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PubMed1978

On the development of the cerebellum of the trout, Salmo gairdneri. V. Neuroglial cells and their development.

The neuroglia of the cerebellum of Salmo gairdneri Richardson, 1836, has been studied in mature and developing specimens with light and electron microscopy. The light microscopic observations were largely carried out on Golgi material. The cerebellum of the trout contains all of the neurologlial cell types described for the mammalian cerebellum, viz. ependymal cells, Golgi epithelial cells, velate protoplasmic astrocytes, smooth protoplasmic astrocytes and oligodendrocytes. In addition two types of glial elements, which combine characteristics of ependymal cells and of velate astrocytes, are found. These elements are designated as ependymoid astrocytes and astrocytoid ependymal cells. Smooth astrocytes and oligodendrocytes were observed only in later stages of development and possibly arise from the secondary matrix. The other glial cell types, as well as transitional forms between these types, are present in rather early stages, and show a similar ultrastructure. It is plausible that all these types develop from the glioblasts produced by the ventricular matrix layer. Many glial cells are radially oriented and keep in contact with the meningeal surface throughout development. The lattice formed by matrix cells in the earliest stages, and by glial cells and the axons of granule cells later on, plays a role in directing the migration of cells. Other functions of the glia, such as dividing the cerebellar cortex in synaptic compartments, are suggested. It may be concluded that the high degree of differentiation of the teleostean cerebellum is also reflected by the morphology of the neuroglia.

Animals↗
PubMed1996

Expression of neolactoglycolipids: sialosyl-, disialosyl-, O-acetyldisialosyl- and fucosyl- derivatives of neolactotetraosyl ceramide and neolactohexaosyl ceramide in the developing cerebral cortex and cerebellum.

The following neolacto glycolipids were identified and their developmental expression was studied in the rat cerebral cortex and cerebellum: Fuc alpha 1-3IIInLcOse4Cer,Fuc alpha 1-3VnLcOse6Cer and (Fuc)2 alpha 1-3III,3VnLcOse6Cer, as well as acidic glycolipids, NeuAc alpha 2-3IVnLcOse4Cer [nLM1], (NeuAc)2 alpha 2-3IVnLcOse4Cer [nLD1], O-acetyl (NeuAc)2 alpha 2-3IVnLcOse4Cer [OAc-nLD1] and their higher neolactosaminyl homologues NeuAc alpha 2-3VlnLcOse6Cer [nHM1] and (NeuAc)2 alpha 2-3VlnLcOse6Cer [nHD1]. These glycolipids were expressed in the cerebral cortex only during embryonic stages and disappeared postnatally. This loss was ascribed to the down regulation of the synthesis of the key precursor LcOse3Cer which is synthesized by the enzyme lactosylceramide: N-acetylglucosaminyl transferase. On the other hand in the cerebellum, these glycolipids increased with postnatal development due to increasing availability of LcOse3Cer. In the cerebellum, only nLM1 and fucosyl-neolactoglycolipids declined after postnatal day 10-15, perhaps due to regulation by other glycosyltransferases. Also, in the cerebellum, nLD1 and nHD1 were shown to be specifically associated with Purkinje cells and their dendrites in the molecular layer and with their axon terminals in the deep cerebellar nuclei, similar to other neolactoglycolipids shown previously.

Aging↗
PubMed1985

Developmental change of endogenous glutamate and gamma-glutamyl transferase in cultured cerebral cortical interneurons and cerebellar granule cells, and in mouse cerebral cortex and cerebellum in vivo.

The developmental change of endogenous glutamate, as correlated to that of gamma-glutamyl transferase and other glutamate metabolizing enzymes such as phosphate activated glutaminase, glutamate dehydrogenase and aspartate, GABA and ornithine aminotransferases, has been investigated in cultured cerebral cortex interneurons and cerebellar granule cells. These cells are considered to be GABAergic and glutamatergic, respectively. Similar studies have also been performed in cerebral cortex and cerebellum in vivo. The developmental profiles of endogenous glutamate in cultured cerebral cortex interneurons and cerebellar granule cells corresponded rather closely with that of gamma-glutamyl transferase and not with other glutamate metabolizing enzymes. In cerebral cortex and cerebellum in vivo the developmental profiles of endogenous glutamate, gamma-glutamyl transferase and phosphate activated glutaminase corresponded with each other during the first 14 days in cerebellum, but this correspondence was less good in cerebral cortex. During the time period from 14 to 28 days post partum the endogenous glutamate concentration showed no close correspondence with any particular enzyme. It is suggested that gamma-glutamyltransferase regulates the endogenous glutamate concentration in cultured neurons. The enzyme may also be important for regulation of endogenous glutamate in brain in vivo and particularly in cerebellum during the first 14 days post partum. Gamma-glutamyl transferase in cultured neurons and brain tissue in vivo appears to be devoid of maleate activated glutaminase.

Age Factors↗
PubMed1985

Ontogenetic development of glutamate metabolizing enzymes in cultured cerebellar granule cells and in cerebellum in vivo.

The ontogenetic development of the enzymes phosphate activated glutaminase (PAG), glutamate dehydrogenase (GLDH), glutamic-oxaloacetic-transaminase (GOT), glutamine synthetase (GS), and ornithine-delta-aminotransferase (Orn-T) was followed in cerebellum in vivo and in cultured cerebellar granule cells. It was found that PAG, GLDH, and GOT exhibited similar developmental patterns in the cultured neurons compared to cerebellum. PAG showed, however, a more pronounced phosphate activation in the cultured granule cells compared to in vivo. The activity of GS remained low in the cultured neurons compared to the increasing activity of this enzyme found in vivo. On the other hand Orn-T exhibited an increase in its specific activity in the cultured cells as a function of time in culture in contrast to the non-changing activity of this enzyme in vivo. Compared to cerebellum the cultured neurons exhibited higher activities of GLDH, GOT, and Orn-T whereas the activity of PAG was only slightly higher in the cultured cells. The activity of GS in the cultured neurons was only 5-10% of the activity in cerebellum in vivo. It is concluded that cultured cerebellar granule cells represent a reliable model system by which the metabolism and function of glutamatergic neurons can be conveniently studied in a physiologically meaningful way.

Animals↗
PubMed1985

Postnatal ontogeny of uridine kinase in the cerebellum, hypothalamus, and cerebral cortex of the rat.

Postnatal developmental patterns of uridine kinase were determined in crude subcellular fractions of the rat cerebellum, hypothalamus and cerebral cortex at ages 3 through 60 days. The highest specific activity and predominant distribution of enzyme was in the 105,000 g supernatant of the 3 brain regions. Enzyme activity in hypothalamus and cerebral cortex was maximum at 3 days and decreased with age; in cerebellum it increased through 13 days and decreased thereafter. Thus, the pattern of activity in hypothalamus and cerebral cortex paralleled changes in DNA and RNA synthesis through age 60 days; in cerebellum, it more closely approximated changes in DNA synthesis during early development. Changes in Km with aging suggest that the brain regions contain more than one form of enzyme. The highest particulate activity was in the microsomal fraction of the cerebellum and hypothalamus at all ages and in the cortex at 35 and 60 days. Relative specific activity for microsomal fractions of the brain regions at 60 days indicate a concentration of the enzyme which may be relevant in the maintenance of RNA activity in adult brain.

Age Factors↗
PubMed1991

Heterogeneity of [3H]-mepyramine binding sites in guinea pig cerebellum and lung.

The nature of histamine receptors in peripheral tissues is still controversial. However, evidence of heterogeneous classes of binding sites for [3H]-mepyramine are reported in the literature. The aim of our study was, therefore, to investigate the nature of this heterogeneity by comparing [3H]-mepyramine binding in a central tissue (cerebellum) and in a peripheral tissue (lung) obtained from guinea pigs and to assess its dependence upon the temperature of incubation. The results revealed that the [3H]-mepyramine interaction in both tissues is temperature-dependent. At 25 degrees C, the interaction between [3H]-mepyramine and the receptors was biphasic in the lung while only a single class of binding site was found in the cerebellum. At 0 degrees C, [3H]-mepyramine interacted with three binding sites in the lung and two in the cerebellum. The behaviour of the reference compounds (clemastine, promethazine and histamine) also supported this temperature-dependence. Moreover, two new compounds (DF 11062 and DF 11113), synthesized in our laboratories and endowed with antihistamine activity, can differentiate between the low affinity site seen at 25 degrees C in the lung and that seen in the cerebellum at 0 degrees C.

Animals↗
PubMed1995

Development of the brainstem and cerebellum in autistic patients.

Studies of magnetic resonance images have revealed morphological disorders of the brainstem and cerebellum in autistic children and adults. When we studied development of the brainstem and cerebellum in autistic patients, we found that although the brainstem and cerebellum significantly increased in size with age in both autistic patients and controls, these structures were significantly smaller in autistic patients than in controls. The speed of development of the pons, the cerebellar vermis I-V and the cerebellar vermis VI-VII was significantly more rapid in autistic patients than in the controls. However, the speed of development of the other brain structures in the posterior fossa did not differ between autistic patients and controls. The regression intercepts of the brainstem and cerebellum as well as those of their components were significantly smaller in autistic patients than in controls. Results suggest that brainstem and vermian abnormalities in autism were due to an early insult and hypoplasia rather than to a progressive degenerative process.

Adolescent↗
PubMedDate not supplied

Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum. Effects of amyloid beta peptide.

The biological roles of nitric oxide (NO) and cGMP as inter- and intracellular messengers have been intensively investigated during the last decade. NO and cGMP both mediate physiological effects in the cardiovascular, endocrinological, and immunological systems as well as in central nervous system (CNS). In the CNS, activation of the N-methyl-D-aspartic acid (NMDA) type of glutamatergic receptor induces Ca(2+)-dependent NOS and NO release, which then activates soluble guanylate cyclase for the synthesis of cGMP. Both compounds appear to be important mediators in long-term potentiation and long-term depression, and thus may play important roles in the mechanisms of learning and memory. Aging and the accumulation of amyloid beta (A beta) peptides are important risk factors for the impairment of memory and development of dementia. In these studies, the mechanism of basal- and NMDA receptor-mediated cGMP formation in different parts of adult and aged brains was evaluated. The relative activity of the NO cascade was determined by assay of NOS and guanylate cyclase activities. In addition, the effect of the neurotoxic fragment 25-35 of A beta (A beta) peptide on basal and NMDA receptor-mediated NOS activity was investigated. The studies were carried out using slices of hippocampus, brain cortex, and cerebellum from 3- and 28-mo-old rats. Aging coincided with a decrease in the basal level of cGMP as a consequence of a more active degradation of cGMP by a phosphodiesterase in the aged brain as compared to the adult brain. Moreover, a loss of the NMDA receptor-stimulated enhancement of the cGMP level determined in the presence of cGMP-phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was observed in hippocampus and cerebellum of aged rats. However, this NMDA receptor response was preserved in aged brain cerebral cortex. A significant enhancement of the basal activity of NOS by about 175 and 160% in hippocampus and cerebellum, respectively, of aged brain may be involved in the alteration of the NMDA receptor response. The neurotoxic fragment of A beta, peptide 25-35, decreased significantly the NMDA receptor-mediated calcium, and calmodulim-dependent NO synthesis that may then be responsible for disturbances of the NO and cGMP signaling pathway. We concluded that cGMP-dependent signal transduction in hippocampus and cerebellum may become insufficient in senescent brain and may have functional consequences in disturbances of learning and memory processes. A beta peptide accumulated during brain aging and in Alzheimer disease may be an important factor in decreasing the NO-dependent signal transduction mediated by NMDA receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1976

Resting and reactive macrophages in the developing cerebellum: an experimental ultrastructural study.

The whole heads of 6 days old rats were exposed to 150R of X-ray irradiation to induce cell-death in the external granular layer of the cerebellum. The animals were sacrificed in a developmental sequence, and the tissue obtained from the cerebellum was prepared for electron microscopy. On the basis of the cytological criteria established for the macrophages in the cerebellum of the normal animals, characteristics of the resting and reactive macrophages and their transformation from one state to the other in the experimental animals are described. In their reactive state the macrophages showed hypertrophic and nuclear changes which were found identical to those seen in the reactive microglial elements. Issues pertaining to the ultrastructural characteristics of the macrophages, their endogenous presence in the developing cerebellum, and their transformation into the microglia cells are discussed.

Animals↗
PubMed1989

Developmental regulation of tyrosine kinase substrate p36 (calpactin heavy chain) in rat cerebellum.

The tyrosine kinase substrate p36 (calpactin heavy chain) is a calcium-dependent membrane- and cytoskeletal-binding protein. Using an affinity-purified antiserum raised against the p36 heavy chain from bovine adrenal medulla, we have examined the cellular distribution of p36 in developing and adult cerebellum. From immunoblotting, the level of p36 in cerebellum was found to decline during development. In dissociated cell cultures of P4 cerebellum, all cell types were labeled by anti-p36. In vibratome sections from cerebella of P10 rats, anti-p36 stained Purkinje cell bodies strongly and all other cell types less strongly, with the exception of cells in the external germinal layer, which were unstained. By 18 days postnatally p36 was present at higher levels in Bergmann glia and astrocytes of the white matter. In sections of adult cerebella, anti-p36 staining was restricted to Bergmann glial processes and to the processes of a subclass of astrocytes in the granular layer and the white matter. At no developmental stage was anti-p36 staining detectable in axons or dendrites in vibratome sections. These results suggest that p36 plays a role in some aspect of cellular differentiation common to all cerebellar cell types and may have additional functions in astrocytes of the adult cerebellum.

Adrenal Medulla↗
PubMed2006

Repetitive TMS of cerebellum interferes with millisecond time processing.

Time processing is important in several cognitive and motor functions, but it is still unclear how the human brain perceives time intervals of different durations. Processing of time in millisecond and second intervals may depend on different neural networks and there is now considerable evidence to suggest that these intervals are possibly measured by independent brain mechanisms. Using repetitive transcranial magnetic stimulation (rTMS), we determined that the cerebellum is essential in explicit temporal processing of millisecond time intervals. In the first experiment, subjects' performance in a time reproduction task of short (400-600 ms) and long (1,600-2,400 ms) intervals, were evaluated immediately after application of inhibitory rTMS trains over the left and right lateral cerebellum (Cb) and the right dorsolateral prefrontal cortex (DLPFC). We found that rTMS over the lateral cerebellum impaired time perception in the short interval (millisecond range) only; for the second range intervals, impaired timing was found selectively for stimulation of the right DLPFC. In the second experiment, we observed that cerebellar involvement in millisecond time processing was evident when the time intervals were encoded but not when they were retrieved from memory. Our results are consistent with the hypothesis that the cerebellum can be considered as an internal timing system, deputed to assess millisecond time intervals.

Adult↗
PubMed2001

Predicting sensory events. The role of the cerebellum in motor learning.

There is growing evidence that the cerebellum is involved in the implicit learning of movement sequences. On the serial reaction time (RT) task patients with cerebellar lesions fail to demonstrate normal decreases in RT and we have shown a similar effect in monkeys with bilateral cerebellar lesions. However, it is not clear if this impairment is unique to sequence learning or whether the cerebellum is also involved in the learning of discrete responses to predictable visual targets. We investigated this possibility in another group of monkeys with bilateral lesions of the cerebellum centred on the lateral nuclei. Three animals were pre-operatively trained to make rapid manual responses to a single target appearing on a touch-sensitive VDU screen. In one condition, a target could appear at any of three possible locations (spatially unpredictable). In a second condition the target always appeared in the same place (spatially predictable). A third condition was similar to the second except that the onset of the target was temporally predictable whereas in the previous conditions this parameter was randomized. Following the lesions, the RT savings earned on the conditions in which the cues were predictable were abolished. This was despite a lack of significant increase in movement times. The results imply that the animals were either failing to predict the spatial location or time of presentation of the target, or that they were unable to use their prediction to improve their reaction times. The function of the cerebellum in motor sequence learning may therefore be part of a more general operation in learning to prepare responses to predictable sensory events.

Animals↗
PubMed2003

A functional MRI study of somatotopic representation of somatosensory stimulation in the cerebellum.

Somatotopic representation in the cerebral cortex of somatosensory stimulation has been widely reported, but that in the cerebellum has not. We investigated the latter in the human cerebellum by functional MRI (fMRI). Using a 1.5 tesla imager, we obtained multislice blood oxygen level-dependent fMRI with single-shot gradient-echo echoplanar imaging in seven right-handed volunteers during electrical stimulation of the left index finger and big toe. In the anterior and posterior cerebellum, activated pixels for the index finger were separate from those for the toe. This suggests that somatosensory stimulation of different parts of the body may involve distinct areas of in the cerebellum as well as the cerebral cortex.

Adult↗
PubMed2003

MRI measurements of the pons and cerebellum in children born preterm; associations with the severity of periventricular leukomalacia and perinatal risk factors.

Our purpose was to measure the size of the pons and cerebellum in preterm babies with periventricular leukomalacia (PVL), and to study their relationship with the severity of PVL and with perinatal risk factors. We examined 33 premature children, mean gestational age 31 weeks, range 26-36 weeks with PVL on MRI, and 27 full-term controls. On MRI at 0.4-5.5 years (mean 1.4 years) we measured the area of the corpus callosum and vermis, the anteroposterior diameter of the pons and the volume of the cerebellum. The area of the corpus callosum was used as a marker of white matter loss and PVL severity. All regional brain measurements except that of the vermis were significantly lower in patients than controls: corpus callosum (mm(2)): 239.6+/-92.5 vs 434.8+/-126.8, P <0.01; pons (mm): 14.8+/-3.0 vs 17.9+/-1.4, P <0.01]; cerebellum (cm(3)): 68.2+/-31.6 vs 100.6+/-28.3, P <0.01; vermis (mm(2)): 808.1+/-292.2 vs 942.2+/-246.2, NS. Significant reduction in the area of the vermis: 411.3+/-203.3 vs 935+/-252.6 mm(2); cerebellar volume: 16.3+/-12.5 vs 96.6+/-20.2 mm(3); and the diameter of the pons: 10.1+/-2.2 vs 17.5+/-1.3 mm ( P<0.01) were observed in seven children with gestational age < or =28 weeks, severe hypotension and large patent ductus arteriosus (PDA). There was a significant correlation between the duration of mechanical ventilation and the size of the vermis, pons and cerebellum (R=-0.65, -0.57 and -0.73, respectively, P <0.01).

Case-Control Studies↗
PubMed1990

Effect of acute ethanol administration on the subcellular distribution of iron in rat liver and cerebellum.

An acute ethanol load (50 mmol/kg, i.p.) produced altogether a decrease in the non-heme iron content of the serum and an increase in the iron content in liver and cerebellum. Subcellular fractionation studies indicated that the non-heme iron accumulated by the liver, 4 hr after the ethanol load, was recovered in light mitochondria, microsomes and cytosol, and that iron accumulated by the cerebellum was localized in heavy mitochondria, light mitochondria, microsomes and cytosol. The low molecular weight chelatable (LMWC) iron content as well as the percentage of total non-heme iron represented by LMWC-iron were increased in the cytosol of liver and cerebellum after the ethanol load. These results suggest that an acute ethanol load induces (i) a shift in the distribution between circulating and tissular non-heme iron; (ii) an increase in the cytosolic LMWC-iron which, by favouring the biosynthesis of reactive free radicals, may contribute to lipid peroxidation in liver and cerebellum.

Animals↗
PubMed1976

The effect of 5-bromodeoxyuridine on the postnatal development of the rat cerebellum: a biochemical study.

The effect of a thymidine analog, 5-bromodeoxyuridine (BrdU), on the postnatal development of the cerebellum was studied. Rats were injected with 15 mg per 100 gram body weight of BrdU twice a day for 3 consecutive days from the second day after birth, and were killed at 5, 7, 15, 22 and 35 days of age. One hour prior to killing, the rats were given tritiated thymidine. The cerebellar DNA, RNA, protein and cerebroside, and the incorporation of thymidine were measured. BrdU administration caused a markedly retarded growth of the body and the cerebellum. At 35 days of age, the weights of the body and the cerebellum were 42 and 69% of the controls. Quantitative measurements of cerebellar nucleic acids and isotope uptake correlated well with previous morphological observation, and indicated that the analog caused a transient inhibition of cell formation and possibly destruction of stem cell population of the external granular layer. This inhibitory effect was compensated later by a more rapid DNA deposition and a prolongation of the period of cell proliferation. However, the restitution was incomplete and resulted in a permanent deficit in the final cell number, as reflected by the reduction in the size of the cerebellum of the BrdU-treated rats.

Age Factors↗
PubMed1977

The effects of postnatal hyper- and hypothyroidism on the development of D-amino acid oxidase in rat cerebellum and brain stem.

Treatment of rats with propylthiouracil for the first 30 days of postnatal life drastically retards the ontogenesis of D-amino acid oxidase in the brain stem and cerebellum. There is a marked terminal deficit of D-AAO in both the brain stem (--64%) and cerebellum (--67%) at 94 days (adults) despite the near euthyroid status at this age. If initiated early enough, thyroxine replacement therapy reverses the effects of PTU on the development of D-AAO. Hyperthyroidism significantly accelerates the development of D-AAO in both brain stem and cerebellum. Nonetheless, animals treated with thyroxine the first month of life display a net deficit of cerebellar D-AAO content in adulthood. The results are discussed in terms of the localization of D-AAO in cell types especially sensitive to thyroid hormone: (1) a cell type which is among the last to derive from the external germinal zone in the developing cerebellum, and which in the adult is located adjacent to the Purkinje cell soma; and (2) mossy fiber neurons and cerebellar glomeruli.

Animals↗
PubMed1979

Morphological identification and biochemical characterization of isolated brain cell nuclei from the developing rat cerebellum.

Cell nuclei from developing rat cerebellum were isolated and the various types of nuclei were characterized and quantified. Nuclear pellets appeared to be both quantitatively and qualitatively representative of the entire cerebellum, and of sufficient purity to perform biochemical studies as well as morphological comparison with histological sections. Isolated nuclei were classified into 6 groups based on nuclear size and shape, heterochromatin aggregations, and nucleoplasmic density. The total population of cerebellar cells primarily consisted of two types of nuclei after day 10. One group of nuclei, resembling those of internal granule neurons or external germinal cells, contributed at least 70% of the total isolated cell nuclei from day 1 to day 90, whereas another nuclear group that was identified as dark oligodendrocytes constituted 8-9% of the total population on days 45 and 90. Nuclear DNA, RNA, and protein content of the cerebellum also were determined throughout postnatal development. DNA concentration markedly declined after day 15, while the RNA/DNA ratio increased until day 3 and remained constant to day 90. The nuclear protein/DNA ratio increased from birth to day 3, decreased to its lowest value on day 10, and increased to day 90. Utilizing DNA values, the total cell population as well as contributions of different cell types were calculated. At birth the cerebellum was estimated to contain 5.9 million cells, increasing to 94 million by day 21. By day 90, 107 million cells were present, of which 8.6 million oligodendrocytes and 93.6 million internal granule cells were estimated.

Aging↗