Case study: Researcher Y

Research: Use of sensitive behaviour tests to understand memory storage and processing as well as the effect of genetic defects, all of which can inform clinical approaches to human disease and disorders.

Animals used: Primarily mice, less frequently rats

Researcher Y (prefers to remain anonymous): ‘Memory and emotional responses are abnormal in a number of terrible neurodegenerative diseases like Alzheimer’s, psychiatric disorders like schizophrenia and depression, and genetic conditions like Williams syndrome. It is important to learn how changes in a wide range of behaviours including loss of memory and changes in response to anxiety arise so we can understand more about these conditions and come up with new approaches to care and treatment.

‘The part of the brain called the hippocampus is at the core of memory processing in humans, so it’s of great interest to us. The hippocampus is also part of the system involved in anxiety and response to threats. It degenerates in Alzheimer’s disease and has been shown to be shrunken in people with long-term depression or schizophrenia. It’s also one of the very few areas of the brain where new nerve cells are formed and connected throughout life. So it’s of interest for a number of reasons.

‘We would like to know more about how we store memories. What changes in the connections between our nerve cells in the brain when we store a memory? It is now beginning to be possible to address what those changes are – we can use genetic manipulations to tease out the molecular basis of memory.

‘This is basic stuff, basic fundamental science, but it leads you to think about the clinical connections and about new therapy approaches for human diseases such as epilepsy and Alzheimer’s where these processes go wrong. We sometimes work with human patients with schizophrenia, or study the brain’s responses to pain and its anticipation using imaging methods in healthy volunteers, often through collaborations with other research groups.

‘We are also interested in developing sensitive behavioural tests so that we are able to determine any differences in the behaviour of mice with different genetic make-ups. For example, we are looking at Down’s syndrome mice, Williams syndrome mice, and FOXP2 mice.

‘Down’s syndrome is caused by the presence an extra copy of a chromosome, while Williams syndrome involves a large deletion of genetic material from a different chromosome. Individuals with Williams syndrome are often highly verbal and sociable (one of my colleagues says it’s unusual for her to be around people with Williams syndrome for any length of time and not receive a proposal of marriage!), but typically have a range of cognitive impairments as well. FOXP2 is a gene that is linked to the development of language abilities in humans.

‘We test the learning and memory capabilities of the mice using specially designed mazes or by seeing how they explore. We might see how they respond to new types of food they are offered, or how they react to darkness or brightly lit areas as simple tests of anxiety. We look at how well they cope with the simple tasks of daily living or look at their social interactions. These tests are sensitive enough to show clear differences in the behaviour of normal mice and mouse models of disease or dysfunction, even though there may be nothing immediately obvious to an observer.

‘Mice can be genetically engineered to have changes that mirror those found in humans. The mouse models, as they are known, allow us to learn about the genetic defects, what function the genes have, and are a way to try to answer questions like: could you turn off the extra genetic products to turn off Down’s syndrome, or what genes are responsible for the changes in behaviour observed in Williams syndrome?

‘There is a group of diseases caused by prions – proteins that have taken up a malformed structure and build up in brain tissue, disrupting brain function. The best known in humans is variant Creutzfeldt Jacob (vCJD) disease, which is strongly connected to BSE in cows.

‘We were able to show in behavioural tests with a mouse model of vCJD that a potential treatment that had been suggested for human vCJD didn’t seem to work. It’s very hard to get quick, informative answers like this in humans, but clinical experience since then seems to fit our conclusions. While disappointing, this does show the value of this type of research and the conclusions that can be drawn.

‘We have also shown that if you give an animal with prion disease a compound to activate its immune system, its symptoms rapidly get worse. That is, activating the immune system brings forward the consequences of the prion disease.

‘This seems to mirror what sometimes happens in humans when their immune system is similarly challenged. Our collaborators are gathering data from elderly patients and their families to see if they sometimes go downhill quite abruptly after an event like a bad fall, or suffering from an infection.

‘These kinds of result can have a potential impact in the care of those with Alzheimer’s. If we understand this connection, we may get a completely new take on how important catching flu or breaking bones is to the progression of disease. It may be that giving flu jabs is not just important to avoid infection, but to stay bright!

‘It’s difficult to get quick fixes here and translate this research into novel treatments. They are very difficult complex diseases but there is a huge market of unmet need.

‘The completion of the Biomedical Sciences Building was really important for the good health of the animals. Our breeding colonies for the mouse models are now on an ultraclean level, meaning that chances of infection are extremely small. Having one central facility also means it is easier for lots of different labs from different disciplines to work together and gain much more information.’