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PubMed1985

Early stages in the formation of the cerebellum in the frog.

The formation of the cerebellum was studied during the first 6 months of the tadpole stage of the bullfrog by using standard histological methods and reconstructions from serial horizontal sections. Three major developmental phases were noted in the formation of the cerebellum. (1) During the first 5 weeks of development, the neuroepithelium proliferated and the dorsal mesencephalic plates increased in size. (2) Starting in the sixth week, a patch of neuroepithelium began to differentiate and gave rise to a small population of Purkinje cells. In subsequent weeks, the area of differentiation continued to spread and a Purkinje cell layer became established along the dorsal margin of the cerebellar plate. (3) In the 12th week, the ventrolateral part of the cerebellar plate began to increase in size and generate two populations of small cells. The lateralmost part of the neuroepithelium in this area generated a group of cells that formed an external granular layer that was one cell deep. Cells of this external granular layer migrated inward into the primitive molecular layer, and by the 26th week only a remnant of an external granular layer remained in the cerebellum. The more medially situated part of the neuroepithelium gave rise to another population of small cells that formed a column, which appeared to be continuous with the Purkinje cells, but differed from them in size. It should be noted that full maturation of the cerebellum occurs during metamorphosis, which in this species remains some 2 years away.

Animals↗
PubMed1985

Multiple vibrissae sensory regions in rat cerebellum: a (14C) 2-deoxyglucose study.

Repetitive tactile sensory stimulation of the right mystacial vibrissae (whiskers) was performed in awake, adult rats. Regions of increased (14C) 2-deoxyglucose (2DG) uptake were mapped autoradiographically in cerebellum. Predominantly ipsilateral activation of multiple discrete granule cell regions occurred in paramedian lobule, crus 2, crus 1, lobulus simplex, and anterior lobe hemisphere. Bilateral and contralateral activation of cerebellum did occur. Multiple small patches, as well as large granule cell regions, were activated. Mossy fiber afferents from the spinal trigeminal nuclei (particularly interpolaris), principal trigeminal sensory nucleus, and superior colliculus could account for metabolic activation of the granular layer. The slight metabolic activation of the molecular layer could have occurred from climbing or parallel fibers. Comparisons of the paramedian lobule granule cell regions activated during repetitive sensory stimulation of the vibrissae (RSSV) to those activated during vibrissae motor cortex stimulation (VMIS) showed regions only activated by RSSV, regions only activated by VMIS, and regions activated by both RSSV and VMIS. The granule cell regions activated during RSSV and VMIS were usually adjacent to or overlapping each other. Regions only activated during RSSV or only during VMIS could represent technical problems in trying to compare vibrissae motor and sensory pathways in two different groups of animals. Alternatively, cerebellar regions activated only during RSSV could process vibrissae tactile inputs. Regions activated only during VMIS could process vibrissae motor and perhaps proprioceptive sensory input. Regions activated during both RSSV and VMIS might process vibrissae proprioceptive sensory input and/or might represent loci where vibrissae motor, proprioceptive sensory, and tactile sensory convergence occur. The results raise the possibility that vibrissae motor, proprioceptive sensory, and tactile sensory pathways could be processed in separate granule cell patches in parts of cerebellum and in the same granule cell patches in other parts of cerebellum.

Afferent Pathways↗
PubMed1986

Observations on the cerebellum of normal-reeler mutant mouse chimera.

The normal-reeler chimera mouse (+/+ in equilibrium with rl/rl) provides an experimental system in which an analysis of the migration of immature neurons in the cerebellum can be accomplished. In the present study, five chimera mice were produced from embryos of the wild-type control (C57Bl/6N) and the reeler mutant mouse (BALB/c) by the aggregation technique. The isozyme pattern of glucosephosphate isomerase (GPI) revealed that the brain tissue in the chimera contained both isozymes of the BALB/c (reeler) and C57Bl/6N (normal) strains, implying that internal mosaicism of the cerebellum truly existed. We found no abnormality in the cerebellum of the chimera mouse: the neuronal and glial subpopulations revealed no difference from those of the control. Such normalization of the cerebellum in the chimera suggests that the disturbance of neuronal migration in the reeler is attributable to an abnormal cell-to-cell interaction between migrating young neurons and the radial glial cells.

Animals↗
PubMed1988

Distribution of cells projecting to thalamus vs. those projecting to cerebellum in subdivisions of the dorsal column nuclei in raccoons.

To learn the distribution of cells projecting to the thalamus, as opposed to the cerebellum, in the mechanosensory nuclei of the dorsal medulla of raccoons, we analyzed the retrograde transport of horseradish peroxidase from the ventrobasal complex of the thalamus and from the cerebellum. We found six nuclear regions projecting heavily to the thalamus with very small projections to the cerebellum: Bischoff's, central cuneate, central gracile, rostral cuneate, rostral gracile nuclei, and cell group z. Two regions showed heavy projections to the cerebellum with no projections to the thalamus: the lateral portion of the external cuneate nucleus and the compact portion of cell group x. Four regions showed more equivalent projections to both target regions: basal cuneate, medial portion of the external cuneate nucleus, medial tongue extension of the external cuneate nucleus, and reticular portion of cell group x. Three more ventral regions were labeled: lateral cervical nucleus from thalamic injections but not from cerebellar injections; central cervical nucleus from cerebellar injections, which crossed the midline, but not from thalamic injections; and lateral reticular nucleus from both target regions. In most medullary regions, most cells project to one target and very few project to the other; we suggest that the cells projecting to the minor target convey samples of the information going to the major target.

Animals↗
PubMed1989

Distribution of corticotropin-releasing factor in the cerebellum and precerebellar nuclei of the cat.

The present study analyzes the distribution of corticotropin-releasing factor-immunoreactive (CRF-IR) fibers and neuronal cell bodies within the cerebellum and brainstem, respectively, of the cat. Within the cerebellum, CRF is present in climbing fibers, mossy fibers, and a population of varicose fibers which traverses the lower molecular layer. CRF-IR fibers are present throughout all lobules of the cat cerebellar cortex, though the density and immunostaining intensity of each fiber system vary. Bands of intensely immunoreactive climbing fibers are prominent within the vermis, intermediate cortex, and crus II. Bands of intensely immunoreactive mossy fiber terminals accompany the climbing fiber bands within the vermis. Collaterals of climbing and mossy fibers contribute to a beaded fiber plexus localized to the Purkinje cell layer. Varicose fibers containing CRF immunoreactivity are present in all deep cerebellar nuclei. CRF-IR neuronal cell bodies are prominent within several brainstem nuclei known to project to the cerebellum: all divisions of the inferior olivary complex, the lateral reticular nucleus, paramedian reticular nucleus, gigantocellular reticular nucleus, raphe nuclei, perihypoglossal complex, medial and inferior vestibular nuclei and cell groups f and x, locus ceruleus, and nucleus subceruleus. This study confirms and extends a previous study of CRF distribution within cerebellar afferent systems of the cat (Cummings et al.: J. Neurosci. 8:543-554, '88) and compares this distribution with previous descriptions in other species. The ubiquitous distribution of CRF throughout the cat cerebellum suggests a primary role for this peptide in signal transduction.

Animals↗
PubMed1991

Effect of thyroid deficiency on glial fibrillary acidic protein (GFAP) and GFAP-mRNA in the cerebellum and hippocampal formation of the developing rat.

The concentrations of glial fibrillary acidic protein (GFAP) and its encoding mRNA in the cerebellum and hippocampal formation were assayed during the development of normal and hypothyroid rats. Neonatal hypothyroidism induced a significant reduction in the GFAP concentration in both regions from day 14. The reduction was especially marked on day 35 in the cerebellum (-43%) and the hippocampal formation (-55%). The immunocytochemical study of vimentin showed that the developmental disappearance of this protein from the Bergmann and internal astrocytes is greatly delayed in the cerebellum of the hypothyroid rats. The reduction in GFAP concentration together with the delayed vimentin-GFAP transition could explain how astrocyte morphogenesis is impaired by neonatal thyroid deficiency. The GFAP-mRNA concentration in the hippocampal formation was reduced throughout the development of thyroid-deficient rats, while the GFAP-mRNA concentration in the cerebellum first increased between birth and day 14 to reach a peak well above the normal value (+78%) and decreased thereafter to reach 53% of the normal value by day 35. This transient increase in the cerebellar GFAP-mRNA concentration may be related to the astroglial hyperplasia that occurs in these animals. The difference between the developmental profile of GFAP and its encoding mRNA, especially under pathological conditions, indicates that two distinct mechanisms control the synthesis or stability of the protein and its messenger RNA, as was previously found in the forebrain of the developing normal rat.

Animals↗
PubMed1995

Strongly GD3+ cells in the developing and adult rat cerebellum belong to the microglial lineage rather than to the oligodendrocyte lineage.

A recent study has shown that ramified microglia in the adult rat optic nerve express the ganglioside GD3 [Wolswijk Glia 10:244-249, 1994], thereby raising the possibility that some GD3+ in the developing rat central nervous system (CNS) belong to the microglial lineage rather than to the oligodendrocyte lineage, as previously thought. To examine this possibility, sections of postnatal and adult cerebellum were double-labelled with markers for rat microglia [the B4 isolectin derived from Griffonia simplicifolia (GSI-B4), the ED1 monoclonal antibody (mAb), and the OX-42 mAb] and anti-GD3 mAbs (the mAbs R24 and LB1). These immunolabellings showed that ramified microglia as well as amoeboid microglia are strongly GD3+ in vivo. Moreover, most, if not all, cells that express high levels of GD3 in sections of developing cerebellum appear to belong to the microglial lineage. These observations contradict previous suggestions that the strongly GD3+ cells in the putative white matter regions of the developing brain are oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells; the cells that give rise to oligodendrocytes in the CNS. The present study did, however, confirm that some O-2A progenitor cells in sections of postnatal cerebellum are weakly GD3+ in vivo. Amoeboid microglia are present in areas of the developing cerebellum where newly generated oligodendrocytes are found, suggesting that these cells play a role in the phagocytosis of the large numbers of oligodendrocytes that die as part of CNS development.

Age Factors↗
PubMed2003

Involvement of the cerebellum in semantic discrimination: an fMRI study.

We investigated, using functional magnetic resonance imaging (fMRI), whether semantic discrimination, an inner linguistic task without overt articulation, can elicit activation in the cerebellum. Six subjects performed three semantic tasks with different loads of discrimination while being scanned. All three semantic tasks activated distributed brain areas, including the right posterior inferior cerebellum. Much stronger activation was found in the cerebellum in more difficult tasks, in terms of the activation volume and signal intensity. These results suggest that the cerebellum activation is involved in semantic discrimination and is modulated by discrimination difficulty.

Adult↗
PubMed2001

Mitochondrial impairment in the cerebellum of the patients with progressive supranuclear palsy.

Abnormalities in energy metabolism and oxidative stress accompany many neurodegenerative diseases, including progressive supranuclear palsy (PSP). Previously, we showed decreased activities of a mitochondrial enzyme complex, alpha-ketoglutarate dehydrogenase complex (KGDHC), and marked increases in tissue malondialdehyde levels in post-mortem superior frontal cortex from the patients with PSP. The current study demonstrates that KGDHC is also significantly diminished (-58%) in the cerebellum from patients with PSP (n = 14), compared to age-matched control brains (n = 13). In contrast to cortex, markers of oxidative stress, such as malondialdehyde, tyrosine nitration or general protein carbonyl modification, did not increase in cerebellum. Furthermore, the protein levels of the individual components of KGDHC did not decline. The activities of two other mitochondrial enzymes were measured to determine whether the changes in KGDHC were selective. The activity of aconitase, a mitochondrial enzyme with an iron/sulfur cluster, is also significantly diminished (-50%), whereas glutamate dehydrogenase activity is unchanged. The present results suggest that the interaction of metabolic impairment and oxidative stress is region-specific in PSP brain. In cerebellum, reductions in KGDHC occur in the absence of increases in common measures of oxidative stress, and may underlie the metabolic deficits and contribute to pathological and clinical manifestation related to the cerebellum in patients with PSP.

Aconitate Hydratase↗
PubMed1997

Role of the striatum, cerebellum, and frontal lobes in the learning of a visuomotor sequence.

This study was designed to examine the role of the striatum, cerebellum, and frontal lobes in the implicit learning of a visuomotor sequence. The performance of patients with idiopathic Parkinson's disease (PD), with damage to the cerebellum, or with a circumscribed lesion to the frontal lobes was thus compared to that of separate groups of matched normal control subjects on an adapted version of the Repeated Sequence Test. This paradigm consists of a visual reaction-time task with a fixed embedded sequence of finger movements to be performed based on presentation of visual stimuli. Subjects received four blocks of trials (i.e., 40 presentations of a 10-item sequence) per day over 6 training days. Following the last experimental session, subjects were also given two tests measuring their declarative knowledge of the sequence. Only PD patients with a bilateral striatal-dysfunction or patients with lesions to the cerebellum failed to improve their performance in the last three training sessions, hence suggesting an impairment late in the acquisition process. Further analyses revealed that such impairment was mainly implicit in nature, and that it could not be ascribed to a general decline in cognitive functioning, to mood disturbances, or to the severity of the motor symptoms. By contrast, the level of declarative knowledge of the sequence did not differ between the three clinical groups and their respective groups of normal subjects. These findings suggest that, unlike declarative memory, the incremental acquisition of a new visuomotor skill depends upon the integrity of both the striatum and the cerebellum, but not of the frontal lobes.

Adult↗
PubMed2002

Pontocerebellar axon guidance: neuropilin-1- and semaphorin 3A-sensitivity gradients across basilar pontine nuclei and semaphorin 3A variation across cerebellum.

To assess the role of semaphorin 3A (Sema3A) and its receptor component neuropilin-1 (Npn-1) in pontocerebellar axon guidance, we compared the distributions of Sema3A, Npn-1, and DiI-labeled pontocerebellar axons in neonatal mouse cerebellum. Between embryonic day 18 and birth there was a large increase in Npn-1 expression in the basilar pontine nuclei (BPN), the major source of pontocerebellar axons. Sema3A expression in cerebellum also increased at this time. In the BPN, Npn-1 and the response of axons to Sema3A were graded with high Npn-1 and Sema3A responsiveness rostrally and lower levels caudally. The Npn-1 gradient was not smooth and cells with higher and lower expression were interspersed. Between birth and postnatal day 5, pontocerebellar axons projected to lobules of the hemispheres, including those with low to moderate levels of Sema3A, but did not enter regions with high levels of Sema3A, including the flocculus and much of the vermis. These results suggest that varying neuropilin levels on BPN axons, which correlated with their varying responses to Sema3A, combined with varying Sema3A levels across cerebellum, may contribute to guiding subsets of BPN axons to their distinct target regions within cerebellum.

Animals↗
PubMed1999

Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space.

We have prepared an atlas of the human cerebellum using high-resolution magnetic resonance-derived images warped into the proportional stereotaxic space of Talairach and Tournoux. Software that permits simultaneous visualization of the three cardinal planes facilitated the identification of the cerebellar fissures and lobules. A revised version of the Larsell nomenclature facilitated a simple description of the cerebellum. This atlas derived from a single individual was instrumental in addressing longstanding debates about the gross morphologic organization of the cerebellum. It may serve as the template for more precise identification of cerebellar topography in functional imaging studies in normals, for investigating clinical-pathologic correlations in patients, and for the development of future probabilistic maps of the human cerebellum.

Cerebellum↗
PubMed2001

The cerebellum and parietal cortex play a specific role in coordination: a PET study.

The synthesis of complex, coordinated movements from simple actions is an important aspect of motor control. Lesion studies have revealed specific brain areas, particularly the cerebellum, to be essential for a variety of coordinated movements, and lend support to the view that the cerebellum is engaged in the integration of simple movements into compound ones. A PET study was therefore conducted to show which brain areas were active specifically during the coordinated execution of an arm and finger movement to visual targets. A two-by-two factorial design was employed, in which subjects either made arm or finger movements alone, made coordinated arm-finger movements, or made no movements. Voxels were identified where activity was significantly greater during the execution of coordinated movements than when movements were made alone and in which this increased activity could not be accounted for simply by the additive effects of the activations for each movement in isolation. The behavioral results showed that subjects coordinated arm and finger movements well during coordination scans. Coordination-specific activations were found in left anterior lobe and bilaterally in the paramedian lobules of the cerebellum. These are known to receive forelimb-specific spinocerebellar proprioceptive inputs that may be related to multijoint movements. The same areas also receive corticocerebellar afference from motor areas that may convey efference copy information to the cerebellum. Coordination-specific activations were also seen in areas of the posterior parietal cortex. The results provide direct evidence in healthy human subjects of specific cerebellar engagement during the coordination of movement, over and above the control of constituent movements.

Adult↗
PubMed1994

Selective loss of the 180-kDa form of the neural cell adhesion molecule in hippocampus and cerebellum of the adult mouse following trimethyltin administration.

The neural cell adhesion molecule (NCAM), a membrane glycoprotein which plays critical roles in cell-cell recognition and in the maintenance of cytoarchitecture in the adult brain, may be modulated in response to injury. To determine whether neurotoxic insult alters the profile of NCAM expression, adult female Balb/c mice were given a single injection of trimethyltin chloride (TMT; 3.2 mg/kg ip) and killed 4 hr to 3 weeks later. Hippocampus and cerebellum were isolated and prepared for light microscopy or SDS-PAGE and immunoblot analysis using the monoclonal antibody 5B8, which recognizes the intracellular domains of the 140- and 180-kDa isoforms of NCAM. NCAM140 appeared unaffected in TMT-treated mice at all time points. In contrast, decreased intensity of the 180-kDa band was apparent in both hippocampus and cerebellum 4 hr after TMT administration; maximal loss of NCAM180 was seen in hippocampal immunoblots 8 to 64 hr after treatment. The decrease in NCAM180 followed a similar but less pronounced course in cerebellum. Recovery of the 180-kDa band in hippocampus and cerebellum was apparent around 64 hr and continued until NCAM180 of mice killed 3 weeks after treatment resembled that of controls. No change in glial fibrillary acidic protein was seen by immunoblot analysis, suggesting that the effect is selective for neurons. TMT-induced loss of NCAM180 may be a direct cytotoxic effect, or may represent a reactive neuronal response to injurious stimuli. In either case, loss of NCAM180 accompanies cell injury following toxicant exposure and may be related to cytoskeletal alterations and destabilization of cellular contacts.

Animals↗
PubMed1993

Obstructed migration of Purkinje cells in the developing cerebellum of the reeler mutant mouse.

It has been considered that cortical malformation in the brain of the reeler mutant mouse is due to a defect in the process of neuroblast migration during development. We examined the process of Purkinje cell migration in the cerebellar primordium of the reeler mutant immunohistochemically and electron-microscopically, employing a specific marker for Purkinje cells and markers for radial glia. To facilitate the recognition of the homozygote of the reeler mutation (r1) at the embryonic stage, we introduced the chromosome carrying the autosomal semi-dominant mutation, hammer-toe (Hm), by crossbreeding and backcross into the heterozygote of the reeler mutation, which is an autosomal recessive and located on the homologous chromosome. Using this double heterozygous strain (+/rl-Hm/+), the homozygote of rl can be selected from littermates by the normal appearance of the feet. Both the heterozygous rl embryos and non-carriers harbor the Hm locus and show the Hm phenotype as a deformity of the feet that can be recognized from the 15th day of gestation. In the cerebellar primordium of control mice, Purkinje cells migrated radially from the ventricular zone towards the cortex. In contrast, most of the migratory Purkinje cells remained in the intermediate zone, and their migration towards the cortex was obstructed in the cerebellum of the reeler mutant. A disorganized arrangement of both the processes and cell bodies of the radial glia was demonstrated in the cerebellar primordium of the reeler by labeling them with the antibody against tenascin, a neuron-glial adhesion molecule, and the monoclonal antibody 1D11, a marker for immature astroglia. Electron-microscopic observations revealed apposition of the migratory cells to the radially oriented glial processes in the intermediate zone of the control cerebellum. In contrast, the apposition of leading processes of the migratory neuroblasts to disorganized processes of the radial glia was observed in the intermediate zone of the reeler cerebellum. These findings suggest that the obstructed migration and disordered cortical alignment of Purkinje cells in the reeler cerebellum is due to dysgenesis and abnormal development of radial glia, resulting in disturbance of contact guidance in the process of Purkinje cell migration.

Animals↗
PubMed1993

The distribution of amyloid plaques in the cerebellum and brain stem in Down's syndrome and Alzheimer's disease: a light microscopical analysis.

The distribution and severity of the neuropathological changes in 57 cases of Alzheimer's disease, and 11 patients with Down's syndrome were investigated with reference to the cerebellum. A modified silver stain and a monoclonal antibody raised against amyloid beta-protein were used to identify amyloid plaques. The highest incidence of amyloid plaques in the cerebellum (93%) was found in the group of patients who developed dementia before 65 years of age. This figure dropped to 56% in those patients with dementia beginning after 75 years. In 37 of these cases the distribution of the pathological changes of the disease were also examined in the brain stem. The severity of the pathological changes in the cerebellum corresponded to the involvement of the brain stem nuclei with connections to the cerebellar cortex. The possibility that the disease process spreads to the cerebellum by involving the fibres from the brain stem is discussed with reference to previous anatomical and neurochemical studies.

Adult↗
PubMed1981

Distribution of the LETS protein (fibronectin) in rat cerebellum. An in vitro and in vivo developmental study.

The distribution of the large, external, transformation-sensitive (LETS; fibronectin) protein was investigated in rat cerebellum, both in vitro and in vivo, by biochemical and immunocytochemical methods. Biochemical analyses indicated that LETS protein is not demonstrable on the surfaces of cerebellar neurons from postnatal rats maintained in cell culture for varying periods of time, but is present on the surfaces of at least some fraction of the total nonneuronal cell population in vitro. Indirect immunofluorescence microscopy with an anti-LETS antiserum substantiated these observations and further indicated that LETS-bearing cells of cerebellum maintained in vitro are probably of endothelial and fibroblastic origin. The LETS protein is arranged in a reticular network of filaments spanning the surfaces of the cells, and the filaments are often extensively interdigitated with each other. At all stages of development investigated (two days postnatal to adult) LETS antigen was observed in vivo to be primarily localized in the meninges covering the surface of the cerebellum and between folia, and in the walls of blood vessels within the tissue. Neuroblasts and neurons of the external and internal granule layers of the cerebellum, respectively, were negative for the presence of LETS antigen.

Animals↗
PubMed1990

Distribution of acid phosphatase and beta-glucuronidase in the hypoplastic cerebellum of jaundiced Gunn rats. An enzyme histochemical study.

Activities of acid phosphatase and beta-glucuronidase in the cerebella of young jaundiced (j/j) and non-jaundiced (j/+; control) Gunn rats were studied with the enzyme histochemical method. The cerebellum of j/+ rats showed high acid phosphatase activities in Purkinje cells and neurons in the cerebellar nuclei. In j/j rats, a number of neurons were lost and numerous microglialike cells with a high acid phosphatase activity appeared in the hypoplastic cerebellum. Although beta-glucuronidase activity was rarely detected in the control cerebellum, a high enzyme activity was observed associated with microglialike cells in j/j rats. The present results provide a cytological basis for the reported differential increase in the activities of these lysosomal enzymes in the j/j rat cerebellum.

Acid Phosphatase↗