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.
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.
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.
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.
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.
Dr Nigel Wood – Dr Alessandro Ciamei – Dr Nicholas Perentos – Dr Sandor Kantor – Dr Koliane Ouk – Dr Sebastian McBride – Dr Tom Furmston – Dr Amadeu Martins – Dr Jayden van Horik – Dr Zhiguang Zheng – Ms Liz Skillings – Ms Eloise Larson – Miss Juliet Aungier – Miss Sandra Pietsch – Mr Roger Mason – Mrs Wendy Leavens – Mrs Abigail Plet – Mrs Mary Harding
- Wood, N.I., McAllister, C.J., Cuesta, M., Aungier, J., Fraenkel, E. and Morton, A.J. (2013) Adaptation to experimental jet-lag in R6/2 mice despite circadian dysrhythmia. PLoS One. 8(2):e55036.
- Morton, A.J. (2013) Circadian and sleep disorder in Huntington's disease. Exp Neurol. 243:34-44.
- Morton, A.J. (2013) Huntington’s disease and sleep. HDBuzz Special Feature
- Morton, A.J. (2013) Simple rules for a good night’s sleep in Huntington’s disease. HDBuzz
- Kantor, S., Szabo, L., Varga, J., Cuesta, M. and Morton A.J. (2013) Progressive sleep and electroencephalogram changes in mice carrying the Huntington’s disease mutation. Brain 136, 2147-2158
- Sawiak, S.J., Wood, N.I., Williams, G.B., Morton, A.J. and Carpenter, T.A. (2013) Voxel-based morphometry with templates and validation in a mouse model of Huntington’s disease. Magnetic Resonance Imaging IN PRESS
- Pouladi, M.A., Morton, A.J. and Hayden, M.R. (2013) Choosing an animal model for the study of Huntington's disease. Nat Rev Neurosci 14, 708-721
- Reid,S.J., Patassini, S., Handley, R.R., Rudiger, S.R., McLaughlan, C.J., Osmand, A., Jacobsen, J.C., Morton, A.J., Weiss, A., Waldvogel, H.J., MacDonald, M.E., Gusella, J.F., Bawden, C.S., Faull, R.L.M., and Snell, R.G. (2013) Further Molecular Characterisation of th OVT73 Transgenic Sheep Model of Huntington’s Disease Identifies Cortical Aggregates. Journal of Huntington’s Disease 2, 279 –295 DOI 10.3233/JHD-130067
- Cuesta, M., Aungier, J. and Morton, A.J. (2012) The methamphetamine-sensitive circadian oscillator is dysfunctional in a transgenic mouse model of Huntington's disease. Neurobiology of Disease 45, 145-55
- Kielar, C., Sawiak, S.J., Navarro Negredo, P., Tse, D.H. and Morton, A.J. (2012) Tensor-based morphometry and stereology reveal brain pathology in the Complexin1 knockout mouse PLoS ONE (in press) 7(2):e32636
- King, A.J., Wilson, A. M., Wilshin, S.D., Lowe, J., Haddadi, H., Hailes, S. and Morton, A.J. (2012) Selfish-herd behaviour of sheep under threat. Current Biology (in press)
- Haddadi, H., King, A.J., Wills, A.P., Fay, D., Lowe, J., Morton, A.J., Hailes, S. and Wilson, A.M. (2012) Determining association networks in social animals; choosing spatial-temporal criteria and sampling rates. Behavioural Ecology and Sociobiology 1-10
- Wood, N.I., Sawiak, S.J., Buonincontri, G., Niu, Y., A.D, Carpenter, A. Giussani, D. A., Morton, A.J. (2012) Direct evidence of progressive cardiac dysfunction in a transgenic mouse model of Huntington’s disease. Journal of Huntington’s Disease 1 65-72
- Gong, B., Kielar,, C, Morton, A.J. (2012) Aggregation precedes ubiquitination during early inclusion formation in a transgenic mouse carrying the Huntington's disease mutation In press PLoS One
- Morton, A.J. and Avanzo, L. (2011) Executive decision-making in the domestic sheep. PLoS ONE 6(1): e15752.
- Williams, R.H, Morton, AJ and Burdakov, D. (2011) Paradoxical function of orexin/hypocretin circuits in a mouse model of Huntington's disease, Neurobiology of Disease 42,(3):438-45
- Duzdevich, D., Li, J. Whang, J., Takahashi, H., Takeyasu, K., Dryden, D.T.F., Morton, A.J. and Edwardson, J.M. (2011) Unusual Structures Are Present in DNA Fragments Containing Super-Long Huntingtin CAG Repeats. PLoS One 6(2): e17119.
- Wood, N.I, Glynn. D, and Morton A.J. (2011) "Brain training" improves cognitive performance and survival in a transgenic mouse model of Huntington's disease. Neurobiology of Disease 42, 427-37
- Haddadi, H., King, A., Wills, A., Fay, D., Lowe, J., Morton, A.J., Hailes, S. and Wilson, A. (2011) Determining association networks in social animals: choosing spatial-temporal criteria and sampling rates. Behavioral Ecology and Sociobiology 65, 1659-1668
- Hobbs-Chell, H., King, A.J., Sharratt, H., Haddadi, H., Rudiger, S.R., Hailes, S., Morton, A.J. and Wilson, A.M. (2011) Data-loggers carried on a harness do not adversely affect sheep locomotion. Research in Veterinary Science 93(1):549-552
- Wood, N.I., Carta, V., Milde, S., Skillings, E.A., McAllister, C.J., Ang, Y.L., Duguid, A., Wijesuriya, N., Afzal, S.M., Fernandes, J.X., Leong, T.W. and Morton A.J. (2010) Responses to environmental enrichment differ with sex and genotype in a transgenic mouse model of Huntington's disease. PLoS One. 2010 Feb 12;5(2):e9077
- Maywood, E.S., Fraenkel, E., McAllister, C.J., Wood, N.I., Reddy, A.B., Hastings, M.H. and Morton, A.J. (2010) Disruption of peripheral circadian timekeeping in a mouse model of Huntington's disease and its restoration by temporally scheduled feeding. Journal of Neuroscience 30, 10199-204.
- Glynn, D., Gibson, H.E., Harte, M.K., Reim, K., Jones, S., Reynolds, G.P. and Morton, A.J. (2010) Clorgyline-mediated reversal of neurological deficits in a Complexin 2 knockout mouse. Human Molecular Genetics 19:3402-12.
- Goodman, A.O., Rogers, L., Pilsworth, S., McAllister, C.J., Shneerson, J.M., Morton, A.J. and Barker, R.A (2010) Asymptomatic sleep abnormalities are a common early feature in patients with Huntington’s disease. Current Neurology and Neuroscience Reports, 11, 211-217
- Goodman, A.O., Morton, A.J. and Barker, R.A. (2010) Identifying sleep disturbances in Huntington’s disease using a simple disease-focused questionnaire. PLoS Currents 2:RRN1189.
- Sawiak, S.J., Wood, N.I., Williams, G.B., Morton, A.J. and Carpenter, T.A. (2009) Use of Magnetic Resonance Imaging for Anatomical Phenotyping of the R6/2 Mouse Model of Huntington's Disease. Neurobiology of Disease 33, 12-9
- Sawiak, S.J., Wood, N.I., Williams, G.B., Morton, A.J. and Carpenter, T.A. (2009) Voxel-based morphometry in the R6/2 transgenic mouse reveals differences between genotypes not seen with manual 2D morphometry. Neurobiology of Disease 33, 20-7
- Pallier, P.N., Drew, C.J. and Morton AJ. (2009) The detection and measurement of locomotor deficits in a transgenic mouse model of Huntington's disease are task- and protocol-dependent: Influence of non-motor factors on locomotor function. Brain Research Bulletin, 78, 347-355
- Morton, A.J., Glynn, D., Leavens, W., Zheng, Z., Faull, R.L.M., Skepper, J.N. and Wight, J.M (2009) Paradoxical delay in the onset of disease caused by super-long CAG repeat expansions in R6/2 mice. Neurobiology of Disease 33, 331-341
- Menalled, L., El-Khodor, B.F., Patry, M., Suárez-Fariñas, M., Orenstein, S.J., Zahasky, B., Leahy, C., Wheeler, V., Yang, X.W., MacDonald, M., Morton, A.J., Bates, G., Leeds, J., Park, L., Howland, D., Signer, E., Tobin, A. and Brunner, D. (2009) Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models. Neurobiology of Disease 35, 319-36.
- Ciamei, A. and Morton, A.J. (2009) Progressive imbalance in the interaction between spatial and procedural memory systems in the R6/2 mouse model of Huntington's disease. Neurobiology of Learning and Memory Oct;92(3):417-28.
- Van der Burg, J.M.M., Bacos, K., N.I., Andreas Lindqvist, A., Wierup, N., Wamsteeker, J.I., Smith, R., Deierborg, T., Kuhar, M., Bates, G.P., Mulder, H., Erlanson-Albertsson, C., Morton, A.J., Brundin, P., Petersén, A. and Björkqvist, M. (2008) Increased metabolism in the R6/2 mouse model of Huntington’s disease. Neurobiology of Disease 29, 41-51
- Gong, B., Lim, M. C. Y., Wanderer, J., Wyttenbach, A. and Morton, A.J. (2008) Time-lapse analysis of aggregate formation in an inducible PC12 cell model of Huntington's disease reveals time-dependent aggregate formation that transiently delays cell death. Brain Research Bulletin 75,146-157
- Ciamei, A. and Morton, A.J. (2008) Rigidity in social and emotional memory in the R6/2 mouse model of Huntington's disease. Neurobiology of Learning and Memory 89, 533-44.
- Wood, N.I., Goodman, A., Van der Burg, J.M.M., Gazeau, V., Brundin, P., Björkqvist, M., Petersén, A., Tabrizi, S., Barker, R.A. and Morton, A.J. (2008) Increased thirst and drinking in Huntington's disease and the R6/2 mouse. Brain Research Bulletin 76, 70-79
- Goodman, A.O.G., Murgatroyd, P.R., Medina-Gomez, G., Wood, N.I., Finer, N., Vidal-Puig,, A.J., Morton, A.J. and Barker, R.A. (2008) The metabolic profile of early Huntington's disease - a combined human and transgenic mouse study. Experimental Neurology 210, 691-8
- Michell, A.W., Goodman, A.O., Silva, A.H., Lazic, S.E., Morton, A.J. and Barker, R.A. (2008) Hand tapping: A simple, reproducible, objective marker of motor dysfunction in Huntington's disease. Journal of Neurology 255, 1145-52
- Bussey, T.J., Padain, T.L., Skillings, E.A., Winters, B.D., Morton, A.J. and Saksida, L.M. (2008) The touchscreen cognitive testing method for rodents: How to get the best out of your rat. Learning and Memory 15, 516-23
- Court, F., Gillingwater, T.H., Melrose, S., Sherman, D.L., Greenshields, K., Morton, A.J., Harris, J.B., Willison, H.J. and Ribchester R.R. (2008) Identity, developmental restriction and reactivity of extralaminar cells capping mouse neuromuscular junctions Journal of Cell Science 121, 3901-11
- Wade, A., Jacobs, P., Morton, A.J. (2008) Atrophy and degeneration in sciatic nerve of presymptomatic mice carrying the Huntington's disease mutation. Brain Research, 1188, 61-68
- Pallier,P.N., Maywood, E.A., Zheng, Z., Chesham, J., Inyushkin, A.N., Dyball, R., Hastings, M., Morton, A.J. (2007) Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington's disease. Journal of Neuroscience, 27, 7869-7878
- Wade, A, Jacobs, P., Morton, A.J. (2007) Atrophy and degeneration in sciatic nerve of presymptomatic mice carrying the Huntington's disease mutation, Brain Research, in press, published on line, 17 July
- Kung VW, Hassam R, Morton AJ, Jones S. (2007) Dopamine-dependent long term potentiation in the dorsal striatum is reduced in the R6/2 mouse model of Huntington's disease. Neuroscience, 146:1571-80
- Lazic, S.E., Goodman, A.O., Grote, H.E., Blakemore, C., Morton, A.J., Hannan, A.J., van Dellen, A., Barker, R.A. (2007) Olfactory abnormalities in Huntington's disease: Decreased plasticity in the primary olfactory cortex of R6/1 transgenic mice and reduced olfactory discrimination in patients. Brain Research 1151:219-26
- Morton, A. J. (2007) Ecstasy. Is the party over? The Biochemist 29 (2) 4-7
- Wanderer, J., Morton, A.J. (2007) Differential Morphology and Composition of Inclusions in the R6/2 Mouse and PC12 Cell Models of Huntington's Disease. Journal of Histochemistry and Cell Biology, 127(5):473-84
- Glynn. D., Sizemore, R.J., Morton A.J. (2006) Early motor development is abnormal in complexin 1 knockout mice. Neurobiology of Disease 25(3):483-95.
- Wood, N., Pallier, P.N., Wanderer, J., Morton, A. J. (2007) Systemic administration of Congo red does not improve motor or cognitive function in R6/2 mice. Neurobiology of Disease 25(2):342-53
- Phillips, W. Morton, A.J., Barker, RA (2006) Limbic neurogenesis/ plasticity in the R6/2 mouse model of Huntington's disease. Neuroreport 17, 1623-1627
- Glynn. D., Reim, K., Brose, N., Morton A.J. (2007) Depletion of Complexin II does not affect disease progression in a mouse model of Huntington's disease (HD); Support for role for complexin II in behavioural pathology in a mouse model of HD. Brain Research Bulletin 72(2-3):108-20
- Hernandez-Espinosa, D. and Morton, A.J. (2006) Calcineurin inhibitors cause an acceleration of the neurological phenotype in a mouse transgenic for the human Huntington's disease mutation. Brain Research Bulletin 69, 669-79
- Morton, A.J., Skilings, E., Bussey, T., and Saksida, L.M. (2006) Measuring cognitive deficits in disabled mice using an automated interactive touchscreen system. Nature Methods 3(10): 767
- Phillips, W. Morton, A.J., Barker, RA (2005) Abnormalities of neurogenesis in the R6/2 mouse model of Huntington's disease are due to the in vivo microenvironment. Journal of Neuroscience, 25, 11586-11594
- Gibson, H.E., Reim, K., Brose, N., Morton, A.J., Jones, S. (2005) Impaired CA3 mossy fibre LTP in the R6/2 mouse model of Huntington's disease and in the complexin II knockout mouse. European Journal of Neuroscience, 22, 1701-1712
- Glynn, D., Drew, C. J., Reim, K., Brose, N. and Morton, A.J. (2005) Profound ataxia in Complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits. Human Molecular Genetics, 16, 2369-2385
- Pallier , P.N., Zheng, Z., Morton, A.J. (2005) Pharmacological imposition of sleep prevents cognitive decline in a transgenic mouse model of Huntington's disease. British Journal of Pharmacology, in press
- Hunt, .J. Morton, A.J. (2005) Atypical Diabetes Associated with Inclusion Formation in the R6/2 Mouse Model of Huntington's Disease is not improved by treatment with hypoglycemic agents. Experimental Brain Research, 166, 220-9
- Henderson, G., Morton, A.J., Little, H (2005) Drug Abuse: from gene through cell to behavior. Current Opinion in Pharmacology, 5, 1-3
- Morton, A.J. (2005) Ecstasy: pharmacology and neurotoxicity. Current Opinion in Pharmacology, 5, 79-87
- Morton, A.J., Hunt, M.J., Hodges, A.K, Lewis, P. D. Redfern, A. J. Dunnett, S. B., Jones, L. (2005) A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington's disease. European Journal of Neuroscience 21,855-870
- Morton, A.J., Wood, N.I., Hastings, M. Hurelbrink, C., Barker, R.A., Maywood, E.A. (2005) Disintegration of the sleep/wake cycle and circadian timing in Huntington's disease. Journal of Neuroscience 25, 157-163.
- Wasle, B., Turvey, M., Larina, O., Thorn, P., Skepper, J. Morton, A.J., Edwardson, J.M. (2005) Syncollin is required for efficient zymogen granule exocytosis. Biochemical Journal 385, 721-7
- Morton, A.J. (2004) Molecular pathogenesis in Huntington's disease. Advances in Clinical Neuroscience and Rehabilitation 4 (1) 9-11
- Richard R. Ribchester, R.R., Thomson, D., Wood, N.I., Hinks, T., Gillingwater, T.H., Wishart, T.M., Court, F.A., Morton, A.J. (2004) Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation, European.Journal of Neuroscience 20, 3092-3114
- Freeman, W. and Morton, A. J. (2004) Regional and progressive changes in brain expression of complexin II in a mouse transgenic for the Huntington's Disease mutation. Brain Research Bulletin 63, 45-55
- Morton, A. J & Edwardson, J. M. (2001) Progressive Depletion of Complexin II in a Transgenic Mouse Model of Huntington's Disease Journal of Neurochemistry 76, 166-172
- Morton, A. J., Lagan, M. A., Skepper,, J. N. & Dunnett, S. B. (2000) Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation Journal of Neurocytology,29, 681-705
- Morton, A. J & Leavens, W. (2000) Mice transgenic for the human Huntington's Disease mutation have reduced sensitivity to kainic acid toxicity Brain Research Bulletin 52 (1) 52-59
- Murphy, K. P. S. J ., Carter, R. J., Lione, L. A., Mangiarini, L., Mahal, A., Bates, G.P. Dunnett, S. B. & Morton, A. J. (2000) Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for the human Huntington's disease mutation. Journal of Neuroscience 20 (12) 5115-5223
- Carter, R. J., Hunt, M.A. & Morton, A. J. (2000) Environmental stimulation increases survival in mice transgenic for exon 1 of the Huntington's Disease gene Movement Disorders 15 925-37
- Hickey, M. A. & Morton (2000) Mice transgenic for the Huntington's Disease mutation are resistant to chronic 3-nitropropionic acid-induced striatal toxicity J Neurochmistry 75, 2163-71
- Carter, R.J., Lione, L.A., Humby, T., Mangiarini, L., Mahal, A., Bates, G.P. Dunnett, S.B. & Morton, A.J. (1999) Characterisation of progressive motor deficits in mice transgenic for the human Huntington's Disease mutation. Journal of Neuroscience 19, 3248-3257
- Lione, L. A., Carter, R. J., Hunt, M. J., Bates, G.P., Morton, A. J. & Dunnett, S. B. (1999) Selective discrimination learning impairments in mice expressing the human Huntington's Disease mutation Journal of Neuroscience 19, 10428-10437.