The focus of our work is to investigate the genetic basis of mammalian behaviour and, in doing so, improve our understanding of how the central nervous system functions in physiological and diseased conditions.
We study genes underlying behaviours that are signature psychiatric diseases such as schizophrenia, depression, bipolar disorder and autism spectrum disorders. In order to do this, we study mice with abnormal behavioural characteristics to identify and investigate the genes and molecular processes responsible.
Circadian rhythms and sleep
One of our main areas of interest is in biological rhythms and sleep, as disordered activity and sleep patterns have been linked to psychiatric disease. For example, schizophrenic patients who wear a watch-like device that tracks their activity have been found to be active at odd hours and sleep for irregular time periods. We are particularly interested in genes that regulate the circadian rhythms (internal body clock) which control our sleep patterns. We have identified a number of strongly inherited genes that influence the timing of sleep and we are examining these further to determine how they operate at a molecular level.
A major role of our circadian clock is to ensure that we wake up and fall asleep at the right time of day, although it also regulates a variety of other processes such as temperature control, metabolic processes and circulating hormone levels. This internal clock is essential for an animal to thrive, allowing it to anticipate and react to changes in its environment, such as the switch from night to day. While this clock ticks away in every cell, all parts of the body need to be synchronised for it to function, in the same way that all clocks in a house must tell the same time. Part of the brain called the suprachiasmatic nucleus of the hypothalamus coordinates our circadian rhythms to ensure that the whole body runs on the same time.
One of the genes we have identified can co-ordinate many important neuropeptides found in this part of the brain, and we are conducting further studies to understand how mutations in this gene can unbalance the behavioural equilibrium in mice and humans. Another mutation we are studying, the after hours (Afh) mutation, results in a lengthening of behavioural rhythms from 24 to 27 hours. We discovered that Afh disrupts molecular oscillations by sparing the clock protein Cry from proteasomal degradation, and identified a point mutation in the F-box gene Fbxl3 which causes this by reducing the efficiency that the Fbxl3 protein interacts with and ubiquitinates Cry. We therefore showed that regulation of Cry is critical for determining the length of the internal mammalian clock. We have also shown that, when the clock is disturbed by this mutation, there are widespread behavioural consequences, including hyperactivity/mania.
Identification and investigation of neurobiological disease traits
We develop our own behavioural tests and use these to prioritise suitable mouse lines for study from Harwell’s Disease Model Discovery Programme. These tests allow us to identify mouse lines that have characteristics which suggest an abnormal neurobiological function or that express signatures of psychiatric disease. These tests include monitoring mice by video recording their home cage activity, assessments of wheel running activity and automated tests of motor function. We then examine the genetic and molecular basis of these behaviours by studying these mouse lines in more detail using techniques such as positional cloning, histological analysis and gene expression analysis in key brain regions.