Research

Professor of Neurobiology and Director of Studies in Medicine and Veterinary Medicine, Newnham College
Tel: +44 (0)1223 334057, Fax: +44 (0)1223 333840, E-mail: ajm41@cam.ac.uk

Research 21

Translational Research for Neurological Disorders

Our research focus is on genetic neurological disorders, particularly Huntington’s disease (HD) and Batten’s disease. We are particularly interested in the early stages of these diseases, because our ultimate goal is to develop treatments for them. A treatment that could slow the disease process once it has started would be a major advance, but the ideal treatment would prevent the onset of symptoms. Such a treatment would need to be started before the disease has really taken hold.

Why Huntington’s disease?

Huntington’s disease (HD) is a devastating neurological genetic disease with fatal outcome. It is a complex disease, with not only motor but also cognitive and psychiatric symptoms. There is limited treatment, and currently no cure for HD.

Huntington’s disease models

We use both transgenic and knock-in models of HD mice for our studies. Much of our work uses the R6/2 mouse model of HD. We have an allelic series of R6/2 mice, with repeat sizes ranging between 42 and >700 CAGs. We have found deficits in cognitive and motor performance, as well EEG and circadian rhythms deficits in R6/2 mice. These reflect the symptoms seen in HD patients.

More recently, we have been testing a sheep model of HD that has been developed by our collaborators in New Zealand and Australia. We are also studying a line of sheep that carries a natural mutation for Batten’s disease.

Understanding normal brain function in mice and sheep

Before we can measure whether or not a treatment improves abnormal behaviours caused by the HD gene, we need reliable measures of normal animal behaviour.

For mouse behavioural testing, we use standard behavioural tasks, such as Morris water maze (to test spatial memory) and rotorod (to test motor performance), to test normal behaviour. But testing cognitive function in mice is particularly challenging. We also use complex behavioural tests such as two choice discrimination using mouse Touchscreens, to measure cognition.

Testing sheep cognition

There are no standard methods for measuring sheep cognition, so we are currently developing methods for testing learning and memory in sheep.

Although sheep are not usually thought to be very clever, our studies suggest that sheep are much more intelligent than they appear. We have tested the ability of sheep to perform tests of executive function. (See Executive Decision-Making in the Domestic Sheep). We found that sheep can perform 'executive' cognitive tasks that are an important part of the human and other primates’ behaviour, but this has not previously been shown to exist in any other large animal. Sheep have great potential, not only for studying HD, but also for studying cognitive function and the evolution of complex behaviours in normal animals.

Why use sheep?

Sheep have complex brains that are similar in size to that of a large monkey, such as rhesus macaque. The part of the brain that degenerates in HD (the caudate nuclei and cortex) is also better developed in sheep than it is in mice. The HD sheep will be very useful for studying the pathology of HD. Sheep also live much longer than mice, so it should be possible to study the early symptomatic phase of HD in a time frame that is much more relevant to human disease.

Cognitive decline is a major therapeutic target in HD. If we can test cognition in sheep, we can see if there is a decline in cognition in the HD sheep. If so, they will be very useful large animal models of HD in which novel therapies can be tested.