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PubMed1978

A chemical study on the development of the human forebrain and cerebellum during the brain 'growth spurt' period. II. Phosphoglyceride fatty acids.

The changes of the fatty acid composition of ethanolamine phosphoglycerides (EPG) and choline phosphoglycerides (CPG) that are associated with the maturation of the human forebrain and cerebellum have been studied. The increase in the n-3 fatty acids and the 22:4(n-6)/22:5(n-6) index in the forebrain during the second half of gestation was confirmed in the present series. In the cerebellum, on the other hand, these two parameters were higher than in the cerebrum and did not show any significant change throughout the period studied. The percentage of 18:1(n-9) changed in an opposite sense in the cerebrum and in the cerebellum, i.e. it decreased with gestational age in the cerebrum, whereas it increased markedly in the cerebellum. Consequently, the 18:0/18:1(n-9) index, which increased with maturation in the cerebrum, decreased in the cerebellum.

Cerebellum↗
PubMed1988

Influence of stereotaxically injected scrapie on neurotransmitter systems of mouse cerebellum.

The 22L strain of scrapie was injected stereotaxically into the cerebellum of C57BL/6J mice to determine its effect on several cerebellar neurotransmitter systems during the early clinical stages of the disease. In this model vacuolar lesions are restricted to the cerebellum with no evidence of vacuolization in other brain regions. Although vacuolar lesions develop throughout all cell layers of the cerebellum, they are most severe in the granule cell layer. Modest but significant (P less than 0.01) reductions in cerebellar weight, glutamate decarboxylase activity, and in the affinity of the N6-[adenine-2,8-3H]cyclohexyladenosine binding sites, were observed in scrapie affected mice. The densities of the high- and low-affinity adenosine receptors were unaffected. Adenosine receptors in the cerebellum are highly localized to the axon terminals of the glutamatergic, GABA receptive granule cells. GABA, benzodiazepine, glutamate, and muscarinic cholinergic receptors were not significantly altered. In addition, the high-affinity uptake of glutamate, and the activity of choline acetyltransferase were not significantly changed. GABA high-affinity uptake was slightly increased. Even though the granule cell layer of the cerebellum had undergone severe vacuolation, only modest neurotransmitter changes were apparent. Although these results suggest a tenuous relationship between scrapie pathology and the integrity of neurotransmitter systems, it is possible that compensatory neurochemical changes in uncompromised neuronal populations may have masked potentially specific neurotransmitter effects.

Animals↗
PubMed1990

Expression of somatostatin receptors is impaired in the cerebellum of developing Brattleboro rats.

Somatostatin (SRIF) receptors are expressed in the external granule cell layer of the rat cerebellum during early postnatal life. The aim of the present study was to investigate the distribution and biochemical characteristics of SRIF binding sites in the cerebellum of homozygous (vasopressin deficient) Brattleboro rats, which exhibit a selective impairment of their granule cell layer. This study has been conducted in 13-day-old rats by means of membrane-binding assay and autoradiography using [125I-Tyr0,DTrp8]S14 as a radioligand. In the cerebellum of homozygous Brattleboro rats, Scatchard plot analysis revealed the existence of a single class of SRIF receptors with similar Kd values as in Long-Evans or heterozygous Brattleboro rats (180-200 pM). Conversely, a marked reduction of the concentration of SRIF binding sites was observed in Brattleboro rats as compared to heterozygous or Long-Evans rats. In homozygous Brattleboro rats, autoradiographic studies revealed that the concentration of SRIF receptors was reduced in all lobules of the cerebellum as compared to Long-Evans. In addition, the magnitude of the decrease of receptor concentration was greater than the loss of granule cells observed in the homozygous Brattleboro rat. These results indicate that the expression of SRIF receptors by immature granule cells of the cerebellum is markedly reduced in Brattleboro rats. Whether the impairment of SRIF receptors in diabetes insipidus rats can directly be ascribed to vasopressin deficiency remains to be determined.

Animals↗
PubMed1992

Expression, but failing maturation of procholecystokinin in cerebellum.

The cerebellum is the only region of the central nervous system which has been found to be devoid of cholecystokinin (CCK). The assays used, however, have been directed against the alpha-amidated C-terminus of fully processed CCK peptides. Using Northern blot analysis and a library of radioimmunoassays specific for different sequences of proCCK in combination with chromatography and enzyme cleavage, we have now examined the expression and processing of proCCK in fetal, neonatal and adult cerebellar tissue from man, pig and rat. In rat cerebellum CCK mRNA was present already in the fetal state. Two weeks after birth the concentrations declined. Also proCCK was found in significant concentrations in the fetal human and rat cerebellum (approximately 20 pmol/g); but already before birth the expression began to decrease towards low concentrations in adults. The adult porcine cerebellum contained 3.2 pmol proCCK and glycine-extended processing intermediates per gram (range less than 0.1-10.4 pmol/g), and 0.8 pmol carboxyamidated CCK per gram (range 0.1-4.1 pmol/g) varying in size from CCK-58 to CCK-5. For comparison, the adult porcine cerebral cortex contained 757 pmol carboxyamidated CCK/g, 20 pmol glycine-extended CCK/g and no proCCK. We conclude that cerebellum expresses proCCK with the highest level of expression in fetal life. In comparison with other regions of the brain, the maturation to transmitter-active, carboxyamidated CCK peptides is, however, attenuated in both fetal and adult cerebellar tissue.

Aging↗
PubMed1993

The cholinergic receptor-linked phosphoinositide metabolism in mouse cerebrum and cerebellum in vivo.

The cholinergic receptor-linked poly-phosphoinositide hydrolysis was studied in mouse cerebrum and cerebellum after prelabeling the brain with [3H]inositol. I.p. injection of Li (8 meq/kg) to C57Bl/6J mice for 4 h resulted in 14- and five-fold increases in [3H]inositol-labeled inositol monophosphate (IP1) in cerebrum and cerebellum, respectively. The labeled inositol bisphosphate (IP2) was also increased 83 and 19% in cerebrum and cerebellum, respectively. Prior injection of atropine (100 mg/kg) resulted in inhibition of Li-induced increases in labeled IP1 by 74 and 56% in cerebrum and cerebellum, respectively. Administration of pilocarpine (20 mg/kg) to the Li-treated mice for 30 min resulted in further increases in labeled IP1 and IP2 and a concomitant decrease in labeled inositol in cerebrum but not in cerebellum. Mass measurements of IP1 and IP2 isomers by HPLC revealed that inositol 1-monophosphate (Ins(1)P), inositol 4-monophosphate (Ins(4)P) and inositol 1,4-bisphosphate (Ins(1,4)P2) were all increased by pilocarpine administration in the Li-treated mouse cerebrum. The effects of pilocarpine administration in mouse cerebrum (increases in IP1 and IP2) could be completely inhibited by preinjection of atropine. Atropine injection also decreased the levels of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. Surprisingly, a decrease in Ins(1,4,5)P3 level was also found in non-Li-treated mice after pilocarpine administration (30 mg/kg, 10-40 min). Except for the increase (20%) in [32P]-labeled PIP in the cerebrum, Li or Li together with pilocarpine administration did not alter the levels of [3H]inositol or [32P]phosphate-labeled phosphoinositides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Evidence for a functional role of the dopamine D3 receptors in the cerebellum.

It has recently been shown that the lobules 9 and 10 of the cerebellum contain high densities of dopamine D3 receptors (and almost no D2 receptors [Bouthenet, M.L., Souil, E., Martres, M.P., Sokoloff, P., Giros, B. and Schwartz, J.C., Brain Res., 564 (1991) 203-219; Sokoloff, P., Giros, B., Martres, M.P., Bouthenet, M.L. and Schwartz, J.C., Nature, 347 (1990) 146-151]), and the functional role of this cerebellar dopamine system is unknown. In this study, using microinjections of dopamine receptor ligands into the lobules 9 and 10 of the cerebellum and into the nucleus accumbens, we show that the cerebellar dopamine D3 receptors have a functional role in the regulation of locomotor activity. When microinjected into the lobules 9 and 10 of the cerebellum, amisulpride (a dopamine D2 and D3 antagonist) and nafadotride (a preferential D3 antagonist) dose-dependently alter locomotor activity. At low doses, both agents stimulate locomotor activity, while inhibition is observed at higher doses. Haloperidol (a D2 antagonist) and apomorphine (a dopamine agonist) have no effects at low doses, but decrease locomotor activity at high doses. Similar effects are found in the nucleus accumbens, however the effects are stronger in the nucleus accumbens than in the cerebellum. Therefore, the dopamine D3 receptor system in lobules 9 and 10 of the cerebellum has a functional role, similar but weaker than the D3 receptor system in the nucleus accumbens.

Amisulpride↗
PubMed1989

Long-lasting inhibitory action of caerulein on climbing fiber system in the cerebellum of the rat.

Caerulein caused a marked decrease in levels of guanosine 3',5'-cyclic monophosphate (cGMP) in the cerebellum in rats. This effect was observed to be dose-dependent after the intraperitoneal administration of caerulein for doses over 20 micrograms/kg and lasted for about 4 hr in doses of 100 micrograms/kg. However, in vagotomized rats, caerulein failed to alter the level of cGMP in the cerebellum. Caerulein suppressed harmaline-induced increases in cGMP in the cerebellum for more than 30 hr. In contrast, the increases in levels of cGMP in the cerebellum, induced by treatment with methamphetamine, apomorphine and picrotoxin, were not inhibited by pretreatment with caerulein. These results suggest that the peripheral administration of caerulein can inhibit the activity of climbing fibers for a long period of time in the cerebellum of the rat through the stimulation of the abdominal vagus nerves.

Animals↗
PubMed1985

The development of type I and type II benzodiazepine receptors in the mouse cortex and cerebellum.

The postnatal development of benzodiazepine (BDZ) receptors was monitored in Heterogeneous Stock (HS) mice, and the BDZ receptors were characterized and categorized into Type I and Type II receptors. When the number of 3H-Flu binding sites (Bmax) was assessed at weekly intervals after the birth of the animal, the number of sites in both the cortex and cerebellum increased significantly if the data was expressed as fmol/mg tissue. On the other hand, no significant change in 3H-Flu binding sites was evidenced in the cortex, and the number of 3H-Flu binding sites in the cerebellum decreased during postnatal development if Bmax values were expressed as fmole/mg protein. When receptor binding data was analyzed for the presence of Type I and Type II BDZ receptors, the changes in KD values for 3H-Flu binding development could be accounted for by changes in relative proportions of Type I and Type II receptors present in the cortex and cerebellum during the maturation process. Type II receptors predominated in both cortex and cerebellum at birth, and Type I receptors proliferated primarily during the first two weeks of postnatal life. In the cortex of adult mice there were approximately equal numbers of Type I and Type II BDZ receptors. In the cerebellum of adult mice, computer assisted analysis of binding data could not distinguish the presence of two distinct BDZ binding sites. However, Hill coefficients and overall binding constants determined from data on CL-218,872 displacement of 3H-Flu binding to cerebellar membranes indicated that cerebellar tissue from adult mice did contain a heterogeneous array of BDZ receptors.

Aging↗
PubMed1986

Barrel rotation and prostration by vasopressin and nicotine in the vestibular cerebellum.

The aim of this study was to determine whether the primary sites for the action of vasopressin and nicotine in producing barrel rotation and prostration in rats were located in the modular cerebellum, i.e., lobule X. When arginine vasopressin was administered into either the fourth ventricles or directly into the nodular cerebellum via chronically implanted cannulae, the rats displayed intermittent barrel rotation and clonic convulsions. The administration of nicotine into the same areas resulted in prostration, atonia and, occasionally, clonic convulsions. A few days after the nodular cerebellum was lesioned with kainic acid, the motor disturbances resulting from either agent were virtually abolished. Histologic studies revealed that kainic acid had destroyed Purkinje and other large neurons, but had left the granular neurons relatively intact. The administration of procaine into either the fourth ventricles or nodular cerebellum blocked the behavioral responses of either vasopressin or nicotine given into the fourth ventricles. It was concluded that the nodular cerebellum is a primary site for the motor disturbances produced by vasopressin and nicotine.

Animals↗
PubMedDate not supplied

The cerebellum and learning processes in animals.

In theories of motor learning, the cerebellum is assumed to be the storage site of the engram. Recent evidence is presented that the cerebellum, in addition to its mediation of learning of simple motor responses, has a role in cognitive behaviors. For this type of learning, it is possible that the storage site is not the cerebellum, but cerebellar target areas. The possible role of the cerebellum in spatial learning and discrimination learning is emphasized. Ascending cerebellar afferents to fronto-parietal association cortex, the limbic system and the superior colliculus and feedback loops from these areas may be the anatomical basis underlying cerebellar modulation of spatial learning. In regard to discrimination learning, the possible significance of pathways arising from the visual cortex to pontine nuclei projecting to the cerebellar hemispheres must be evaluated. Although much remains to be resolved, the cerebellum seems to contribute to various emotions such as fear, the neural basis of which being cerebellar contributions to the reticular activating system, the limbic system and two-way hypothalamo-cerebellar connections.

Animals↗
PubMed1995

Distribution of AMPA-selective glutamate receptor subunits in the human hippocampus and cerebellum.

The distribution of AMPA-selective subunits, GluR1-4, was determined in the human hippocampus and cerebellum by in situ hybridization and immunocytochemistry. In the hippocampus, in situ hybridization revealed that GluR1 and GluR2 mRNAs were similarly distributed and highly expressed in the dentate gyrus, with lower levels in the CA regions. GluR3 and GluR4 mRNAs were expressed at very low levels. Immunocytochemical studies showed that GluR1- and GluR2/3-immunoreactivity were highest in the dentate molecular and granular layers. In the CA regions, GluR1 and GluR2/3 staining was observed in pyramidal cell bodies and surrounding neuropil and was more intense in CA4/3/2 compared with CA1. GluR4-immunoreactivity was low throughout the hippocampus. In the cerebellum, GluR1 and GluR4 transcripts were expressed in the granular and Purkinje cell/Bergmann glia layers. GluR2 mRNA was highly expressed in the granular layer and individual Purkinje cells, while GluR3 mRNA was not detectable in the cerebellum. GluR1- and GluR4-immunoreactivity were localized to Purkinje cells and putative Bergmann glia, as well as their processes extending into the molecular layer. GluR2/3 staining was intense in Purkinje cells, with moderate staining in the granular layer. Thus, GluR1-4 subunits are differentially distributed in the hippocampus and cerebellum. In addition, the distribution of subunit mRNA and protein correlate well with each other and with the glutamatergic neuroanatomy of the hippocampus and cerebellum.

Aged↗
PubMed1992

P400 protein is one of the major substrates for Ca2+/calmodulin-dependent protein kinase II in the postsynaptic density-enriched fraction isolated from rat cerebral cortex, hippocampus and cerebellum.

Concanavalin A-binding glycoprotein with 250 K M(r) found in the postsynaptic density (PSD)-enriched preparation (or synaptic cytoskeleton) from rat cerebellum was identified with P400 protein from the physicochemical properties and enrichment in the cerebellum. Proteins homologous to the cerebellar 250 K M(r) protein occurred in the PSD-enriched preparations from rat cerebral cortex and from hippocampus, although the contents in the preparations were very low. The 250 K M(r) proteins in the PSD-enriched preparations from cerebellum and from cerebrum were highly phosphorylated by Ca2+/calmodulin (CaM)-dependent protein kinase II. The protein of synaptic plasma membrane (SPM) and PSD-enriched fractions prepared from cerebral cortex were not phosphorylated by the cAMP-dependent protein kinase endogenous to the fractions, whereas the protein from cerebellum was done in SPM and PSD-enriched fractions. The facts suggest that P400 or P400-like protein is closely associated with Ca2+/CaM-dependent protein kinase II in the PSD-enriched preparations, especially in the preparation from cerebral cortex. Phosphorylation of the protein by Ca2+/CaM-dependent protein kinase II may play an important role in the postsynaptic function in both cerebellum and at least in some areas of cerebrum.

Animals↗
PubMed1991

Dopaminergic innervation and binding in the rat cerebellum.

In the present study, we used an antiserum against dopamine (DA), and specific [3H]ligands in order to shed more light on the dopaminergic system of the rat cerebellum. The immunocytochemical approach showed that the entire rat cerebellum is innervated by DA fibers. All cerebellar layers were found to receive a considerable amount of DA afferents but the molecular layer was the most heavily innervated. The analysis of [3H]DA and [3H]spiperone binding showed that in the rat cerebellum there exists DAergic binding with kinetic parameters similar to those reported for the mouse cerebellum. The results of the present study support the existence of a DA system in the rat cerebellum.

Afferent Pathways↗
PubMed1991

Distinct cellular expression of pertussis toxin-sensitive GTP-binding proteins in rat cerebellum.

Immunohistochemical localization of pertussis toxin-sensitive GTP-binding proteins in rat cerebellum was investigated using antibodies raised against purified G alpha o and synthetic peptides corresponding to specific sequences of G alpha i1, G alpha i2 and G alpha o was detected mostly in the molecular layer but not in the cell body of the Purkinje cells. G alpha i1 and G alpha i2 were found predominantly in the molecular layer and in addition in the cell body of the Purkinje cells. G alpha i3 was not detected in rat cerebellum. Immunoblot analysis demonstrated that in the cerebellum membrane G alpha 0 was most abundant and surprisingly the amount of G alpha i2 was much higher than that of G alpha i1. Thus, each pertussis toxin substrate was found to be expressed differently in rat cerebellum. The different patterns of expression imply that each subtype of GTP-binding proteins may have a specific function in modulating the neuronal activity in rat cerebellum.

Amino Acid Sequence↗
PubMed1986

Altered histofluorescent pattern of noradrenergic innervation of the cerebellum of the mutant mouse Purkinje cell degeneration.

The Purkinje target cells for noradrenergic fibers originating in the locus coeruleus are considered to be of importance in the regulation of noradrenergic input to the cerebellum. The availability of a mouse mutant, Purkinje cell degeneration provides a non-surgical means for studying cellular regulation of innervation. Using a glyoxylic acid histofluorescent method for visualizing noradrenergic fibers, the observations have been made that the density of green histofluorescent neurites is markedly increased in both the granule and molecular layers of the cerebellum of Purkinje cell degeneration mice, following spontaneous degeneration of the Purkinje cells. However, because of tissue shrinkage, tissue concentration of norepinephrine also increases, but total tissue content of norepinephrine is unchanged in whole cerebellum and outer cerebellar cortex. These findings indicate that the relative number of noradrenergic afferents to the molecular layer of the cerebellum is not reduced following spontaneous degeneration of Purkinje cells. Therefore, Purkinje target cells do not appear to be essential for maintenance of afferent inputs in mature cerebellum.

Adrenergic Fibers↗
PubMed1988

Effect of hypothyroidism on the expression of three microtubule-associated proteins (1A, 1B and 2) in developing rat cerebellum.

The microtubule-associated proteins 1A, 1B and 2 are present at high levels in Purkinje cell dendrites of normal adult rat cerebellum but show characteristic changes in localization during cerebellar development that allow examination of the effects of hypothyroidism on the development of both Purkinje cells and granule cells. Neonatal rats were made hypothyroid by treatment with propylthiouracil from the day of birth (post-natal day 0, P0). The expression of the microtubule-associated proteins 1A, 1B and 2 in the cerebellum of hypothyroid animals was examined using immunocytochemical techniques and compared to the normal developmental pattern in control animals. The normal developmental decrease in microtubule-associated protein 1A and 1B levels in parallel fibres was delayed in the cerebellum of hypothyroid animals and these proteins persisted in parallel fibres until after P20. Microtubule-associated protein 1B but not 1A was still present in parallel fibres in less mature folia at P30 in hypothyroid rats suggesting that the expression of these two microtubule-associated proteins is regulated separately. In the molecular layer staining with anti-microtubule-associated protein 2 was enriched in Purkinje cell dendrites in normal and hypothyroid cerebella and the stained Purkinje cell dendrites in hypothyroid cerebellum demonstrated a typical deformed morphology at P15. The results show that the restricted subcellular localization of these microtubule-associated proteins is maintained in the cerebellum of hypothyroid rats but the developmental changes in their expression are delayed.

Aging↗
PubMed1993

Localization and characterization of PACAP receptors in the rat cerebellum during development: evidence for a stimulatory effect of PACAP on immature cerebellar granule cells.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are abundant in the brain and particularly in the cerebellum of adult rats. In contrast, the occurrence of PACAP binding sites has not been investigated during ontogenesis. The aim of the present study was to determine the distribution and biochemical characteristics of PACAP binding sites in the rat cerebellum during postnatal development, and to examine the effect of PACAP on immature cerebellar granule cells. Autoradiographic studies revealed that PACAP binding sites are transiently expressed in a germinative matrix of the cerebellar cortex, the external granule cell layer, and in the medulla, from postnatal days 8 to 25. A population of PACAP binding sites persisted in the internal granule cell layer in the mature cerebellum. Emulsion-coated cytoautoradiography, performed on cultured immature granule cells from eight-day-old rat cerebellum, demonstrated that transient PACAP binding sites are expressed by cerebellar immature granule cells. Biochemical characterization of binding revealed the occurrence of two classes of PACAP recognition sites exhibiting, respectively, high (Kd = 0.39 +/- 0.08 nM) and low (Kd = 21.2 +/- 9.4 nM) affinity for PACAP27. The two naturally occurring forms PACAP38 and PACAP27 were equipotent in competing for [125I]PACAP27 binding. In contrast, the [Des-His1]PACAP38 analog was eight times less efficient and vasoactive intestinal polypeptide only induced weak displacement of the binding. Exposure of cultured immature granule cells to PACAP27 resulted in a dose-dependent stimulation of the production of cAMP, indicating that PACAP binding sites represent authentic receptors positively coupled to adenylate cyclase. These results show that PACAP receptors are actively expressed in the cerebellum of rats during postnatal development. The presence of functional PACAP receptors in the external granule cell layer suggests that PACAP may play a role in the control of proliferation and/or differentiation of granule cells.

Adenylyl Cyclases↗
PubMed1994

Neural cell adhesion molecule and D3 protein in the cerebellum of weaver mutant mice.

Weaver (wv/wv) mutant mice are characterized by extensive granule cell degeneration and can therefore be used as a model for brain degeneration that does not involve blood-brain barrier damage. The ontogeny of the neural cell adhesion molecule (NCAM) and the neuronal antigen D3 protein were investigated in cerebellum and forebrain of weaver mutant mice up to post-natal day 60. In the forebrain the concentration of both proteins was virtually unchanged. In cerebellum, in contrast, the concentration of D3 decreased markedly whereas that of NCAM remained unchanged. Similar findings were obtained at post-natal day 30 in the cerebellum of other neurologic mutants, namely the staggerer (sg/sg) and reeler (rl/rl). At this age the concentration of a synaptic vesicle marker, synaptophysin, was severely decreased in the cerebellum of all three mutants. The concentration of neuron-specific enolase was less affected, whereas the concentrations of the glial markers glutamine synthetase and glial fibrillary acidic protein were both increased. The NCAM/D3 concentration ratio, which probably reflects the ongoing rate of synaptic remodelling, was increased during the whole ontogeny of weaver mutant mice as compared with heterozygous controls. At post-natal day 30, the ratio was increased by 180% in weaver, by 170% in staggerer and by 60% in reeler cerebellum. These findings lend further support to the usefulness of the NCAM/D3 ratio as a marker of neural plasticity and synaptic remodelling in both animals and man.

Aging↗