Temporal discrimination in the cerebellar cortex during conditioned eyelid responses

Little is known about mechanisms used by the nervous system to encode time. In light of recent evidence, cerebellar cortex involvement in the learned timing of conditioned eyelid responses shows promise as an area of investigation into neural timing mechanisms. Lesion studies indicate that the cerebellar cortex is necessary for response timing, but do not rule out the possibility that response timing is encoded afferent to the cerebellum. To differentiate between precerebellar and cerebellar cortical timing mechanisms, rabbits were trained by pairing direct stimulation of mossy fibers in the cerebellum as the conditioned stimulus (CS) with an eyeshock unconditioned stimulus (US). We find that individual animals can produce diffently timed conditioned responses when trained with a mossy fiber CS that has been paired with the US at various interstimulus intervals. The fact that differently timed responses can be conditioned using constant-frequency stimulation of an invariant subset of mossy fibers as the CS suggests that timing information in the afferent input to the cerebellum is not essential. Two rabbits trained with single-pulse stimulation in the cerebellum as the CS also learned differently timed conditioned responses; suggesting that fiber recruitment during a stimulus train does not convey the necessary temporal coding to the cerebellar cortex. Together with the lesion data, these findings suggest that the learned timing of conditioned eyelid responses occurs in the cerebellar cortex. Received: 25 August 1997 / Accepted: 12 January 1998     

Phenotypic expansion of Bosch–Boonstra–Schaaf optic atrophy syndrome and further evidence for genotype–phenotype correlations

Bosch–Boonstra–Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss‐of‐function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in‐frame deletions in the DNA‐binding domain (DBD), and 32 individuals with other types of variants including whole‐gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. We corroborate previously described clinical characteristics including developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. We also confirm a vision phenotype that includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment. Additionally, we expand the vision phenotype to include alacrima and manifest latent nystagmus (fusional maldevelopment), and we broaden the behavioral phenotypic spectrum to include a love of music, an unusually good long‐term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Furthermore, we provide additional evidence for genotype–phenotype correlations, specifically supporting a more severe phenotype associated with DBD variants.     

成人小脑髓母细胞瘤的临床及病理研究

目的探讨成人小脑髓母细胞瘤的临床病理特点、组织发生学及影响预后的因素。方法对我院１９７４～１９９５年间２７例成年人（≥１６岁）小脑髓母细胞瘤进行了观察。结果本组年龄１６～５５岁，平均２５．８岁，肿瘤发生于小脑蚓部２１例，小脑半球６例。随访２１例，７例已生存２．５～１７年，１４例死亡。平均生存时间４１．６个月。１年生存率为７１．４％，５年及１０年生存率均１４．３％。组织学类型：经典型１４例，促纤维增生型１３例。结论通过电镜观察及突触素、神经元特异性烯醇化酶和胶质纤维酸性蛋白免疫组化染色观察，证实髓母细胞瘤是具有向神经元及胶质细胞双向分化潜能的原始神经外胚叶肿瘤。影响预后的因素包括年龄、肿瘤部位、治疗手段以及组织学类型     

Hydrogen peroxide mediates damage by xanthine and xanthine oxidase in cerebellar granule neuronal cultures

The free radical-generating system of xanthine and xanthine oxidase is commonly used experimentally as a source of superoxide anion, which can produce oxidative stress, leading to cellular damage and death. Models of oxidative stress are important in elucidating pathologies associated with increased levels of reactive oxygen species, including stroke and neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We therefore, examined the effect of the xanthine/xanthine oxidase system on the viability of postnatal cerebellar granule neurones obtained from 8-day old Sprague–Dawley rat pups. Xanthine (100 μM) and xanthine oxidase (0.02 U/ml) applied for 1 or 6 h reduced the viability of cells at 8 div assessed using the alamar blue assay, and induced morphological changes, such as shrinkage of the cell bodies and neurites. Heat-inactivation of xanthine oxidase resulted in complete loss of its activity. Superoxide dismutase (250 U/ml) failed to modify the damage by xanthine and xanthine oxidase, while catalase (250 U/ml) completely prevented it. When applied alone, xanthine oxidase significantly lowered cell viability, an effect that was blocked by allopurinol and catalase, but not by superoxide dismutase. The results indicate that xanthine and xanthine oxidase can produce predominantly hydrogen peroxide instead of the superoxide anion. Cerebellar granule cells in culture may also possess significant levels of endogenous xanthine.     

Antioxidant enzyme systems in skeletal muscle atrophied by immobilization

To clarify the mechanism of oxidative stress in skeletal muscle atrophied by immobilization, we investigated the change of antioxidant enzyme activities in a typical slow red muscle, the soleus. Atrophied soleus muscles were collected from male Wistar rats (16 weeks old), one ankle joint of which had been immobilized in the fully extended position for 7 days. Also, soleus muscles were collected from intact age-matched rats as control. The activities of Mn-containing superoxide dismutase (Mn-SOD), Cu,Zn-containing superoxide dismutase (Cu,Zn-SOD), Se-dependent glutathione peroxidase (Se-GSHPx), glutathione S-transferase (GST), catalase, and glutathione reductase (GSSGRx) were measured. The activities of Cu,Zn-SOD, GST, and GSSGRx were significantly higher in atrophied muscles, while the others were unchanged. Increased Cu,Zn-SOD and unchanged Mn-SOD levels might reflect increased generation of superoxide anions in the cytoplasm rather than in the mitochondria. Owing to the enhancement of Cu,Zn-SOD and the unaltered Se-GSHPx and catalase activities, hydrogen peroxide is thought to be increased in the cytoplasm. Because there is also an increase of iron in the microsomes of atrophied muscles, the production of hydroxyl radicals, the most aggressive of radicals, might consequently be elevated.     

On the identification of the afferent axon terminals in the nucleus lateralis of the cerebellum an electron microscope study

Summary Axon terminals in the neuropil of the lateral nucleus can be divided into six classes, each with a specific constellation of characteristics that consistently occur together. Two of these classes have synaptic varicosities with elliptical synaptic vesicles, one in a dense, the other in a sparse matrix, and both make axosomatic and axodendritic synapses. The remaining four classes all have round synaptic vesicles and do not make axosomatic synapses. In the first of these four, the vesicles are tightly packed in a dense matrix, in another they are loosely dispersed, and in the third they are clustered. In the fourth, large granular vesicles predominate. Of these six classes, the most numerous belong to the axons of the Purkinje cell terminal arborization. These boutons resemble their counterparts in the cerebellar cortex, the recurrent collaterals of the Purkinje axon. They have elliptical and flat synaptic vesicles in a dark matrix. The varicosities terminate on somata and dendrites of large and small neurons and constitute the majority of their input. Purkinje axons constitute 86% of the total population of terminals on large neuronal perikarya and 50% of those on their dendrites, but only 78% on the somata of small neurons and 31% on their dendrites. The terminals of climbing fiber collaterals are recognized by their resemblance in electron micrographs to the terminals of the climbing fiber arborization in the cerebellar cortex. They bear round synaptic vesicles packed into a dense axoplasmic matrix and make Gray's type 1 axodendritic synapses with large and small neurons. These axons are restricted to the lateral and ventral aspects of the nucleus and constitute 5% of the terminals on large cell dendrites and 6% of those on small neurons. The axons tentatively identified as collaterals of mossy fibers are myelinated fibers with a light axoplasm containing round synaptic vesicles, dispersed throughout their varicosities. They make Gray's type 1 synapses and constitute a fair percentage of the total axodendritic contacts in the neuropil, 22% on large neurons and 28% on small neurons. The bases for these tentative identifications are discussed in detail, as are the various synaptic relationships undertaken by each class of axon. The remaining 4 classes of axons of the neuropil will be described in subsequent papers.Supported in part by U.S. Public Health Service grants NS 10536 and NS 03659, Training grant NS 05591 from the National Institute of Neurological Diseases and Stroke, and a William F. Milton Fund Award from Harvard University.     

Polyarteritis Nodosa with Atrophy of the Left Hepatic Lobe

A 73-year-old Japanese man with a history of partial gastrectomy due to gastric cancer 4 years previously was admitted because of intermittent fever. The patient developed abdominal pain, erythema, and myalgia in addition to the fever during the final clinical course, and died of acute heart failure. Autopsy disclosed atrophy of the left lobe of the liver and acute myocardial infarction. Neither metastasis nor recurrence of the cancer was observed. Small and medium-sized arteries of the visceral organs showed various stages of necrotizing vasculitis with narrowing of the lumina. The vasculitis was most prominent in the left lobe of the liver and in the heart. Narrowing of the portal vein due to portal tract inflammation in addition to vasculitis of the hepatic arteries may have induced ischemia and infarction, which had resulted in atrophy of the left hepatic lobe. Acta Pathol Jpn 42: 662–666, 1992.     

An HRP and autoradiographic study of cerebellar corticonuclear-nucleocortical reciprocity in the monkey

Summary Combined injections of ³H-leucine and HRP were made into the monkey cerebellar cortex in order to identify any reciprocal connections between the corticonuclear and the nucleocortical pathways. These combined intraaxonal labeling experiments have demonstrated a considerable overlap of orthogradely labeled Purkinje cell axons and terminals with retrogradely labeled HRP-positive neurons in the ventrolateral region of the dentate nucleus following combined injections into the lateral hemisphere, and in the dorsal area of the dentate following combined injections into medial cortical areas of the anterior lobe. There were also areas within the deep cerebellar nuclei where orthogradely labeled corticonuclear terminals did not overlap with retrogradely labeled nucleocortical neurons.     

A patient with novel MBOAT7 variant: The cerebellar atrophy is progressive and displays a peculiar neurometabolic profile

Mutations in the MBOAT7 gene have been described in 43 patients, belonging to 18 families, showing nonspecific clinical features (intellectual disability [ID], seizures, microcephaly or macrocephaly, and mild to moderate cerebellar atrophy) that make the clinical diagnosis difficult. Here we report the first Italian patient, a 22.5‐year‐old female, one of the oldest reported, born to apparently consanguineous parents. She shows severe ID, macrocephaly, seizures, aggressive outbursts, hyperphagia. We also documented progressive atrophy of the cerebellar vermis, that appeared not before the age of 7. The whole‐exome sequencing of the trio identified a novel homozygous variant c.1057_1058delGCinsCA (p.Ala353His) in the MBOAT7 gene. The variant is considered to be likely pathogenic, since it is absent from population database and it lies in a highly conserved amino acid residue. This disorder has a neurometabolic pathogenesis, implicating a phospholipid remodeling abnormalities. A brain hydrogen‐magnetic resonance spectroscopy (H‐MRS) examination in our patient disclosed a peculiar neurometabolic profile in the cerebellar hemispheric region. This new finding could address the clinical suspicion of MBOAT7‐related disorder, among the wide range of genetic conditions associated with ID and cerebellar atrophy. Moreover, the documented progression of cerebellar atrophy and the worsening of the disease only after some years open to the possibility of a therapeutic window after birth.     

Horizontal optokinetic ocular nystagmus in wildtype (B6CBA+/+) and weaver mutant mice

Summary Horizontal optokinetic nystagmus (OKN) evoked by a random dot pattern moving at a constant speed around the animal was investigated in wild-type mice and Weaver mutants (cerebellar impairment) by means of chronically implanted EOG-electrodes. The shape of OKN in the homozygotic Weaver mouse was clearly different from that in normal mice. The OKN in the mutant showed inconstant velocity during the slow phase. Nystagmus frequency of the mutant was significantly below that of normal controls for velocities of 1.4 to 25 degrees · s^-1. In one group of normals the mean slow-phase gain was relatively constant for stimulus angular velocities between 1.4 and 15 degrees · s^-1 and declined thereafter. In a second group the mean slow-phase gam decreased gradually between stimulus angular velocities from 1.4 to 15 degrees · s^-1 and thereafter with a steeper slope. In mutants gain decreases with increasing stimulus velocity over the entire range tested (1.4 to 42 degrees · s^-1). Normals and mutants with one eye occluded exhibited strong OKN when the pattern was moved in a temporonasal direction; little response was obtained by stimuli moving in a naso-temporal direction.