Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153640 (Cerebellum)
 1,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of treatment with reserpine (5 mg.kg-1, s.c., 24 h prior to sacrifice) or 6-hydroxydopamine (6-OHDA; 250 mg.kg-1, s.c., for 4 days, one week before sacrifice) on the content of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) were compared in a variety of tissues from the guinea-pig. Reserpine and 6-OHDA treatment markedly reduced the NA content of all peripheral organs investigated. Reserpine treatment also caused depletion of the content of NPY-LI in larger blood vessels and in organs containing mainly perivascular nerves. Furthermore, reserpine treatment depleted NPY-LI in the heart, spleen and adrenal gland. In other organs dominated by parenchymal adrenergic innervation such as genital organs (vas deferens, uterus) or iris, treatment with 6-OHDA but not reserpine caused significant depletions of NPY-LI. The urinary bladder and gastrointestinal tract seem to be mainly innervated by non-adrenergic NPY-containing neurons resistant to reserpine and 6-OHDA treatment. The content of NPY-LI was elevated in sympathetic ganglia after reserpine treatment while no increase in axonal transport occurred in the sciatic nerve. Cerebellum was the only studied area in the central nervous system where the NPY content was depleted by reserpine or 6-OHDA treatment suggesting presence of NPY-LI in perivascular nerves. The reserpine-induced depletion of NPY-LI in the spleen, kidney and skeletal muscle was prevented by preganglionic denervation. This suggests that enhanced nerve impulse discharge in sympathetic nerves caused a situation where NPY release exceeded the amount which could be replaced by axonal transport.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reserpine-induced depletion of neuropeptide Y in the guinea-pig: tissue-specific effects and mechanisms of action. 312 15

A neuropathological study was performed on two patients with Salla disease, one male and one female, from different families. They both died at the age of 41 years. Both patients showed increased excretion of free sialic acid in the urine, psychomotor retardation starting in the 1st year of life, ataxia and spasticity. Several family members of both families were affected with the same disease indicating the hereditary character of the disorder. The neuropathological investigation revealed strikingly similar changes in the two cases. Macroscopically the cerebral white matter was severely reduced. Histologically marked loss of axons and myelin sheaths was accompanied by pronounced astrocytic proliferation. The remaining axons frequently showed ovoid swellings surrounded by a myelin sheath. The reduction of the number of myelin sheaths seemed proportional to the numerical reduction of axons. Many cortical nerve cells displayed in relation to age an abnormal amount of lipofuscin. Neurofibrillary tangles were observed in nerve cells of the neo-cortex, nucleus basalis of Meynert and locus ceruleus. Cerebellum showed moderate loss of Purkinje cells. In the spinal cord axonal degeneration was observed in both ascending and descending tracts.
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PMID:Neuropathology of Salla disease. 328 34

Diisopropyl phosphorofluoridate (DFP) produces organophosphorus-ester induced delayed neurotoxicity (OPIDN) in the hen, human and other sensitive species. We studied the effect of single dose of DFP (1.7 mg/kg/s.c.) on the expression of alpha tubulin which is one of the major sub-unit of tubulin polymers that constitute an important constituent of cellular architecture. The hens were sacrificed at different time points i.e. 1, 2, 5, 10, and 20 days. Total RNA was extracted from the following brain regions: cerebrum, cerebellum, and brainstem as well as spinal cord. Northern blots prepared using standard protocols were hybridized with alpha tubulin as well as with beta-actin and 28S RNA cDNA (controls) probes. The results indicate a differential/spatial/temporal regulation of alpha tubulin levels which may be the result of perturbed microtubule dynamics not only in the axons but also in perikarya of neurons in the CNS of DFP treated hens. In the highly susceptible tissues like brainstem and spinal cord the initial down-regulation of mRNA levels could be attributed to DFP induced stress response resulting in inhibited cell metabolism and or cell injury/cell death. Increase in levels of mRNA at 5 days and thereafter coincided with increased tubulin transport which may be due to increased phosphorylation of tubulins in both axons and perikarya and other intraaxonal changes resulting in impaired axonal transport. DFP induced decreased rate of tubulin polymerization resulting in increased levels of free tubulin monomers may be involved in the altered alpha tubulin mRNA expression at different time points by autoregulatory circuits. Cerebellum being the less susceptible tissue showed only a moderate decline at day 2, while the alpha tubulin remained at near control levels at day 1. Delayed down-regulation may be due to the co-ordinated up or down-regulation of different sub-types of alpha and beta tubulins as well as the differential response of specialised cell types in cerebellum. Continuous overexpression of alpha tubulin in cerebrum from the beginning may be its effective protective strategy to safeguard itself from neurotoxicity. Differential expression pattern observed could be due to the differential susceptibility and variability in the rate of axonal transport of different regions besides the tubulin heterogenity of CNS. Hence our results indicte differential expression of alpha tubulin is either one of the reasons for the development of OPIDN or the result of progressive changes taking place during OPIDN.
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PMID:Altered time course of mRNA expression of alpha tubulin in the central nervous system of hens treated with diisopropyl phosphorofluoridate (DFP). 1135 81

The climbing fiber input to the cerebellum is crucial for its normal function but those factors which control the development of this precisely organized pathway are not fully elucidated. The neurotrophins are a family of peptides, which have many roles during development of the nervous system, including the cerebellum. Since the cerebellum and inferior olive express neurotrophins and their receptors, we propose that neurotrophins are involved in the regulation of climbing fiber development. Here we review the temporo-spatial expression of neurotrophins and their receptors at key ages during climbing fiber development and then examine evidence linking neurotrophins to climbing fiber development, including some of the intracellular pathways involved. During prenatal development the expression of neurotrophins in the hindbrain coupled with their function in neurogenesis and migration, is consistent with a role of NT3 in inferior olivary genesis. Subsequently, cerebellar expression of two neurotrophins, NT3 and NT4, is concurrent with olivary receptor expression and the time of olivary axonal outgrowth and this continues postnatally during early climbing fiber synaptogenesis on Purkinje cells. The expression-pattern of neurotrophins changes with age, with falling NGF, NT3 and NT4 but increasing granule cell BDNF. Importantly, olivary expression of neurotrophin receptors, and therefore climbing fiber responsiveness to neurotrophins, falls specifically during maturation of the climbing fiber-Purkinje cell synapse. The function of BDNF is less certain, but experimental studies indicate that it has a role in climbing fiber innervation of Purkinje cells, particularly synaptogenesis and synaptic plasticity. Its importance is highlighted by the overlap of BDNF signalling with several cellular pathways, which regulate climbing fiber maturation. From the data presented, we propose not only that neurotrophins are involved in climbing fiber development, but also that several act in a specific temporal order.
Cerebellum 2002 Dec
PMID:Climbing fiber development: do neurotrophins have a part to play? 1287 65

The somatotopical organization of the climbing fiber input to the paravermal region of lobulus simplex (LS, lobule Vla) was charted in the cerebellar cortex of anaesthetized rats. From medial to lateral in LS, zones a2, c1, c2 and c3 were identified. Forelimb responses were found in both LS and the paramedian lobule (PML) and simultaneous recordings from the c1 zone in both lobules showed that trial-by-trial fluctuations in climbing fiber field size evoked by ipsilateral forelimb stimulation did not occur in synchrony, suggesting that the two parts of the same zone are not closely linked by their climbing fiber input. Electrophysiological mapping in combination with a double fluorescent axonal tracing strategy (mix of Fluoro-Emerald and green beads, and mix of Fluoro-Ruby and red beads) revealed that the two parts of the c1 zone receive climbing fiber input from similar territories in the medial and dorsal accessory olives, but that only 4% of the total population of labelled cells have axons that branch to supply climbing fiber afferents to both regions of cortex. The corticonuclear output of the two parts of the zone was found in mainly overlapping regions of the transitional region between the anterior and posterior divisions of nucleus interpositus. Overall, the results suggest that the olivocerebellar and corticonuclear projections of cerebellar zones are similarly organized in rat and cat, implying that the function of individual zones is conserved between species.
Cerebellum 2002 Jul
PMID:Structure-function relations of two somatotopically corresponding regions of the rat cerebellar cortex: olivo-cortico-nuclear connections. 1287 79

Spatial localization and axonal branching in mossy fiber projections to two rostrocaudally-separated regions of the 'forelimb' c1 zone in lobulus simplex and paramedian lobule were studied in rats using a retrograde double-labelling tracer technique. In four animals the two cortical regions were localized electrophysiologically and each was micro-injected with tracer material, yielding a total of eight different cases. Single- and double-labelled cell bodies were plotted in the basal pontine nucleus (BPN), nucleus reticularis tegmenti pontis (NRTP), and the lateral reticular nucleus (LRN). As a control, cells labelled in the contralateral inferior olive were also counted. The parts of the c1 zone in lobulus simplex and the paramedian lobule were found to receive mossy fiber inputs from similar regions of BPN, NRTP and LRN. Double-labelled cells were not found in NRTP but were present in BPN and LRN (on average 6% and 25% of the smaller single-labelled population, respectively). The incidence of double-labelled cells in the olive and LRN was positively correlated, but no relation was found between olive and BPN, suggesting a zonal organization within the mossy fiber projections from LRN, but not from the pons. In quantitative terms, the c1 zone in lobulus simplex received a greater density of mossy fiber projections from BPN, NRTP and LRN than the c1 zone in the paramedian lobule. This suggests that the two parts of the same cerebellar cortical zone differ, at least partially, in regard to their inputs from three major sources of mossy fibers. This is consistent with the modular hypothesis and could enable a higher degree of parallel processing and integration of information within different parts of the same zone.
Cerebellum 2002 Jul
PMID:Pontine and lateral reticular projections to the c1 zone in lobulus simplex and paramedian lobule of the rat cerebellar cortex. 1287 80

Prion protein (PrP(c)) is a cell membrane glycoprotein particularly abundant in the synapses. Prion diseases are characterized by the replacement of the normal PrPc by a protease-resistant, sheet-containing isoform (PrP(CJD), PrP(Sc), PrP(BSE)) that is pathogenic. Creutzfeldt-Jakob disease (CJD) in humans, scrapie (Sc) in sheep and goats, and bovine spongiform encephalopathy (BSE) in cattle are typical prion diseases. Classical CJD can be presented as sporadic, infectious or familial, whereas the new variant of CJD (nvCJD) is considered a BSE-derived human disease. Spongiform degeneration, glial proliferation, involving astrocytes and microglia, neuron loss and abnormal PrP deposition are the main neuopathological findings in most human and animal prion diseases. Yet recent data point to synapses as principal targets of abnormal PrP deposition. Loss of synapses is an early abnormality in experimental scrapie. Decreased expression of crucial proteins linked to exocytosis and neurotransmission, covering synaptophysin, synaptosomal-associated protein of 25,000 mol wt (SNAP-25), synapsins, syntaxins and Rab3a occurs in the cerebral cortex and cerebellum in sporadic CJD. Moreover, impairment of glomerular synapses and attenuation of parallel fiber pre-synaptic terminals on Purkinje cell dendrites is a cardinal consequence of abnormal PrP metabolism in CJD. Accumulation of synaptic proteins in the soma and axonal torpedoes of Purkinje cells suggests additional impairment of axonal transport. Increase in nuclear DNA vulnerability leading to augmented numbers of cells bearing nuclear DNA fragments is a common feature in the brains of humans affected by prion diseases examined at post-mortem, but also in archival biopsy samples processed with the method of in situ end-labeling of nuclear DNA fragmentation. This form of cell death is reminiscent of apoptosis found in experimental scrapie in rodents. It is not clear that all forms of cell death in human and animal prion diseases are due to apoptosis. Yet new observations have shown cleaved (active) caspase-3 (17 kDa), a main executioner of apoptosis, expressed in scattered cells in the brains of mice with experimental scrapie and in the cerebellum of patients with sporadic CJD. Together, these data suggest activation of the caspase pathway of apoptosis in human and animal prion diseases.
Cerebellum 2002 Jul
PMID:Synaptic pathology and cell death in the cerebellum in Creutzfeldt-Jakob disease. 1287 83

Presynaptic terminals occur along unmyelinated axons in specialized compartments called axonal varicosities or synaptic boutons. Since the first descriptions of varicose axons by Cajal and others, the spatial organization of varicosities along axons has attracted the attention of neuroscientists. Quantitative light- and electron-microscopic analyses of varicosity spacing in the cerebellum and elsewhere have recently provided a clearer picture of this organization, and theoretical analyses now incorporate varicosity spacing as an essential parameter in structural models of neural connectivity. Here we review the salient features of varicosity spacing, with emphasis on cerebellar parallel fibers as a model system. Measured globally across the entire approximately 5 mm lengths of parallel fibers, the overall mean spacing of varicosities is 5.2 microm. Measured locally, however, mean spacing follows a proximodistal gradient, increasing with distance from the point of bifurcation from the ascending axon. Measured at the level of individual varicosities, parallel fiber varicosity distributions follow a distinct pattern characterized by a fixed relationship between the spacing variability and mean. This pattern equally describes varicosity distributions in a number of other brain regions, and therefore appears to constitute a general scaling relationship for excitatory varicose axons. We further discuss evidence for common principles underlying the placement of both varicosities and synapses along axons.
Cerebellum 2003
PMID:Axonal varicosity distributions along parallel fibers: a new angle on a cerebellar circuit. 1288 Jan 78

Cerebellar Purkinje neurons play a significant role in the development and early maintenance of cerebellar afferent topography. Anterograde intra-axonal labeling experiments were designed to identify any role for Purkinje cells in maintaining spinocerebellar mossy fiber afferent topography in shaker mutant rats with adult onset Purkinje cell heredodegeneration. Following the death of Purkinje cells myelinated spinocerebellar axons persist and their terminal mossy fiber morphology remains normal in appearance and size. The relative percentage of labeled projections to each of the five anterior lobe lobules was comparable in mutant and normal rats. Finally, unfolded reconstructions of the anterior lobe illustrated that the organization of labeled terminals in clusters, patches and discontinuous parasagittally oriented stripes or transversely oriented bands were spatially distributed the same in both normal and mutant rats. These findings strongly infer that Purkinje cells are not necessary for the persistence and maintenance of spinocerebellar afferent pathways in adult animals.
Cerebellum 2003
PMID:Persistence of spinocerebellar afferent topography following hereditary Purkinje cell degeneration. 1288 32

The 440-kDa isoform of brain ankyrin, 440-kDa ankyrinB, is a neuron-specific protein and is confined to axons. Cerebellum is one of the areas characteristically altered by methylmercury intoxication both in the adult and during development. When rat cerebellar neurons matured for 7 days in vitro were exposed to methylmercury at 0.03 microM for 48 hr, viability of the cells was unaffected. However, the immunocytochemical staining of 440-kDa ankyrinB diminished drastically, whereas that of microtubule-associated protein-2, which is localized in dendrites and cell bodies, and of glial fibrillary acidic protein (GFAP), a marker for astroglial cells coexisting in the culture, remained unchanged. To confirm these observations, a simplified dot blot assay was established to determine 440-kDa ankyrinB and several other marker proteins in cultured cell samples. With this assay, we found that methylmercury at a submicromolar range induced a decrease of 440-kDa ankyrinB and an increase of GFAP in a dose-dependent manner in cerebellar cells in primary culture. Surprisingly, another axonal protein, tau, remained mostly in its intact molecular sizes even in the presence of 0.3-1.0 microM methylmercury, though its immunocytochemical localization was substantially altered. These results indicate that selective loss of the axonal protein 440-kDa ankyrinB is associated with the early stage of degeneration of cerebellar neurons induced by methylmercury. Therefore, 440-kDa ankyrinB should be useful as a specific and sensitive marker for the neurotoxicity of methylmercury.
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PMID:Selective disappearance of an axonal protein, 440-kDa ankyrinB, associated with neuronal degeneration induced by methylmercury. 1294 9


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