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BACKGROUND AND PURPOSE - Long considered to have a role limited largely to motor-related functions, the cerebellum has recently been implicated as being involved in both perceptual and cognitive processes. Our purpose was to determine whether cerebellar activation occurs during cognitive tasks that differentially engage the component processes of word identification in reading.
METHODS - Forty-two neurologically normal adults underwent functional MR imaging of the cerebellum with a gradient-echo echo-planar technique while performing tasks designed to study the cognitive processing used in reading. A standard levels-of-processing paradigm was used. Participants were asked to determine whether pairs of words were written in the same case (orthographic processing), whether pairs of words and non-words rhymed with each other, respectively (phonologic assembly), and whether pairs of words belonged to the same category (semantic processing). Composite maps were generated from a general linear model based on a randomization of statistical parametric maps.
RESULTS - During phonologic assembly, cerebellar activation was observed in the middle and posterior aspects of the posterior superior fissure and adjacent simple lobule and semilunar lobule bilaterally and in posterior aspects of the simple lobule, superior semilunar lobule, and inferior semilunar lobule bilaterally. Semantic processing, however, resulted in activation in the deep nuclear region on the right and in the inferior vermis, in addition to posterior areas active in phonologic assembly, including the simple, superior semilunar, and inferior semilunar lobules.
CONCLUSION - The cerebellum is engaged during reading and differentially activates in response to phonologic and semantic tasks. These results indicate that the cerebellum contributes to the cognitive processes integral to reading.
NeuroD, a bHLH transcription factor, is implicated in differentiation of neurons and pancreatic beta cells. NeuroD-null mice die shortly after birth due to severe neonatal diabetes. To examine if there is postnatal neuronal phenotype in these mice, we rescued them from neonatal lethality by introducing a transgene encoding the mouse neuroD gene under the insulin promoter. These mice survive to adulthood but display severe neurological phenotype due to neuronal deficit in the granule layers of the cerebellum and hippocampus. We show here that NeuroD is required for these postnatally generated microneurons to undergo proper differentiation, the absence of which results in cell death.
Angelman syndrome (AS) is a human genetic disorder characterized by mental retardation, seizures, inappropriate laughter, abnormal galt, tremor and ataxia. There is strong genetic evidence that the disorder is associated with a maternally expressed, imprinted gene mapping to chromosome 15q11-13. Affected patients demonstrate varied molecular abnormalities, including large maternal deletions, uniparental paternal disomy (UPD). Imprinting mutations and loss of function mutations of E6-associated-protein (E6-AP) ubiquitin-protein ligase (UBE3A). All of these abnormalities are associated with loss of maternal expression of UBE3A. Although mutations in UBE3A cause AS, indicating that maternal-specific expression of UBE3A is essential for a normal phenotype, evidence for maternal-specific expression of UBE3A has been lacking. Using mice with partial paternal UPD encompassing Ube3a to differentiate maternal and paternal expression, we found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was only moderately or not at all reduced in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in the mouse model.
The human glutamic acid decarboxylase (GAD) gene was transferred into rat cerebellar granule neurons. Following adenoviral-mediated gene transfer, nearly 100% of the neurons had transgene expression that persisted for the duration of their survival in culture. GABA levels were elevated both in the growth media and in lysates of GAD-modified granule neurons. In GAD-modified neurons, extracellular GABA levels steadily increased with time, whereas intracellular GABA levels peaked 10 days after gene transfer. GAD-modified neurons released both glutamate and GABA into the surrounding media before and after potassium-induced stimulation, but only the release of glutamate was sensitive to potassium stimulation. These data suggest that glutamatergic neurons, which initially contained no detectable GABA, can be genetically modified to release GABA constitutively.
Growing evidence suggests that non-N-methyl-D-aspartate receptor activation may contribute to neuronal death in both acute and chronic neurological diseases. The intracellular processes that mediate this form of neuronal death are poorly understood. We have previously characterized a model of kainic acid neurotoxicity using cerebellar granule cell neurons in vitro and we sought to determine the mechanism of kainic acid-induced neuronal degeneration. We found DNA laddering by agarose gel electrophoresis, cellular DNA fragmentation by in situ end labeling of DNA, and chromatin condensation using a fluorescent DNA intercalating dye, in cerebellar granule cells following exposure to kainic acid (100 microM). Aurintricarboxylic acid protected cerebellar granule cells from kainic acid-induced death. While the morphological and biochemical features of neuronal death induced by kainic acid resembled low K(+)-induced apoptosis in cerebellar granule cells, the time interval from the institution of the death promoting condition to neuronal death was shorter with kainic acid and did not require new protein or RNA synthesis. These results demonstrate that kainic acid receptor activation can induce transcription-independent apoptosis in neurons. This in vitro model should be useful in identifying the intracellular pathways that link kainic acid receptor activation with apoptosis.
Growing evidence suggests that non-N-methyl-D-aspartate receptor activation may contribute to neuronal death in both acute and chronic neurological diseases. The intracellular processes that mediate this form of neuronal death are poorly understood. We have previously characterized a model of kainate neurotoxicity using cerebellar granule cell neurons in vitro and we sought to determine the mechanism of kainate-induced neurons degeneration. We found DNA, and chromatin condensation using a fluorescent DNA intercalating dye, in cerebellar granule cells following exposure to kainate (100 microM). Aurintricarboxylic acid protected cerebellar granule cells from kainate-induced death. While the morphological and biochemical features of neuronal death induced by kainate resembled low-K(+)-induced apoptosis in cerebellar granule cells; the time interval from the institution of the death-promoting condition to neuronal death was briefer with kainate and did not require new protein or RNA synthesis. These results demonstrate that kainate receptor activation can induce transcription-independent apoptosis in neurons. This in vitro model should be useful in identifying the intracellular pathways that link kainate receptor activation with apoptosis.
Neurotrophins activate the Trk tyrosine kinase receptors, which subsequently initiate signaling pathways that have yet to be fully resolved, resulting in neuronal survival and differentiation. The ability of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) to activate GTP binding to p21ras was investigated using cultured embryonic chick neurons. In both sympathetic and sensory neurons, the addition of NGF markedly increased the formation of Ras-GTP. The magnitude of the effect was found to depend upon the developmental stage, peaking at embryonic day 11 in sympathetic neurons and at embryonic day 9 in sensory neurons, times when large numbers of neurons depend on NGF for survival. Surprisingly, following the addition of BDNF, no formation of Ras-GTP could be observed in neurons cultured with BDNF. When sensory neurons were cultured with NGF alone, both NGF and BDNF stimulated GTP binding to Ras. In rat cerebellar granule cells, while the acute exposure of these cells to BDNF resulted in the formation Ras-GTP, no response was observed following previous exposure of the cells to BDNF, as was observed with sensory neurons. However, this desensitization was not observed in a transformed cell line expressing TrkB. In neurons, the mechanism underlying the loss of the BDNF response appeared to involve a dramatic loss of binding to cell-surface receptors, as determined by cross-linking with radiolabeled BDNF. Receptor degradation could not account for the desensitization since cell lysates from neurons pretreated with BDNF revealed that the levels of TrkB were comparable to those in untreated cells. These results indicate that in neurons, the pathways activated by NGF and BDNF are differentially regulated and that prolonged exposure to BDNF results in the inability of TrkB to bind its ligand.
Serotonin N-acetyltransferase (NAT) activity in chicken pineal homogenates is increased 16-fold in the presence of high-molarity phosphate buffer (0.35 M) as compared with its activity in low-molarity (0.05 M) phosphate buffer. This phosphate effect on NAT does not depend on ionic, osmotic, or pH changes; rather, it appears to be a direct effect of phosphate on NAT activity. Phosphate also stabilizes NAT activity to thermal inactivation and inactivation caused by incubation at 4 degrees C for 48 h. Stimulation of NAT activity by phosphate occurs only in chick pineal and retina, not in chick cerebrum, cerebellum or liver, nor in rat pineal or other tissues tested. There is a correlation between the occurrence of the phosphate effect and the occurrence of endogenous NAT circadian rhythmicity and light inactivation. The effect of phosphate on NAT activity in homogenates may reflect physiological mechanisms of NAT regulation.
A new rapid, facile and reliable method based on microcolumn cation-exchange chromatography has been developed for separating free antagonist [3H]dihydroalprenolol from that bound to solubilized beta-adrenergic receptors.
3-Acetylpyridine (3-AP) administration to rats results in degeneration of the dopamine (DA) innervation of the striatum as well as degeneration of the olivocerebellar system. We now report that administration of this pyridine neurotoxin results in a decrease in striatal DA concentration which is restricted to the dorsolateral aspects of the caudatoputamen. 3-AP treatment did not alter DA levels in the ventromedial striatum, the nucleus accumbens, or the anteromedial prefrontal cortex. Both 3-AP and another pyridine neurotoxin, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), potently inhibited in vitro MAOB activity and in contrast weakly inhibited MAOA activity. However, in vitro inhibition of MAOB by the selective inhibitor deprenyl did not prevent or attenuate 3-AP-induced striatal DA depletion. These data indicate that 3-AP administration to rats not only results in degeneration of the olivocerebellar system, but also effects degeneration of the DA innervation of the dorsolateral striatum, the striatal sector thought to subserve motoric and sensorimotor function. 3-AP-induced nigrostriatal degeneration differs from that elicited by MPTP in that the former is not prevented by deprenyl pretreatment. The 3-AP-induced degeneration of both extrapyramidal and cerebellar motor systems may offer insight into the mechanisms involved in degeneration of the two motor systems in certain strains of rodents (such as the Weaver mutant mouse), and suggests that the sequelae of administration of this pyridine may serve as a useful model for olivopontocerebellar atrophy-associated parkinsonism.