The Striatal Project
Functional repair of the neostriatum with striatal grafts
To develop valid experimental models of Huntington's disease that enable sensitive and accurate evaluation of alternative therapeutic strategies for treatment and repair in the human disease. The striatal project provides the preclinical studies that are designed to provide the basis for introducing new therapies for Huntington's disease (see the HD transplantation project).
This involves the parallel development of :
· adequate models of human Huntington’s diseases in rat and mouse;
· techniques for reliable preparation and transplantation of cells;
· better tests of motor and cognitive function to assess deficits and recovery;
· analysis of the extent and mechanisms of functional recovery;
· preclinical studies oriented towards translation of cell repair strategies from laboratory models to the clinic.
Mechanisms of striatal degeneration
In the human disease the huntingtin gene mutation leads to primary degeneration of neurons of the striatum. The mechanisms of toxicity are not fully understood but involve disturbances in cellular metabolism. Similar profiles of degeneration can be modelled in experimental animals by selective excitotoxins and metabolic toxins.
It is now also possible to introduce the huntingtin gene defect into transgenic animals (see the Transgenic Project). These three types of striatal damage are being compared in order to understand the mechanisms of damage, to identify strategies for alleviation and repair, and to provide better models of the human disease to evaluate new therapies.
Improved transplant procedures
It is now established that embryonic striatal grafts can alleviate both movement and some cognitive deficits in experimental models of Huntington's disease. However, the procedures are not optimal. Improvements can be achieved both through empirical analysis of the parameters of graft tissue dissection, preparation and implantation, and by understanding the mechanisms of repair necessary for each level of functional recovery.
In particular, it is necessary to establish the degree to which grafts can become fully integrated anatomically within the host brain, to what extent they actually repair the damaged circuitry, and what additional training the repaired system (and host animal or patient) needs to restore lost function.
Analysis of striatal function
As well as the obvious difficulties with movement (dyskinesias and 'chorea'), Huntington's disease also involves cognitive and emotional impairments. We are developing improved tests of motor, cognitive, and emotional functions in experimental animals as the basis for evaluating alternative strategies of treatment in valid models of the human disease.
In order to better understand the relationship between transplantation repair and functional recovery, we need to understand the principles of underlying functional organisation of cognitive systems in the brain. A major focus of our analysis is to use operant tests to evaluate the dependence of higher cognitive abilities (as assessed in tests such as ‘delayed alternation’) on intact corticostriatal pathways of the brain. A second focus is on the development of tests to evaluate the role of the corticostriatal system in motor learning and ‘habit’ formation
Analysis of striatal repair by transplantation
Behavioural analysis is necessary to identify the extent and limitations of recovery with alternative treatment strategies as the basis for designing the most efficacious procedures for clinical application.
At one level the recovery is empirical – can the transplant operation actually alleviate impairments in motor and cognitive domains?
At a second level, we need to understand the levels of anatomical repair necessary to provide functional recovery, so that we can develop new therapies based on a sound understanding of the underlying biological principles. This will also allow us to solve problems of limited repair and/or side effects though rational understanding rather than empirical guesswork.
At a third level, critical analysis of the behaviour of transplanted animals has revealed – and continues to reveal – unpredicted aspects of transplant biology, such as the fact than animals with striatal grafts must ‘learn to use the transplant’. Such a discovery has profound influence on the need for ‘rehabilitation’ as an important component in any clinical trial.
In preparation for clinical trials, the methods developed in experimental models require validation when applied to human cells. Human fetal cells are collected as a key component in the HD transplantation project). Following determination of the conditions for their preparation, selection, storage and growth in tissue culture, their suitability for application requires validation first in animal models. We therefore validate target protocols in terms of safety (they are uncontaminated and do not form tumours), specificity (they differentiate into just the correct populations of neurons after transplantation as do rat and mouse fetal cells), and function (they integrate into the brain and alleviate motor and cognitive deficits) in the rodent models validated in the preceding programmes.
Selected recent publications
- Döbrössy MD, Dunnett SB (2006) The effects of lateralised training on spontaneous forelimb preference, lesion deficits and graft mediated functional recovery after unilateral striatal lesions in rats. Exp Neurol 199: 373-383.
- Dunnett SB, Rosser AE (2006) Cell transplantation for Huntington's disease. Should we continue? Brain Res Bull in press.
- Dunnett SB, White A (2006) Striatal grafts alleviate bilateral striatal lesion deficits in operant delayed alternation in the rat. Exp Neurol 199: 479-489.
- White A, Dunnett SB (2006) Fronto-striatal disconnection disrupts operant delayed alternation performance in the rat. NeuroReport 17: 435-441.
- Döbrössy MD, Dunnett SB (2005) Optimising plasticity: environmental and training associated factors in transplant-mediated brain repair. Rev Neurosci 16: 1-21.
- Döbrössy MD, Dunnett SB (2005) Training specificity, graft development and graft mediated functional recovery in a rodent model of Huntington's disease. Neuroscience 132: 543-552.
- Dunnett SB, Meldrum A, Muir JL (2005) Frontal-striatal disconnection disrupts cognitive performance of the frontal-type in the rat. Neuroscience 155: 1055-1065.
- Mazzocchi-Jones D, Döbrössy MD, Dunnett SB (2005) Striatal grafts and synaptic plasticity. In: The Basal Ganglia VIII (Bolam JP, Ingham CA, Magill PJ, eds), pp 313-320. New York: Springer.
- Döbrössy MD, Dunnett SB (2004) Environmental enrichment affects striatal graft morphology and functional recovery. Eur J Neurosci 19: 159-168.
- Fricker-Gates RA, White A, Gates MA, Dunnett SB (2004) Striatal neurons in striatal grafts are derived from both post-mitotic cells and dividing progenitors. Eur J Neurosci 19: 513-520.
- Fricker-Gates RA, Muir JL, Dunnett SB (2004) Transplanted hNT cells ('LBS neurons') in a rat model of Huntington's disease: good survival, incomplete differentiation and no functional recovery. Cell Transplant 13: 123-136.
- Döbrössy MD, Dunnett SB (2003) Motor training affects recovery of function after striatal lesions and grafts. Exp Neurol 184: 184-194.
- Hurelbrink CB, Tyers P, Armstrong RJE, Dunnett SB, Barker RA, Rosser AE (2003) Long-term hibernation of human fetal striatal tissue does not adversely affect its differentiation in vitro or graft survival: implications for clinical trials in Huntington's disease. Cell Transplant 12: 687-695.
- Döbrössy MD, Dunnett SB (2001) The influence of environment and experience on neural grafts. Nat Rev Neurosci 2: 871-879.
- Dunnett SB, Brasted PJ (2001) An operant analysis of fronto-striatal function in the rat. In: Methods of Behavioral Analysis in Neuroscience (Buccafusco J, ed), pp 201-229. Totowa, N.J.: Humana.
- Fricker-Gates RA, Lundberg C, Dunnett SB (2001) Neural transplantation: restoring complex circuitry in the striatum. Rest Neurol Neurosci 19: 119-138.
- Meldrum A, Dunnett SB, Everitt BJ (2001) Role of corticostriatal and nigrostriatal inputs in malonate-induced striatal toxicity. NeuroReport 12: 89-93.
- Armstrong RJE, Watts C, Svendsen CN, Dunnett SB, Rosser AE (2000) Survival, neuronal integration and fibre outgrowth of propagated human neural precursor grafts in an animal model of Huntington's disease. Cell Transplant 9: 55-64.
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