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The Brain Repair Group

The Transgenic Project

Functional analysis of behavioural deficits in transgenic mice


Goals

To develop batteries of behavioural tests that enables the efficient and sensitive screening of transgenic mice, in order to identify the profile of deficits associated with particular transgenic lines, to evaluate the efficacy of cell based therapies, and to analyse the relationships between behavioural and genetic phenotypes, patterns of anatomical pathology, and profiles of gene expression.


Background

The group has been involved over 20 years in behavioural testing of a variety of lines of transgenic mouse - first a Lesch-Nyhan model, then a variety of amyloid precursor protein lines and glial deficient models, and most recently with a focus on genetic models of Huntington’s disease.

Since moving to Cardiff in 2000 the group has collaborated with Dr Lesley Jones, School of Medicine, in a joint programme to understand the pathogenic basis of Huntington’s disease, in particular how the specific mutation in the huntingtin gene is translated to specific corticostriatal pathology, and specific patterns of cognitive and motor impairment.


Studies in progress

· Validation of longitudinal screening batteries for evaluating motor and cognitive deficits in different transgenic and knock-in models of HD in the mouse;9 hole mouse box

· Development of new operant tests based on the automated 9 hole box apparatus that are sensitive to specific cognitive impairments prior to development of overt phenotypes;

· Characterisation of behavioural profiles in the background mouse strains that have been used to generate different genetic models, in order to separate gene-specific and strain-specific phenotypes;

· Microarray of gene expression and histological analysis of htt pathology across the lifespan, for covariation with the longitudinal development of behavioural phenotypes;

· Development of biostatistical methods with the power for identification of covariation across domains;

· Validation of new rat transgenic models of HD in particular using operant analysis of motor learning and cognition;

· Application of the mouse and rat models to evaluate novel pharmacological, neuroprotective and cell transplantation strategies of alleviation and repair.


Selected recent publications

  • Brooks SP, Betteridge H, Trueman RC, Jones L, Dunnett SB (2006) Selective extra-dimensional set shifting deficit in a knock-in mouse model of Huntington's disease. Brain Res Bull 69: 452-457.
  • Jones L, Goldstein DR, Hughes GP, Strand A, Collin F, Dunnett SB, Kooperberg CL, Aragaki A, Olson JM, Augood SJ, Faull RL, Luthi-Carter R, Moskvina V, Hodges AK (2006) Assessment of the relationship between pre-chip and post-chip quality measures for Affymetrix GeneChip expression data. BMC Bioinformatics 7: 211.
  • Brooks SP, Pask T, Jones L, Dunnett SB (2005) Behavioural profiles of inbred mouse strains used as transgenic backgrounds. II: cognitive tests. Genes Brain Behav 4: 307-317.
  • Morton AJ, Hunt MJ, Hodges AK, Lewis PD, Redfern A, Dunnett SB, Jones AL (2005) Combination drug treatment alleviates cognitive impairment and reverses gene expression changes in a transgenic mouse model of Huntington's disease. Eur J Neurosci 21: 855-870.
  • Trueman R, Brooks SP, Dunnett SB (2005) Implicit learning in a serial choice visual discrimination task in the operant 9-hole box by intact and striatal lesioned mice. Behav Brain Res 159: 313-322.
  • Bensadoun JC, Brooks SP, Dunnett SB (2004) Free operant and discrete trial performance of mice in the 9-hole box apparatus: validation using amphetamine and scopolamine. Psychopharmacology (Berl) 174: 396-405.
  • Brooks SP, Pask T, Jones AL, Dunnett SB (2004) Behavioural profiles of inbred mouse strains used as transgenic backgrounds. I: motor tests. Genes Brain Behav 3: 206-215.
  • Dunnett SB, Bensadoun JC, Pask T, Brooks SP (2003) Assessment of motor behaviour in transgenic mice. In: Mouse Behaviour Phenotyping (Crawley JN, ed), pp 1-12. Washington: Society for Neuroscience.
  • Baird AL, Meldrum A, Dunnett SB (2001) The staircase test of skilled reaching in mice. Brain Res Bull 54: 243-250.
  • Morton AJ, Lagan M, Skepper JN, Dunnett SB (2000) Progressive formation of inclusions in the brains of mice transgenic for the human Huntington's disease mutation parallels neurological decline. J Neurocytol 29: 679-702.
  • Murphy KP, Carter RJ, Lione LA, Mangiarini L, Mahal A, Bates GP, Dunnett SB, Morton AJ (2000) Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation. J Neurosci 20: 5115-5123.
  • Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, Morton AJ, Dunnett SB (1999) Characterisation of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J Neurosci 19: 3248-3257.
  • Lione LA, Carter RJ, Bates GP, Morton AJ, Dunnett SB (1999) Selective discrimination learning impairments in mice expressing the human Huntington's disease mutation. J Neurosci 19: 10428-10437.

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