IMPC: Cognitive and ethological characterisation of mice lacking melatonin MT2 receptors

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Melatonin is a hormone made by a small gland at the base of the brain, which regulates sleep/wake patterns and circadian rhythms. Apart from these well-characterised roles, melatonin also acts in poorly-understood ways to affect cognitive processes such as alertness, and to modulate the brain circuitry underlying psychiatric diseases such as depression, schizophrenia and bipolar disorder. This project will perform an initial characterisation of mice lacking one of the proteins through which melatonin exerts its actions on brain cells, known as the melatonin MT2 receptor. Mice lacking the melatonin MT2 receptor appear perfectly normal, although there is some evidence to suggest that their sleeping patterns may be slightly disturbed, and that they may have some memory deficits in simple tests. The study will examine a) whether their daily activity and sleeping patterns differ from normal mice; b) the extent to which their brain chemistry is altered in the circuitry associated with psychiatric diseases such as depression, schizophrenia and bipolar disorder; and c) whether they have impaired performance in a cognitive task closely related to that used in human clinical studies - where the mice can select a series of responses using a touchscreen, and hence demonstrate their ability to sustain attention. The results will reveal the extent to which loss of melatonin's effects on the MT2 receptor may contribute to deficits in wakefulness and alertness, and to susceptibility to psychiatric disease. This will set the stage for future more detailed characterisation of the physiological and pathological function of MT2 receptors, and is likely to illuminate the exploitation of MT2 receptors as a target for current and future psychiatric drug development. In addition, if the specific circuitry associated with affective/psychotic diseases is compromised in these mice, the information will open a new avenue to studying treatment strategies aimed at normalising functional activity in this network.