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
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.Knolle, F., Goncalves, R.P. and Morton, A.J. (2017) Sheep recognize familiar faces and unfamiliar human faces from two-dimensional images. In Press Royal Society Open Science 101098/rsos.171228
Kantor, S., Varga, J., Kulkarni, S. and Morton, A.J. (2017) Chronic paroxetine treatment prevents the emergence of abnormal EEG oscillations in Huntington's disease mice. In Press Neurotherapeutics 10.1007/s13311-017-0546-7
Knolle, F., McBride, S.D., Stewart, J.E., Goncalves, R.P. and Morton, A.J. (2017) A stop-signal task for sheep: introduction and validation of a direct measure for the stop-signal reaction time. Animal Cognition 20 615–626
Skene, D.J., Middleton, B., Fraser, C.K., Pennings, J.L., Kuchel, T.R., Rudiger, S.R., Bawden, C.S. and Morton, A.J. (2017) Metabolic profiling of presymptomatic Huntington's disease sheep reveals novel biomarkers. 7, 43030
Kantor,
S., Varga, J., Kulkarni, S. and Morton, A.J. (2017) Chronic paroxetine
treatment prevents the emergence of abnormal EEG oscillations in
Huntington’s disease mice. In Press Neurotherapeutics
Jacobsen, J.C., Erdin, S., Chiang, C., Hanscom, C., Handley, R.R., Barker, D.D., Stortchevoi, A., Blumenthal, I., Reid, S.J., Snell, R.G., MacDonald, M.E., Morton, A.J., Ernst, C., Gusella, J.F. and Talkowski, M.E. (2017) Potential molecular consequences of transgene integration: The R6/2 mouse example.
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Sheep
in the testing system. The sheep enters the ambulatory circuit through a gate at the beginning of the entering corridor that is opened by the handler. Walking along the corridor, the sheep activates an infra-red sensor to initiate the trial. Upon trial initiation, an auditory starting signal is presented via speakers and stimuli are presented on the computer screens that are integrated into the wall of the operant system. In order to select one stimulus, the sheep breaks an infrared beam above the feed trough below the relevant screen. A food reward is delivered into the trough (for a correct response). The delivery of the food (or an auditory error signal for an incorrect selection) indicates the end of the trial. The sheep then proceeds through a one-way gate back to the entering corridor and initiates the next trial. |
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Training
1-3 This video was made for demonstration purposes and was not part of the original training. The video shows examples of the sheep’s choice of the correct stimuli during each training stage. Example stimuli are identical to those used during the training. |
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Recognising
learned and very familiar faces This video was made for demonstration purposes and was not part of the original training. The video shows first an example of a sheep’s choices during the probe test where the sheep has to chose the picture of the celebrity in all different persectives, and then the selection of the very familiar face (handler). |
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The first
time seeing a photo of her handler The video clip in this sequence was part of the original experiment. In this trial, the sheep sees a 2D image of the handler for the first time. The handler’s photo is on the left, the unfamiliar face is on the right. (A different handler is running the session.) This sheep has already learned to perform the task using the faces of celebrities, so she is expecting to see two faces on the screens (one learned familiar, one unfamiliar). The sheep approaches the screens - sees the photo of the unfamiliar face, and expects therefore the other photograph to be one of the familiar faces (celebrity) that she has learned. (We intermixed the handler’s face amongst the celebrity faces that they had learned to recognize.) Note her reaction when she sees a picture of her handler. She double checks the stranger face, and then, after a pause, choses the handler's photograph. |
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A mouse performs in the two-choice
discrimination task 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. |
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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). [More] |
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Roslyn fixates on her self-image Roslyn spends long periods of time fixating on her self-image either with both eyes (binocular) or with one eye (monocular). [More] |
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Two sheep looking at each other via the mirror Doris fixates on the mirror image of Roslyn and then appears to check this against the real image of Roslyn beside her. Both sheep have been flock member for the last 4 years. [More] |
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Gerty investigates behind the mirror. After following the self-image across the length of the mirror, Gerty attempts to investigate behind the mirror. [More] |
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Gerty demonstrates signs of contingency behaviour Gerty demonstrates signs of contingency behaviour whereby she moves her head or body in front of the mirror whilst monitoring the subsequent movements made by the self-image. [More] |
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