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S B Dunnett

Publications and source records attributed to S B Dunnett.

At least 19 recordsLinked to original sources
PubMed2006

Selective extra-dimensional set shifting deficit in a knock-in mouse model of Huntington's disease.

People with early-stage Huntington's disease have been found to have a specific deficit in performing an extra-dimensional shift. To date no evidence of this deficit has been identified in transgenic or knock-in rodent models of the disease. The aim of the present paper then, was to test whether homozygous knock-in mice derived from the Hdh(CAG(150)) mouse line were impaired in any of five 2-choice discrimination tasks (simple, compound, compound reversal, intra-dimensional shift and extra-dimensional shift), and whether these mice were impaired at recalling these tasks on the following day. On the extra-dimensional shift task the Hdh(CAG(150)) homozygous mice required a greater number of trials to reach criteria than mice and the percentage of correct choices within the trials was also significantly reduced compared with the animals. For the recall tasks, a deficit for recalling the compound reversal test was found in the Hdh(CAG(150)) homozygous mice for both number of trials required to reach criteria and percentage of correct choices within the trials. Recall for the intra-dimensional shift task was also impaired in these animals when measured by the percentage of correct choices. Our results demonstrate a pronounced deficit in the Hdh(CAG(150)) mice not only on extra-dimensional shift performance in agreement with human studies, but also on recall tasks for both the compound reversal and the intra-dimensional shift tasks.

Animals↗
PubMed2006

Neural transplantation in Huntington's disease: the NEST-UK donor tissue microbiological screening program and review of the literature.

Neural transplantation of human fetal tissue for Huntington's disease (HD) is now entering the clinical arena. The safety of the procedure has now been demonstrated in a number of studies, although the efficacy of such an approach is still being investigated. Stringent but practicable screening of the donor tissue for potential pathogens is an essential prerequisite for successful implementation of any novel transplant program that uses human fetal tissue. In this article we summarize the UK-NEST protocol for the screening of human fetal tissue being grafted to patients with mild to moderate HD. We describe the results of microbiological screening of 87 potential tissue donors in a pilot study, and of the first four donor-recipient patients included in the UK-NEST series. The rationale for the adoption and interpretation of the various tests is described and our methodology is compared with those previously used by other centers. This article therefore presents a comprehensive, logical yet pragmatic screening program that could be employed in any clinical studies that use human fetal tissue for neurotransplantation.

Brain Tissue Transplantation↗
PubMed2005

Delivery of sonic hedgehog or glial derived neurotrophic factor to dopamine-rich grafts in a rat model of Parkinson's disease using adenoviral vectors Increased yield of dopamine cells is dependent on embryonic donor age.

The poor survival of dopamine grafts in Parkinson's disease is one of the main obstacles to the widespread application of this therapy. One hypothesis is that implanted neurons, once removed from the embryonic environment, lack the differentiation factors needed to develop the dopaminergic phenotype. In an effort to improve the numbers of dopamine neurons surviving in the grafts, we have investigated the potential of adenoviral vectors to deliver the differentiation factor sonic hedgehog or the glial cell line-derived neurotrophic factor GDNF to dopamine-rich grafts in a rat model of Parkinson's disease. Adenoviral vectors containing sonic hedgehog, GDNF, or the marker gene LacZ were injected into the dopamine depleted striatum of hemiparkinsonian rats. Two weeks later, ventral mesencephalic cell suspensions were prepared from embryos of donor ages E12, E13, E14 or E15 and implanted into the vector-transduced striatum. Pre-treatment with the sonic hedgehog vector produced a three-fold increase in the numbers of tyrosine hydroxylase-positive (presumed dopaminergic) cells in grafts derived from E12 donors, but had no effect on E13-E15 grafts. By contrast, pre-treatment with the GDNF vector increased yields of dopamine cells in grafts derived from E14 and E15 donors but had no effect on grafts from younger donors. The results indicate that provision of both trophic and differentiation factors can enhance the yields of dopamine neurons in ventral mesencephalic grafts, but that the two factors differ in the age and stage of embryonic development at which they have maximal effects.

Adenoviridae↗
PubMed2005

Frontal-striatal disconnection disrupts cognitive performance of the frontal-type in the rat.

The prefrontal cortex is considered to provide executive control of response selection and planning in diverse cognitive tasks, translated into action via descending subcortical projections (or 'loops') through the basal ganglia. We have used a disconnection strategy to demonstrate first that bilateral fronto-striatal disconnection disrupts rats' abilities to perform delayed alternation, the classic test of prefrontal function in rats and monkeys, and second that crossed unilateral cortical and striatal lesions on opposite sides similarly disrupt rats' abilities to perform the same cognitive task. We found that effective disconnection requires interruption of interhemispheric transfer, achieved by transection of the anterior corpus callosum. This produces a moderate deficit in its own right, which is not exacerbated by additional prefrontal and striatal lesions in one hemisphere. Conversely, the animals are significantly more impaired after crossed prefrontal and striatal lesions of similar total magnitude. The results demonstrate than an intact cortico-striatal pathway is necessary to sustain performance on a classical prefrontal task, and provide a model within which to assess circuit reconstruction with novel cell therapies for brain repair.

Animals↗
PubMed2005

In vivo transgene expression from an adenoviral vector is altered following a 6-OHDA lesion of the dopamine system.

We have investigated the in vivo dynamics of an adenovirus-based, LacZ expressing vector, RAd36, at different doses, when injected unilaterally into the corpus striatum of normal rats. We have further investigated the characteristics of this vector in the presence of a 6-OHDA lesion of the nigrostriatal pathway. The dopamine-depleting lesion had an effect on both the number and the distribution of cells transduced by the adenoviral vector. The lesioned side of the brain contained significantly greater numbers of beta-galactosidase positive cells than the unlesioned side at 3 days, 1 week and 4 weeks post-injection and the distribution of transduced cells was altered by the presence of a dopamine lesion. We conclude that the increased levels of transgene expression seen in the lesioned hemisphere are due to a change in the diffusion characteristics of the injected vector in the lesioned hemisphere. These results indicate that, when investigating the use of virus-based vectors, ultimately for use in gene therapies in the CNS, the in vivo dynamics of the vector need to be assessed not only in the normal brain, but also in the pathological brain state such as animal models of target diseases.

Adenoviridae↗
PubMed2005

Training specificity, graft development and graft-mediated functional recovery in a rodent model of Huntington's disease.

Neuronal function and morphology are affected by the environment and the behavioral experience. Here we report on the effects of differential training protocols on the development and the functional recovery mediated by intrastriatal striatal grafts. Rats were trained exclusively on the left or the right paw to perform on the skilled staircase task before being lesioned unilaterally in the dorsal striatum with quinolinic acid. E15 whole ganglionic eminence suspension grafts were implanted into the lesioned striatum. Subsequent testing probed unilateral performance of the affected contralateral paw, as well as bilateral performance. The grafted animals were initially as impaired as the lesioned, but partially recovered their performance with additional training. Grafted animals with appropriate previous experience initially performed better on the staircase test, but the advantage was transient. Furthermore, the grafted animals performed better with their affected paw under forced choice than under conditions when both paws were simultaneously probed. Improvements of the grafted animals were also observed on tests of forelimb akinesia and asymmetry. Morphological data suggest that the training conditions influenced the development specifically of striatal-like, but not of non-striatal like, neurones within the grafts. The grafts were smaller containing less striatal-like neurones in animals that were trained on the contralateral side prior to lesioning and grafting. The results support the hypothesis that unilateral training sensitizes the striatum that subserves the motor learning, leading to exacerbated excitotoxic lesions and to an environment less conducive for graft development.

Animals↗
PubMed2005

Behavioural profiles of inbred mouse strains used as transgenic backgrounds. II: cognitive tests.

One of the characteristic manifestations of several neurodegenerative diseases is the progressive decline in cognitive ability. In order to determine the suitability of six mouse strains (129S2/Sv, BALB/c, C3H/He, C57BL/6j, CBA/Ca and DBA/2) as transgenic background strains, we investigated the performance on a variety of tasks designed to identify subtle changes in cognition. In addition, a test of exploratory behaviour was used to probe the level of underlying anxiety in these mouse strains, as anxiety can be a confounding factor on behavioural performance generally. The C3H/He mice exhibited the least anxiogenic behavioural profile spending most time on the open arms of the maze, in contrast to the 129S2/Sv mice which spent the least amount of time in this location and were the quickest to move into a closed arm. The C3H/He mouse strain failed to acquire a visual discrimination task and failed to demonstrate learning on a water maze spatial learning task, in contrast to the CBA/Ca, DBA/2 and C57BL/6j strains which demonstrated a degree of learning in both tasks. No significant strain differences were identified on the object recognition task. These data, taken together, suggest that care must be taken when choosing cognitive tasks to be used with particular mouse strains and that task sensitivity must be considered as a critical element to research protocols with regard to these mouse strains.

Analysis of Variance↗
PubMed2004

Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons.

The pathological significance of intracellular Abeta accumulation in vivo is not yet fully understood. To address this, we have studied transgenic rats expressing Alzheimer's-related transgenes that accumulate Abeta intraneuronally in the cerebral and hippocampal cortices but do not develop extracellular amyloid plaques. In these rats, the presence of intraneuronal Abeta is sufficient to provoke up-regulation of the phosphorylated form of extracellular-regulated kinase (ERK) 2 and its enzymatic activity in the hippocampus while no changes were observed in the activity or phosphorylation status of other putative tau kinases such as p38, glycogen synthase kinase 3, and cycline-dependent kinase 5. The increase in active phospho-ERK2 was accompanied by increased levels of tau phosphorylation at S396 and S404 ERK2 sites and a decrease in the phosphorylation of the CREB kinase p90RSK. In a water maze paradigm, male transgenic rats displayed a mild spatial learning deficit relative to control littermates. Our results suggest that in the absence of plaques, intraneuronal accumulation of Abeta peptide correlates with the initial steps in the tau-phosphorylation cascade, alterations in ERK2 signaling and impairment of higher CNS functions in male rats.

Amyloid beta-Peptides↗
PubMed2004

Complement regulatory proteins are expressed at low levels in embryonic human, wild type and transgenic porcine neural tissue.

Allotransplantation of human foetal neural tissue for neurodegenerative disorders has been shown to provide clinical benefit but is limited by a number of issues including donor supply. The use of porcine foetal tissue as an alternative source of cells is being investigated but xenotransplants survive poorly as a result of immunological rejection, which may involve complement. In this study we investigated the expression of the membrane-bound complement regulatory proteins--decay accelerating factor (DAF), membrane co-factor protein (MCP) and CD59 in embryonic neural tissue. Cells were derived from human foetuses, wild-type porcine foetuses and porcine foetuses transgenic for human complement regulatory proteins and analysed using flow cytometry and immunocytochemistry. Functional assessment of human complement regulatory protein expression in transgenic porcine tissue was assessed by C3b deposition and cell survival on exposure to human complement. Human and wild-type porcine foetal neural tissue expressed moderate levels of MCP and CD59 but low or no levels of DAF. Neural tissue from porcine foetuses transgenic for human MCP (E174) expressed the transgene but failed to significantly inhibit human C3b deposition compared with non-transgenic tissue. In contrast, foetal neural tissue from two different human DAF transgenic pig lines (A74 and E71) known to express high levels of human DAF on endothelial cells, failed to express significant levels of human DAF in foetal neural tissue. Complement regulatory proteins such as MCP and CD59 are expressed in the human and wild-type embryonic brain but in contrast, DAF is expressed at very low levels. Pigs transgenic for human DAF express very low levels of human DAF on embryonic neural tissue. In pigs transgenic for human MCP, the transgene is expressed at similar levels to that in human embryonic neural tissue but at an insufficient level to prevent activation of the complement cascade. Thus alternative approaches to reducing complement activation by xenografted neural foetal tissue will be required if this process proves to be important in the rejection process.

Animals↗
PubMed2004

Behavioural profiles of inbred mouse strains used as transgenic backgrounds. I: motor tests.

One of the characteristic manifestations in several neurodegenarative diseases is the loss of voluntary motor control and the development of involuntary movements. In order to determine the suitability of six mouse strains as transgenic background strains we investigated performance on a variety of tasks designed to identify subtle changes in motor control. On both the accelerating and the staggered speed rotarod all six mouse strains performed well. However, latency to fall from the rod was sensitive to both rotarod speed and repeated exposure to the apparatus. Performance of the DBA/2 mouse strain was highly variable across the time points used. On the acoustic startle test CBA mice showed the greatest degree of reactivity to the acoustic startle stimuli with both the C57 and DBA showing the least. Complex strain differences were also identified on measures of habituation to the startle stimuli and variations in the prepulse noise level, and prepulse/startle delay. Gait analysis using the footprint test did not reveal strain differences on measures of base width, overlap or stride length but the 129S2/Sv strain took significantly longer to traverse the runway than the other mouse strains. Finally, the swim tank test detected complex strain differences in swim speed, and the number of fore- and hindpaw paddles required to swim the length of the tank. These data taken together suggest that choice of background strain is a crucial consideration for the repeated behavioural assessment of motor deficits in transgenic mouse models of disease.

Acoustic Stimulation↗
PubMed2003

The role of pretraining on skilled forelimb use in an animal model of Huntington's disease.

After a unilateral striatal lesion, animals have generally been seen to have a bilateral impairment in paw reaching, with the contralateral paw being more affected. However, most studies to date have not used a pretraining paradigm to assess maximal capacity for paw reaching, to compare with any lesion-induced loss. This study compared animals that were pretrained with naive animals in their ability to paw reach after a striatal lesion, to address the role of the striatum in either acquisition or execution of this motor task. All lesioned animals showed a significant decrease in reaching ability with their contralateral paw compared with the ipsilateral paw. Pretrained lesioned animals showed a clear lesion deficit with the contralateral paw immediately after lesion, and no impairment whatsoever with the ipsilateral paw. Naive lesioned animals showed delayed acquisition of the task with both paws, possibly due to postural deficits, and a lasting deficit on the contralateral side. The variability of performance between animals was higher in the naive lesioned group. These results suggest that animals should be pretrained on the staircase task prior to lesion to enable maximum sensitivity in detecting both loss and recovery of function of skilled forelimb use.

Animals↗
PubMed2003

Staging and preparation of human fetal striatal tissue for neural transplantation in Huntington's disease.

Transplantation of human fetal central nervous system tissue has been shown to be of benefit in Parkinson's disease, and is currently being explored as a therapeutic option in Huntington's disease. The success of a neural transplant is dependent on a number of factors, including the requirement that donor cells are harvested within a given developmental window and that the cell preparation protocols take account of the biological parameters identified in animal models. Although many of the criteria necessary for a successful neural transplant have been defined in animal models, ultimately they must be validated in human studies, and some issues can only ever be addressed in human studies. Furthermore, because neural transplantation of human fetal tissue is limited to small numbers of patients in any one surgical center, largely due to practical constraints, it is crucial that tissue preparation protocols are clearly defined and reproducible, so that (i) multicenter trials are possible and are based on consistent tissue preparation parameters, and (ii) results between centers can be meaningfully analyzed. Here we describe the preparation of human fetal striatum for neural transplantation in Huntington's disease, and report on the validation of a method for estimating the developmental stage of the fetus based on direct morphometric measurements of the embryonic tissue.

Algorithms↗
PubMed2002

Alpha Gal is widely expressed in embryonic porcine stem cells and neural tissue.

Fetal porcine neural xenografts are an alternative to human fetal tissue for cell based treatments of a number of neurodegenerative conditions but are currently limited by host immunological rejection. The expression of a major immunological epitope, Galalpha1-3Galbeta1-4GlcNAcbeta-R (alphaGal) was determined on stem cells and primary cells derived from E26 porcine fetal brains. alphaGal was detected on the majority of neural stem cells and cells from primary cell suspensions. The expression of this epitope paralleled the binding of human IgG and IgM to the cells, a binding that was significantly reduced with anti-alphaGal depleted human serum. This study demonstrates that alphaGal expression is extensive in embryonic porcine neural cells and will be of relevance to any clinical trials using this tissue.

Animals↗
PubMed2002

Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475.

OBJECTIVES: Huntington's disease (HD) is an inherited autosomal dominant condition in which there is a CAG repeat expansion in the huntingtin gene of 36 or more. Patients display progressive motor, cognitive, and behavioural deterioration associated with progressive cell loss and atrophy in the striatum. Currently there are no disease modifying treatments and current symptomatic treatments are only partially effective in the early to moderate stages. Neural transplantation is effective in animal models of HD and offers a potential strategy for brain repair in patients. The authors report a safety study of unilateral transplantation of human fetal striatal tissue into the striatum of four patients with HD. SUBJECTS AND METHODS: Stereotaxic placements of cell suspensions of human fetal ganglionic eminence were made unilaterally into the striatum of four patients with early to moderate HD. All patients received immunotherapy with cyclosporin A, azathioprine, and prednisolone for at least six months postoperatively. Patients were assessed for safety of the procedure using magnetic resonance imaging (MRI), regular recording of serum biochemistry and haematology to monitor immunotherapy, and clinical assessment according to the Core Assessment Protocol For Intrastriatal Transplantation in HD (CAPIT-HD). RESULTS: During the six month post-transplantation period, the only adverse events related to the procedure were associated with the immunotherapy. MRI demonstrated tissue at the site of implantation, but there was no sign of tissue overgrowth. Furthermore, there was no evidence that the procedure accelerated the course of the disease. CONCLUSIONS: Unilateral transplantation of human fetal striatal tissue in patients with HD is safe and feasible. Assessment of efficacy will require longer follow up in a larger number of patients.

Adult↗
PubMed2001

Differential effects of unilateral striatal and nigrostriatal lesions on grip strength, skilled paw reaching and drug-induced rotation in the rat.

Lateralised motor deficits associated with basal ganglia dysfunction were compared in separate groups of rats receiving unilateral 6-hydroxydopamine-induced lesions of the dopaminergic nigrostriatal pathway, quinolinic acid-induced lesions of the striatum, or sham control injections. Amphetamine induced ipsilateral rotation in both lesion groups, whereas a low ('supersensitive') dose of apomorphine induced rotation only in the nigrostriatal lesion group. Both lesions induced impairments in skilled paw reaching with the contralateral paw in the 'staircase' test; by contrast the striatal lesions also induced a marked impairment with the ipsilateral paw, which was unaffected by the nigrostriatal lesion. A previously reported increase in grip strength with the contralateral paw after nigrostriatal lesion was replicated, whereas striatal lesions induced only minor bilateral deficits in this test. The results are discussed in the context of the utility, reliability and validity of alternative tests of motor deficit in animal models of Parkinson's and Huntington's diseases.

Amphetamine↗
PubMed2001

Role of corticostriatal and nigrostriatal inputs in malonate-induced striatal toxicity.

The striatal neuronal loss evident following cellular metabolic compromise may be dependent upon the presence of glutamate and dopamine within the striatum. In order to investigate the relative roles of corticostriatal and nigrostriatal projections in malonate-induced neuronal loss, the extent of toxicity was quantified in animals with cortical lesions to deplete the striatum of glutamate, nigrostriatal lesions to deplete the striatum of dopamine, or both. We found that malonate-induced striatal toxicity was significantly reduced following lesions of either the glutamatergic or dopaminergic afferents to the striatum. The extent of attenuation following the loss of both inputs within the same animal was similar to that seen following lesions of either alone. These data suggest that malonate-induced toxicity in the striatum depends upon the integrity of interactive influences from both glutamatergic and dopaminergic afferents.

Adrenergic Agents↗
PubMed2001

The staircase test of skilled reaching in mice.

The "staircase" test has become established for measurement of side-specific deficits in coordinated paw reaching in rats, and has been shown to reveal impairments on the contralateral side following unilateral lesions in a wide range of motor structures of the brain. As mice become more widely used in behavioural neuroscience, we have scaled down the staircase reaching test for application to this latter species. We here validate the test in C57BL/6J mice by (a) establishing the optimal dimensions of the apparatus, (b) comparing the effects of test parameters including sex, test duration, levels of deprivation and alternative reward pellets, and (c) demonstrating contralateral deficits after aspirative lesions of the motor cortex. Differences between mice and rats in normal performance of the task are noted. The staircase test provides a simple objective test of skilled motor function that allows measurement of lateralised effects without unduly constraining the animal, and which may prove as useful for mice as has previously been demonstrated in rats.

Animals↗