Only $2.99/month

TE - Neuro Roberton

Terms in this set (37)

The present study aimed to produce a detailed longitudinal characterization of the neuronal pathology in the YAC128 transgenic mouse brain, to determine the similarity of this mouse model to other mouse models and the human condition in the spatial and temporal deposition pattern of the mutant protein fragments. Brain samples were taken from mice aged between 4 and 27 months of age, and assessed using S830 and GFAP immunohistochemistry, stereology and electron microscopy. Four month old mice did not exhibit intra-nuclear or extra-nuclear inclusions using the S830 antibody. Diffuse nuclear staining was present in the cortex, hippocampus and cerebellum from 6 months of age onwards. By 15 months of age, intra-nuclear inclusions were visible in most brain regions including nucleus accumbens, ventral striatum, lateral striatum, motor cortex, sensory cortex and cerebellum. The ventral striatum had a greater density of inclusions than the dorsal striatum. At 15 and 24 months of age, the mice showed increased reactive astrogliosis in the cortex, but no differences were found in the striatum. Necrotic cell death with vacuolation, uneven cell membrane and degenerated Golgi apparatus were detected ultrastructurally at 14 months of age, with some cells showing signs of apoptosis. By 26 months of age, most cells were degenerated in the transgenic animals, with lipofuscin granules being more abundant and larger in these mice than in their wildtype littermates. Our results demonstrate a progressive and widespread neuropathology in the YAC128 mice line that shares some similarity to the human condition.
Environmental enrichment (EE) and exercise have been implicated in influencing behaviour and altering neuronal processes associated with cellular morphology in both 'normal' and injured states of the CNS. Using a rodent model of Huntington's disease, we investigated whether prolonged EE or involuntary exercise can induce morphological and cellular changes within embryonic striatal transplants. Adult rats were trained on the Staircase test - requiring fine motor control to reach and collect reward pellets - prior to being lesioned unilaterally in the dorsal neostriatum with quinolinic acid. The lesioned animals received E15 whole ganglionic eminence cell suspension grafts followed by housing in EE or standard cages. Half of the animals in standard cages received daily forced exercise on a treadmill. The grafted animals showed significant functional recovery on both the Staircase test and in drug-induced rotation. Neither the housing conditions nor the training had an impact on the behaviour, with the exception of the treadmill reducing the ipsilateral drug-induced rotation observed amongst the lesioned animals. However, the animals housed in the EE had significantly increased striatal brain-derived neurotrophic factor (BDNF) levels, and graft neurons in these animals exhibited both greater spine densities and larger cell volumes. Animals on forced exercise regime had reduced BDNF levels and grafted cells with sparser spines. The study suggests that the context of the animal can affect the plasticity of transplanted cells. Appropriately exploiting the underlying, and yet unknown, mechanisms could lead the way to improved anatomical and potentially functional integration of the graft.
Although Parkinson's disease has traditionally been considered as a motor disorder1,2, there has been much recent interest in the nature and the neural substrates of parkinsonian dementia3,4 and cognitive dysfunction4. These disabilities, which can induce visuospatial impairment5 and visual 'neglect'6, may also have a bearing on the controversy about the normal functions of the nigrostriatal dopamine (DA) projection and the basal ganglia2,7-9. The observations that neurones in both substantia nigra and striatum respond to sensory events in terms of neuronal firing10,11 or DA release12,13, also suggest a role for striatum in sensorimotor integration. An important behavioural correlate of this integration is the 'sensorimotor neglect' syndrome14 in animals with unilateral lesions of the nigrostriatal projection who fail to orient to contralateral sensory events. However, this neglect may arise not from contralateral sensory inattention14,15, but from an inability to express this sensory selection via motor output. We present here two lines of evidence that unilateral striatal DA depletion in the rat does not affect sensory attention to visual signals of reward, but rather impairs the initiation (though not the completion) of contralateral motor acts. These results not only help to clarify the function of the nigrostriatal DA projection, but also show that depletion in this system is linked specifically to a process of response initiation, which may be the fundamental impairment in Parkinson's disease.
Experimental therapies for Parkinson's disease (PD) are commonly validated in unilateral animal models using simple tests of motor asymmetry such as rotation, stepping and cylinder tests. However, the human disorder is considerably more complex than this, and alternative tests that permit a more complete evaluation of the efficacy and mechanism of action of novel treatments are needed. In this study, an operant task that assesses the selection, initiation and execution of lateralized movements was used to investigate the effects of embryonic dopamine cell transplants in the unilateral medial forebrain bundle (MFB) lesion model of PD. Lesioned Lister Hooded rats had a pronounced contralateral selection and initiation deficit, as well as an impairment in execution of movements bilaterally. They also attempted fewer trials and made more procedural errors than unlesioned rats. Transplantation of fetal dopaminergic neurons to the striatum led to a marked improvement in specific parameters and a more modest improvement in others. The graft improved the contralateral selection deficit and the execution of movements bilaterally, but had no effect on the initiation of contralateral movements. Transplanted rats also attempted more trials and made fewer errors. In contrast, the more commonly used stepping and cylinder tests revealed no functional effect of the graft. This data suggests that this operant task may be a powerful tool for validating and elucidating the mechanism of action of experimental brain repair therapies prior to entering the clinic.
Huntington's disease (HD) is a debilitating, genetically inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioral changes manifest as a range of motor, cognitive, and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold standard rWGE grafts, against the clinically relevant hWGE grafts, on a range of behavioral tests of motor function. Lister hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested postlesion and postgraft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test, and vibrissae-evoked touch test. At 21 weeks postgraft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilized behavioral performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products.
Huntington's disease (HD) produces severe neurodegeneration in the striatum leading to disabling motor impairments, including the loss of control of skilled reaching movements. Fetal GABAergic transplants can physically replace the lost striatal cells but with only partial success in functional recovery. Here, we aimed to determine the extent and quality of the repair produced by fetal cell transplantation through an in-depth analysis of reaching behavior in the quinolinic acid-lesioned rat model of HD. Control, quinolinic acid-lesioned plus sham graft, and quinolinic acid-lesioned plus graft groups of rats were assessed in skilled reaching performance prior to and following lesion surgery and 3 months following injection of 400,000 fetal whole ganglionic eminence-derived cells into the striatum. This was compared to their performance in two more rudimentary tests of motor function (the adjusting step and vibrissae-evoked hand-placing tests). Grafted rats demonstrated a significant improvement in reaching success rate (graft +59%, shamTX +3%). Importantly, the quality of reaching behavior, including all components of the movement, was fully restored with no identifiable differences in the normal behavior shown by control rats. Postmortem immunohistochemical examination verified the survival of large intrastriatal grafts, and Fluoro-Gold tracing indicated appropriate outgrowth to the globus pallidus. Our study illustrates for the first time the detailed analysis of qualitative improvement of motor function following brain repair in a rat model of HD. The results demonstrate significant improvements not only in gross movements but also in the skilled motor patterns lost during HD. Fetal GABAergic cell transplantation showed a demonstrable ability to restore motor function to near normal levels, such that there were few differences from intact control animals, an effect not observed in standard tests of motor function.