Challenge 2: Cognition

Objective

To develop a prototype of a wireless 16-32 channel recoding system that can acquire and transmit data for a minimum of 24 hours but ideally for more than ten days, that can be replaced or recharged with minimal discomfort for the animal and is small enough to be carried by a mouse without affecting its behaviour or welfare.

Background

Many brain disorders including schizophrenia and Alzheimer’s disease are characterised by severe impairments in cognition that are still both poorly understood and treated. There is mounting evidence that some deficits in cognitive function arise through a break down in the coordinated activity of neuronal networks responsible for memory, learning and decision-making. The hippocampus and medial prefrontal cortex are two regions of the brain thought to be central to cognitive processes. The coordinated activity of hippocampal-prefrontal networks is specifically engaged in mice learning to navigate a maze to find food; a paradigm that measures hippocampus-dependent spatial working memory. It is possible to record both the individual activity of the hippocampal neurons involved as well as the rhythmic activity that arises within networks of neurons using multi-site in vivo electrophysiology. By implanting electrodes in multiple brain regions and then recording brain activity while mice run on a T-maze, the rhythms and oscillations that are essential for synchronisation can be identified. Such recordings, in conjunction with behavioural outcome (e.g. how long it takes to find the food, the acquisition of the task and the error rate), will provide for greater validity of the cognitive tasks and disease models employed in drug discovery and consequently, much greater certainty of clinical impact.

An automated, computer controlled, modular maze has recently been developed. In this apparatus, mice perform multiple trials with reduced variability and at a much greater rate. The scientific and welfare advantages of this apparatus can only be fully realised if the animals are freely moving. Therefore there is a need to monitor neuronal activity in the hippocampal-prefrontal networks without requiring the animals to be tethered in any way. Some progress in this respect has been made with the introduction of a wireless multi-channel system for mice and rats by Triangle BioSystems. However the performance characteristics of this system (weight, size and battery life) are not adequate to exploit fully the advantages of the automated T-maze. Furthermore, software needs to be developed linking electrophysiology with behaviour, not only for this challenge, but ideally in a manner that is readily adapted to the wider use of wireless electrophysiology in other behavioural paradigms e.g. those using operant lever pressing or touchscreen techniques.

3Rs benefits

Traditional T-maze rewarded alternation tasks require intense handling which may alter the affective state of the mouse and so alter cognitive performance. This has been confirmed in a recent study which showed that handling history modified stress levels and subsequent behavioural responses5. In the automated maze both handling and tethering are avoided. The mouse is able to enter the maze at will at pre-programmed times during the light/dark cycle without any human intervention. This allows the mice to perform when they are naturally more active (i.e. in the dark period). Furthermore, the mouse remains in visual, auditory and olfactory contact with cage mates during the inter-trial interval, giving additional welfare benefits. Automation greatly increases the number of trials an animal can complete in a 24 hour period allowing greater statistical power from fewer animals. For long term recording, lighter and smaller devices with greatly increased battery life will minimise stressful handling. Finally, the potential reduction and refinement benefits of such a device could also be realised in other behavioural experiments if the software is sufficiently adaptable.

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Full Challenge information

Assessment information

 

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Budget information

Up to £500k

Sponsor(s)

Lilly

Duration

Up to three years