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PubMed1981

Selective survival of beta 1-adenergic receptors in rat cerebellum following neonatal x-irradiation.

Although beta 2-adrenergic receptors predominate in adult rat cerebellum, a small number of beta 1-receptors are also present. To investigate the cellular localization of beta 1- and beta 2-adrenergic receptors, the effects of intermittent neonatal X-irradiation focused on the cerebellum were determined on the densities of the two subtypes of beta-adrenergic receptor. This treatment destroys the late-maturing cerebellar interneurons including the granule, basket and stellate cells. A 60--70% loss of cerebellar mass was observed in 2-, 6- and 12-week-old animals. The large early-maturing Purkinje cells are resistant to the effects of X-irradiation. The total number of beta-adrenergic receptors per cerebellum, measured by Scatchard analysis of saturation isotherms of specific [125I]iodohydroxybenzylpindolol (IHYP) binding, was reduced by 70--80% in 2-, 6- and 12-week-old animals. The relative proportion of beta 1- and beta 2-receptors was determined by analyzing the inhibition of specific IHYP binding by the beta 1 selective antagonist practolol. The total number of beta 2-adrenergic receptors per cerebellum was reduced by 81--83% in 6- and 12-week-old X-irradiated rats. However, the number of beta 1-adrenergic receptors per cerebellum in 6- and 12-week-old X-irradiated rats was not significantly different from that in control animals. The results suggest that beta 2 receptors in the rat cerebellum are primarily associated with the small interneurons destroyed by neonatal X-irradiation. The beta 1 receptors may be located on a cell population which is unaffected by this treatment, possibly on cerebellar Purkinje cells.

Animals↗
PubMed1985

Biochemical and immunohistochemical evidence for the presence of motilin in pig cerebellum.

The presence of motilin in rat and porcine cerebellum was investigated by using high performance liquid chromatography (HPLC) coupled with radioimmunoassay or immunohistochemistry. The antibodies used for this study were raised against synthetic gastrointestinal porcine motilin, which is, so far, the only known sequence of this peptide. The results obtained show the presence of a sharp peak of motilin-like immunoreactivity after HPLC of porcine cerebellum extracts, with an elution time corresponding to that of synthetic porcine motilin. Motilin-like immunoreactivity was also detected immunohistochemically in porcine cerebellum. However no motilin-like immunoreactivity was detected in rat cerebellum biochemically or immunohistochemically. This finding suggests that if a motilin-like neuropeptide is present in rat cerebellum, its molecular form differs from that present in porcine cerebellum.

Animals↗
PubMed1988

Serotonin concentration and turnover in cerebellum and other brain regions of pcd mutant mice.

The Purkinje cell degeneration (pcd) mutant mouse is characterized by a loss of Purkinje cells in the cerebellum. Loss of granule cells occurs and is severe in pcd mutants after 9 months of age. Since Purkinje cells and granule cells represent two groups of target cells for serotonin neurons projecting from raphe nuclei and other brain areas, the content and turnover of serotonin in the cerebellum were determined in pcd mice aged 3-15 months. The content of serotonin was not decreased in pcd mouse cerebellum but tended to be slightly increased after 7 months. The ratio of 5-hydroxyindoleacetic acid (5-HIAA) to serotonin was significantly decreased in cerebellum at 7-15 months but not at 3 or 6 months. The decrease in this ratio is indicative of decreased serotonin turnover. Similar changes were not seen in brainstem or hypothalamus in mice up to 14 months old, but slight decreases were observed at 15 months. Another index of turnover, the accumulation of 5-HIAA after administration of probenecid to block its efflux from brain, was decreased by 46% in 7-month-old pcd mice in the cerebellum but not in the brainstem or hypothalamus. The decrease in serotonin turnover in pcd mouse cerebellum occurs subsequent to and perhaps due to the loss of the target Purkinje and granule cells.

Aging↗
PubMed1978

Alteration of the activity and molecular from of thymidine kinase during development and aging in the mouse cerebellum.

Protein, DNA and thymidine kinase levels were assayed during development and aging in the mouse cerebellum. A roughly parallel increase in protein and DNA content occurred from birth, reaching a plateau at 18 days; these adult levels increased by 30% in the 23 month-old cerebellum. Thymidine kinase activity reached a maximum at 6 postnatal days, then decreased steadily to reach, at 18 days, the low level that was maintained in the adult. The thymidine kinase synthesized in the aged cerebellum differed from that in the neonate by having (i) an increased specific activity, (ii) a faster migrating species upon electrophoresis, (iii) an inhibition by dCTP, and (iv) a lower affinity for the substrate thymidine (higher Km). Mathematical calculations indicated the appearance of a larger number of smaller sized cells in the aged cerebellum, when compared with the young adult. Histological analysis established that the newly synthesized cells were localized in the molecular layer of the old cerebellum. It appears that senescence in the mouse cerebellum may be associated with an increased synthesis of glial cells.

Aging↗
PubMed1984

Differential interactions of GABA agonists, depressant and convulsant drugs with [35S]-t-butylbicyclophosphorothionate binding sites in cortex and cerebellum.

Effects of three GABA agonists, four GABA antagonists and convulsants (picrotoxinin, alpha-dihydropicrotoxinin [DHP], pentamethylenetetrazole [PTZ] and isopropylbicyclophosphate ester) and three depressant drugs (pentobarbital, (+)etomidate and etazolate) were investigated on [35S]t-butylbicyclophosphorothionate (TBPT) in cortex and cerebellum. All the convulsants tested were equipotent in inhibiting [35S]TBPT binding in cortex and cerebellum. Convulsants like picrotoxinin inhibited [35S]-TBPT binding competitively in both cortex and cerebellum. In contrast, gamma-aminobutyric acid (GABA) agonists (muscimol, GABA and 4,5,6,7-tetrahydroisoxazol[5,4-C]pyridine-3-ol [THIP]), and depressants like etazolate, (+)etomidate and pentobarbital were more potent inhibitors of [35S]TBPT binding in cerebellum than in cortex. GABA inhibition of [35S]TBPT binding appears to be mediated through a low-affinity site. GABA and pentobarbital inhibited [35S]TBPT binding in cortex and cerebellum noncompetitively. Depressants like pentobarbital appear to interact with the TBPT sites allosterically. These results suggest that depressant and convulsant drugs that modulate GABAergic transmission interact differently with the TBPT binding sites in cortex and cerebellum.

Animals↗
PubMed1983

Plasminogen activator in the developing rat cerebellum: biosynthesis and localization in granular neurons.

The histochemical localization of plasminogen activator (PA) and the level of the translatable mRNA species coding for active PA were analyzed during ontogenesis of normal and of irradiation-agranulated rat cerebellum. Autoradiographic localization of PA activity was performed by plasminogen-dependent fixation of [125I]fibrin degradation products to frozen sections of developing rat cerebellum. Both the immature external and the adult internal granular layers were intensely labeled, in addition to labeling of meninges. In the irradiation-aggranulated cerebellum, PA labeling could be observed in residual granular neurons which went through their final division prior to the irradiation protocol. The concentration of the mRNA species directing the synthesis of catalytically active PA (PAmRNA) was monitored by an in ovo bioassay, using Xenopus oocytes as a translation system. A major species of 80,000 and a minor species of 50,000 apparent molecular weight of active PA were translated by mRNA from either control or X-irradiated cerebellum throughout ontogenesis. These could be detected by electrophoretic analysis of extracts and incubation media of microinjected oocytes. Both the content and the concentration of PAmRNA were found to be the highest at the stage of cerebellar development when granular neurons proliferate and migrate. These observations suggest that a major portion of the PA activity in the rat cerebellum is synthesized and localized in granular neurons through cerebellar ontogenesis, and that PA activity in the developing cerebellum is largely determined by the level of translatable mRNA coding for this enzyme.

Animals↗
PubMed1988

Survival and development of embryonic and postnatal cerebellum transplanted into adult rat hosts: effect of growth as explants in culture prior to transplantation.

The survival and organization of embryonic and postnatal cerebellum transplanted into intracephalic cavities in adult rat hosts was studied before and after growth as explants in tissue culture. It is well known that embryonic cerebellum survives transplantation and develops a typical cerebellar cytoarchitecture. This study demonstrates that early postnatal cerebellum survives transplantation poorly if at all using the intracephalic transplant paradigm. Postnatal cerebellum is capable of extensive growth and organization in explant culture; however, prior growth in explant culture did not enhance survival in the transplant situation. On the other hand, embryonic cerebellum grown in explant culture for as long as two weeks, to an age comparable to the postnatal cerebellar transplants, survives transplantation and develops similar cytoarchitectural features to directly transplanted embryonic cerebellum.

Aging↗
PubMed1992

Abnormal expression of embryonic neural cell adhesion molecule (N-CAM) in the developing mouse cerebellum after neonatal administration of cytosine arabinoside.

We have previously found that neonatal administration of cytosine arabinoside (Ara-C) induces cerebellar malformation, including arrest of granule cell migration and destruction of glial palisade. In the present study, the expression of neural cell adhesion molecule (N-CAM) and its distribution were examined in the mouse malformed cerebellum induced by neonatal Ara-C administration. Western blot analysis demonstrated that, in the control group, the embryonic form of N-CAM (E-N-CAM) was expressed in the 7-day-old mouse (P7) cerebellum, but not in the P14 cerebellum which exhibited only the adult form of N-CAM (A-N-CAM). On the other hand, E-N-CAM was expressed in the Ara-C treated cerebellum not only at P7 but also at P14. Immunohistochemical studies revealed that E-N-CAM was observed in the area below the external granular layer (EGL) of the P7 cerebellum in both the control and Ara-C treated mice. In contrast, E-N-CAM immunoreactivity was found in the arrested EGL cells in the Ara-C treated cerebellum of P14 mice but not in the age-matched controls. Therefore, E-N-CAM was aberrantly expressed in the arrested EGL at P14. From the present and previous findings, it was speculated that the aberrant expression of E-N-CAM in the arrested EGL cells is attributed to abnormal cellular interactions, probably arrested EGL cell-to-Bergmann glia.

Animals↗
PubMed1989

In situ hybridization analysis of the somatostatin-containing neuron system in developing cerebellum of rats.

We used in situ hybridization histochemistry to examine the postnatal development of the somatostatin (SRIF) synthesizing system in the cerebellum of rats. There are numerous hybridizing neurons from 1 to 9 days after birth. These occur throughout the cerebellum including the developing medulla and cortex except in the external granular cell layer. The lateral cerebellar nucleus also contains SRIF gene-containing cells. The intensity of the signals for SRIF mRNA in the cerebellum decreases with age. There is a drastic decrease in SRIF mRNA in the lateral cerebellar nucleus. SRIF cells cannot be detected in the lateral cerebellar nucleus of adult rats, whereas a small, yet significant number of SRIF cells are scattered in the cerebellar medulla. However, the cerebellum of adult rats still contains a significant number of labeled cells in the granular cell layer, although the intensity for SRIF mRNA decreases from 14 days after birth to adulthood. SRIF gene-expressing cells in the cerebellar cortex are located primarily in the granular cell layer and appear to correspond to Golgi cells judging from their characteristic features. These results are consistent with our previous immunohistochemical study on the decrease of SRIF immunoreactivity in the cerebellum of adult rats. These findings, together with a recent study of transient SRIF receptor-expressing cells in the developing cerebellum suggest that SRIF acts during cerebellar development.

Aging↗
PubMed1985

On the location of gamma-aminobutyrate and benzodiazepine receptors in the cerebellum of the normal C3H and Lurcher mutant mouse.

Binding of gamma-aminobutyrate and benzodiazepine receptor ligands has been studied in the cerebellum of adult normal (C3H) and Lurcher mutant mice. The adult mutant has lost all Purkinje cells and more than 90% of the granule cells in the cerebellar cortex. When compared with their normal littermates Lurcher mice displayed large decreases in the number of high-affinity binding sites for [3H]muscimol, a synaptic gamma-aminobutyrate receptor ligand, in washed cerebellar homogenates. This observation was consistent with the extensive loss of gamma-aminobutyrate receptive Purkinje and granule cells from the Lurcher cerebellum. However, specific binding of the benzodiazepine-receptor ligand [3H]flunitrazepam to Lurcher cerebellum remained unchanged. Indeed quantitative autoradiography, employing [3H]flunitrazepam as a photoaffinity label, showed no significant differences in the density of labelling between Lurcher and normal littermate mice in any region of the cerebellum. These benzodiazepine binding sites in washed homogenates or tissue sections displayed a gamma-aminobutyrate-induced enhancement of [3H]flunitrazepam binding which occurred to the same extent in both Lurcher and normal cerebellum, a facilitatory effect which could be blocked by the addition of bicuculline methobromide. Our results suggest that a large proportion of the high-affinity, specific benzodiazepine binding sites in mouse cerebellum are not coupled to the synaptic gamma-aminobutyrate receptors thought to be labelled by high affinity [3H]muscimol binding. Further, that benzodiazepine binding sites do not appear to be enriched on either the soma or dendrites of Purkinje cells, as has been suggested from previous studies. Investigations at the electron microscope level are now required to elucidate the cellular location of benzodiazepine binding sites in the cerebellar cortex and to examine whether or not they are likely to be exposed to gamma-aminobutyrate in vivo.

Animals↗
PubMed1992

Quantification of 5-hydroxytryptamine1A receptors in the cerebellum of normal and X-irradiated rats during postnatal development.

5-Hydroxytryptamine1A receptors were studied in rats during the first postnatal month in the normal cerebellum and in the granule cell-deprived cerebellum produced by X-irradiation at postnatal day 5. Quantitative autoradiographic studies on sagittal sections of cerebellar vermis, using [1251]BH-8-MeO-N-PAT as radioligand or specific anti-receptor antibodies, revealed that 5-hydroxytryptamine1A receptors existed in the molecular/Purkinje cell layer but at variable density from one lobule to another. Thus, in both normal and X-irradiated rats, the posterior lobules were more heavily labelled than the anterior ones, and the density of 5-hydroxytryptamine1A sites decreased progressively in all the cerebellar folia down to hardly detectable levels at postnatal day 21. However, the intensity of labelling remained higher at postnatal day 8 and postnatal day 12 in X-irradiated rats than in age-paired controls. Measurements of [3H]8-OH-DPAT specific binding to membranes from whole cerebellum confirmed that the density of 5-hydroxytryptamine1A sites per mg membrane protein (Bmax) was higher in X-irradiated animals than in age-paired controls. However, on a "per cerebellum" basis, no significant difference could be detected between the total number of 5-hydroxytryptamine1A sites, which progressively increased in both control and X-irradiated animals during the first postnatal month. These results therefore show that 5-hydroxytryptamine1A receptors are not located on developing granule cells. The progressive decrease in 5-hydroxytryptamine1A receptor density during the first postnatal month did not reflect a transient expression of 5-hydroxytryptamine1A receptors in the cerebellum of newborn rats, but resulted from the progressive "dilution" of these sites in this growing structure. The higher density of 5-hydroxytryptamine1A sites in X-irradiated rats simply reflected a lower "dilution" due to the delayed growth of the cerebellum in these animals.

Aging↗
PubMedDate not supplied

Studies on the mechanism of sprouting of noradrenergic terminals in rat and mouse cerebellum after neonatal 6-hydroxydopa.

The effect of various pharmacologic agents on the noradrenergic innervation of rat cerebellum was observed. It was found that the neurotoxin 6-hydroxydopa (6-OHDOPA), when given to rats at birth, caused a 46% reduction at 5 weeks of age in tyrosine hydroxylase activity in the locus coeruleus, the nucleus of origin for noradrenergic fibers innervating the cerebellum. At the same time, however, both tyrosine hydroxylase activity and NE content were elevated by 50% in the cerebellum. By treating gravid mice with the 6-OHDOPA, which crosses the placental barrier to affect the brains of developing pups, a dissociation has been shown between the elevated cerebellar NE levels and reduced telencephalic NE content. None of the other assorted pharmacological agents--namely amphetamine, metaraminol, apomorphine, alpha-methyl-p-tyrosine. L-dihydroxyphenylalanine and tyramine--when given at birth, caused a permanent elevation in cerebellar NE content. This series of studies suggests that a reduced number of noradrenergic perikarya are providing a greater innervation of the cerebellum than in control rats. Also, alteration of the telencephalic noradrenergic fibers, which are also derived from the locus coeruleus, does not appear to be a necessary event for the initiation of sprouting of noradrenergic fibers in the cerebellum. Because none of the acute-acting pharmacological agents caused a permanent elevation of NE in the cerebellum, it appears that damage, and not mere stimulation or blockade, is a necessary event for initiation of sprouting.

Animals↗
PubMed1993

Visualization of taurine, GABA and glutamate in developing feline cerebellum by immunohistochemistry.

The localization of taurine, GABA and glutamate in developing feline cerebellum was performed using antibodies raised against the amino acids conjugated to bovine serum albumin with glutaraldehyde. Distinct patterns of immunostaining were observed for each of the amino acids. Taurine-like immunoreactivity reached a peak at 4 weeks after birth, as did GABA-like immunoreactivity, whereas glutamate-like immunoreactivity was greatest in the mature cerebellum. Purkinje cells are all taurine-positive in cerebellum from neonatal animals, whereas in the mature cerebellum they appear to contain only GABA and glutamate, with virtually no taurine, in contrast to observations reported with rodent cerebellum. Ultrastructural studies and immunogold labelling visualized by electron microscopy show that the band of taurine-like immunoreactivity observed in newborn feline cerebellum is localized within dendrites, axons and glial processes. Granule cells migrating through this region also show prominent taurine-like immunoreactivity.

Animals↗
PubMed1990

Calsequestrin, a component of the inositol 1,4,5-trisphosphate-sensitive Ca2+ store of chicken cerebellum.

The presence and distribution of calsequestrin (CS), Ca2+ pump, and inositol 1,4,5-trisphosphate (IP3) receptor were investigated biochemically and immunologically in microsomal (P3) fractions isolated from chicken cerebrum and cerebellum. Two different batches of polyclonal antibodies specific for chicken skeletal muscle CS identified a Ca2+ binding, CS-like protein that was extremely enriched in cerebellum P3 fractions and absent from all cerebrum fractions. The cerebellum CS-like protein was deemed authentic CS because the N-terminal amino acid domain and peptide mapping were identical to those of skeletal muscle CS in the same species. CS was detected in striated muscles and cerebellum only. Cerebellum P3 fractions were also found to be considerably enriched in Ca2+ pump and IP3 receptor compared with the homologous cerebrum fractions, as judged by measurements of Ca2+ uptake, Ca2(+)-ATPase activity, IP3-induced Ca2+ release, and [3H]IP3 binding, respectively. Cerebellum microsomal fractions therefore appear to contain membrane fragments endowed with Ca2+ pump, IP3 receptor, and CS, i.e., three key components of a Ca2+ storage organelle.

Animals↗
PubMed2006

The role of the basal ganglia and cerebellum in language processing.

The roles of the cerebellum and basal ganglia have typically been confined in the literature to motor planning and control. However, mounting evidence suggests that these structures are involved in more cognitive domains such as language processing. In the current study, we looked at effective connectivity (the influence that one brain region has on another) of the cerebellum and basal ganglia with regions thought to be involved in phonological processing, i.e. left inferior frontal gyrus and left lateral temporal cortex. We analyzed functional magnetic resonance imaging data (fMRI) obtained during a rhyming judgment task in adults using dynamic causal modeling (DCM). The results showed that the cerebellum has reciprocal connections with both left inferior frontal gyrus and left lateral temporal cortex, whereas the putamen has unidirectional connections into these two brain regions. Furthermore, the connections between cerebellum and these phonological processing areas were stronger than the connections between putamen and these areas. This pattern of results suggests that the putamen and cerebellum may have distinct roles in language processing. Based on research in the motor planning and control literature, we argue that the putamen engages in cortical initiation while the cerebellum amplifies and refines this signal to facilitate correct decision making.

Adult↗
PubMed2005

Different pontine projections to the two sides of the cerebellum.

This study analyzed the projections of the basilar pontine nuclei (BPN) and of the nucleus reticularis tegmenti pontis (NRTP) to the two sides of the cerebellum in the rat. It showed that the two sides of the cerebellar cortex were innervated by different percentages of BPN (about 82% of the cells project to the contralateral cortex and 18% to the ipsilateral) and NRTP cells (some 60% project to the contralateral cortex and 40% to the ipsilateral). In comparison to projections traced to the cortex, only a few fibers were traced to the nuclei of the same animals. Most of the projections of the BPN to the cerebellar nuclei were traced to the lateralis and posterior interpositus nucleus of the contralateral side (95%), while a few were traced to homologous nuclei of the ipsilateral side (5%). Thus, the BPN principally control the activity of the contralateral cerebellum, with a much less important control over the activity of the ipsilateral cerebellum. Vice versa, the NRTP, which project to the lateralis, interpositus, and medialis nuclei of the two sides, with percentages (64% contra- and 36% ipsilateral) similar to those reported for the projections to the cortex, is more concerned in the bilateral control of the cerebellum, although with a moderate contralateral prevalence. The fact that projections of the BPN were principally traced to the contralateral nuclei, from which the efferent projection fibers from the cerebellum originate, suggests that the BPN are principally involved in the motor control of the contralateral body. Conversely, the bilateral projections of the NRTP to the cerebellar nuclei suggest that the NRTP is mainly involved in bilateral motor activities. The comparison of the projections to the cortex and nuclei of the cerebellum of single animals supports the co-existence of coupled (i.e., projections to the cortex and the corresponding nuclei) and uncoupled (i.e., projections to the cortex but not to the nuclei) projection patterns, from both the BPN and the NRTP. These features of the pontocerebellar projections open new vistas on the functional architecture of this pathway.

Animals↗
PubMed2005

Cell-specific expression of the epm1 (cystatin B) gene in developing rat cerebellum.

Cystatin B (cystB) is an anti-protease implicated in EPM1, a degenerative disease of the central nervous system. This work analyzes the pattern of expression of cystB in developing and adult cerebellum, identifying the cystB positive cells by double immune-fluorescence microscopy using specific cell markers. In primary glial cells, cystB is found in progenitor and differentiated oligodendrocytes as well as in astrocytes. In the cerebellum, only oligodendrocyte progenitors express cystB. In myelin-producing cells, cystB synthesis is strongly down-regulated and the protein is not detectable. Astrocytes and Bergmann glia express cystB at all the developmental stages analyzed both in the cell body and in the fibers. Most neurons of developing and adult rat cerebellum do not express detectable amounts of cystB, with the exception of the Purkinje cells and of some cells of the differentiated molecular layer. In human cerebellum, cystB is present in Purkinje cells and Bergmann glial fibers only. cystB is also found in the cortical neurons of the dentate gyrus of the hippocampus. In rat cerebellum, cystB forms a complex with a number of proteins, two of which are specific to the nervous system. The cellular co-localization of cystB and its partners in developing and adult cerebellum is also shown.

Aging↗
PubMed2003

EAAT4 mRNA expression is preserved in the cerebellum of prion protein-deficient mice.

To study the mechanism underlying the selective degeneration of Purkinje cells in the cerebellum of the Nagasaki (Ngsk) prion protein-deficient (PrP(-/-)) mice, the mRNA levels of glutamate transporter EAAT4, the marker highly specific for Purkinje cell synapses, were analyzed by semi-quantitative reverse transcription-polymerase chain reaction. EAAT4 mRNA was expressed in the cerebellum of PrP(-/-) mice presenting with cerebellar ataxia, at the levels identical to those in the cerebellum of non-ataxic PrP(+/-) mice. Furthermore, EAAT4 mRNA was identified in the cerebrum of both PrP(-/-) and PrP(+/-) mice, although its levels were much lower than those in the cerebellum. These results indicate that Purkinje cell degeneration found in the cerebellum of PrP(-/-) mice is not primarily caused by glutamate neurotoxicity, although it remains to be investigated whether preserved expression of EAAT4 might represent a compensatory mechanism for protecting against Purkinje cell degeneration in the PrP(-/-) mice cerebellum.

Amino Acid Transport System X-AG↗