disrupting long-term memory) by arousing chicks at random times during Session 1. In these chicks, determination of the effect on IMM neuronal responsiveness to the IS, and on memory, of slow (0.75 Hz) and theta (5-6 Hz) transcranial stimulation during Session 1. Sleep will be monitored using EEG from skull electrodes, nuchal EMG and video monitoring. Bilaterally implanted tetrodes in the IMM will be used for neuronal recording, followed by off-line spike sorting. The EEG will be subjected to real-time frequency analysis and used with rectified EMG to identify sleep phases. Sleep will be disrupted automatically by the interface monitoring the electrophysiological signals.

Potential beneficiaries of the research (i) Those who would benefit from learning more about memory mechanisms. The neuroscience research community; school students; academic colleagues who are not science specialists; commercial organisations; the Home Office (Animals (Scientific Procedures) Act section and others); health professionals; the wider public who may be informed of the research via the media. (ii) Those who would benefit from the application of the results of the research (indirectly because the research employs an animal model of human memory). Patients suffering from certain neurological and psychiatric disorders; human subjects, such as night-shift workers, who are subject to occupational modification of their sleep patterns; medical professionals; those involved in the production of medical and neurophysiological equipment. Communication of the research Results will be communicated normally via the scientific literature. In addition, seminars in schools and talks to lay audiences will be organised each year in continuation of current practice. Relevant results will be communicated to the Home Office Inspectorate and existing links with radio, television, the Civil Service, Government and commercial organisations will be employed as in the past to communicate the results to as wide an audience as possible. Current development of equipment and software in our laboratory will be exploited commercially or made available to user communities as appropriate. All communications activities will rely on assistance from the University of Cambridge Office of External Affairs and Communications (OEC). The University Computing Service will advise on publicity website design, which will be effected by the RA, the technician, the PI and the Computer Officer whose time is costed in the resources requested. Any medical benefits flowing from the research are likely to be realised after publication in the usual way. However, information flow will be facilitated by publicising findings via the Cambridge Neuroscience website, which communicates significant new findings to a wide, multidisciplinary community within and outside the University of Cambridge. Attendance at meetings of the Society for Neuroscience can be particularly effective for establishing scientific and commercial links. Funds have therefore been requested to allow the PI and the RA to attend two successive annual meetings of the Society. Exploitation and Application Commercially exploitable findings will be handled by Cambridge Enterprise, an organisation associated with the University of Cambridge and available for this purpose. Exploitable findings might include the identification of a particular sleep phase which is closely associated with memory consolidation and a brain stimulation regime which is particularly effective on consolidation. Results will be monitored continuously to identify exploitable findings. Cambridge Enterprise will advise as necessary on protection of such findings at the end of the project. Capability Outreach activities will be conducted by the PI, the RA and Professor Sir Gabriel Horn, who will collaborate in all phases of the project. Professor Horn and I have substantial experience of describing our work to the general public but we will, as in the past, rely on the OEAC and the Press Officer in the Department of Zoology for advice. Communication training for the RA will be organised as appropriate, with the assistance of OEAC and courses offered by the University Human Resources team. Resource for the activity The resources needed for Impact activities are a component of the salary of a Computer Officer and the sum requested for Travel.