Director of Studies in Medicine and Veterinary
Medicine, Newnham College
Tel: +44 (0)1223 334057, Fax: +44 (0)1223 333840, E-mail: email@example.com
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.
Video: A mouse performs in the two-choice discrimination task
Stimuli are presented on the touchscreen in pairs, one the correct S+ and the other the incorrect S-. A nose poke to the S+ results in a tone and the onset of a light in the food hopper accompanied by delivery of a reward pellet. Incorrect responses are followed by a correction procedure, where the house light is extinguished for 5 seconds. Both discriminative stimuli are presented an equal number of times during a session. The left-right arrangement is determined pseudorandomly, with a constraint that a given stimulus cannot appear on the same side of the screen on more than 3 consecutive trials.
Video: Gerty performs in the two-choice discrimination task
This video was not part of an actual experiment. It was shot the day after Gerty had learned to do this discrimination (i.e. she had reached criterion).
Gerty has learned that if she chooses the side with the ‘x’, there will be a reward (a few sheep nuts) in the bucket. Sometimes she makes her decision very quickly, other times (e.g. choice number 3) you can see that she appears to be comparing the symbols quite deliberately.
Gerty procedes through the task at her own pace. Note that she shows some behaviours in the video that are not typically seen during the task. This is because she had never done the task in the presence of a second person before. For example, she checks with the operator on some of the discriminations when she sees the person operating the video camera (who is not usually there). However, she does not gain information about the correct choice from the operator. Until the sheep has made her choice, the operator remains near the previous exit gate, with her back turned so the sheep cannot see her face.
Gerty got 100% correct in this run.
Gerty is a two year old Welsh mountain ewe. She was named after Gerty Cori, who won a Nobel Prize in Physiology or Medicine in 1947, for the discovery of the course of catalytic conversion of glycogen.