A review of the neurotransmitter system associated with cognitive function of the cerebellum in Parkinson's disease

The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.

Functional origins of the vertebrate cerebellum from a sensory processing antecedent

The structure of the cerebellar cortex is remarkably similar across vertebrate phylogeny. It is well developed in basaljawed fishes, such as sharks and rays with many of the same cell types and organizational features found in other vertebrategroups, including mammals. In particular, the lattice-like organization of cerebellar cortex (with a molecular layer of parallel fibres,interneurons, spiny Purkinje cell dendrites, and climbing fires) is a common defining characteristic. In addition to the cerebellarcortex, fishes and aquatic amphibians have a variety of cerebellum-like structures in the dorso-lateral wall of the hindbrain.These structures are adjacent to, and in part, contiguous with, the cerebellum. They derive their cerebellum-like name from thepresence of a molecular layer of parallel fibers and inhibitory interneurons, which has striking organizational similarities to themolecular layer of the cerebellar cortex. However, these structures also have characteristics which differ from the cerebellum. Forexample, cerebellum-like structures do not have climbing fibres, and they are clearly sensory. They receive direct afferent inputfrom peripheral sensory receptors and relay their outputs to midbrain sensory areas. As a consequence of this close sensory association,and the ability to characterise their signal processing in a behaviourally relevant context, good progress has been made indetermining the fundamental processing algorithm in cerebellar-like structures. In particular, we have come to understand thecontribution to signal processing made by the molecular layer, which provides an adaptive filter to cancel self-generated noise inelectrosensory and lateral line systems. Given the fundamental similarities of the molecular layer across these structures, coupledwith evidence that cerebellum-like structures may have been the evolutionary antecedent of the cerebellum, we address the question:do both share the same functional algorithm? [Current Zoology 56 (3): 277-284, 2010].

The cerebellum, the hypothalamus and behavior

The cerebellum has been classically considered as the subcortical center for motor control. However, accumulating experimental evidence has revealed that it also plays an important role in cognition, for instance, in learning and memory, as well as in emotional behavior and nonsomatic activities, such as visceral and immunological responses.

The microstructural effects of aqueous extract of Garcinia kola(Linn) on the hippocampus and cerebellum of malnourished mice

Objective:To assess the neuroprotective effects of aqueous extract of Garcinia kola on neurotoxin administered malnourished mice adopting histological procedure.Methods:The study was carried out using thirty-two adult malnourished mice which were randomly assigned into four groups(n=8):A,B,C and D.Group A served as control,while the other groups served as the experimental groups.Animals in group A were fed malnourished diet ad libitum and given water liberally.Animals in group B were administered with 3-Nitropropionic acid(3-NP)(neurotoxin)only at 20 rag/kg body weight,group C were given only Garcinia kola extracts,and group D were pre-treated with Garcinia kola extracts at 200 mg/kg for seven days prior to administration of neurotoxin at 20 mg/kg body weight.After three days of neurotoxins administration in the relevant groups,the brains were excised and fixed in formal calcium for histological processing.Results:The study showed that hippocampal and cerebellar neurons of animals in group B exhibited some cellular degeneration and blood vessel blockage,which were not seen in groups A,C and D.Cresyl violet staining was least intense in group B than in groups A,C and D.Despite the fact that animals in group D has equal administration of 3-Nitropropionic acid concentration,there were no traces of neural degeneration as it was evidenced in group B.Conclusions:It is concluded that Garcinia kola has protective effects on the neurons of the hippocampus and cerebellum of malnourished mice.

GLUTAMATE－IMMUNOREACTIVE NEURONS IN MEDULLARY RAPHE－CEREBELLUM PATHWAY IN THE KITTEN

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The Distribution of the Stress Protein HSP70 in the Cerebellum of Patients with Schizophrenia

Data accumulated from neuro-imaging, clinical and morphological studies suggest that the cerebellum is involved in cognitive functions and thus may be important in the etiopathogenesis of schizophrenia, since patients show cognitive abnormalities. In the present study, we have attempted to localize cellular metabolic dysfunctions applying the immunohistochemical and Western blot method to demonstrate the expression of the stress protein HSP70, which is a marker of cellular metabolic dysfunction in the brain. We studied the post mortem brains’ cerebellum of 12 normal controls and 10 schizophrenics. We have used the polyclonal antibody rabbit anti-HSP70 on paraffin sections as well as on nitrocellulose membranes. Bound antibody was detected using the indirect method of streptavidin-peroxidase-DAB. The results in the cerebellum of controls showed intense HSP70 immunoreaction in the synaptic glomeruli of the granular cell layer, in the cytoplasm and dendrites of Purkinje cells. In the same areas of the cerebellum of schizophrenics the HSP70 immunoreactivity was minimal. These results suggest that the reduced levels of HSP70 in the cerebellum are likely to contribute synergistically to the cognitive dysfunction in schizophrenia. This may suggest abnormality of protective neural mechanisms in such pathological conditions.

Immunolocalization of Ephexin-1 in the Developing Canine Cerebellum

Ephexin-1 functions as guanine nucleotide exchange factors for the Rho-type GTPases which have important roles in neuronal development including axon guidance, migration, morphogenesis, and plasticity of neurons. As little is known about ephexin-1 in the cerebellum, we investigated the immunolocalization of ephexin-1 in the developing canine cerebellum. While the cellular maturation was followed by the temporal pattern, the calbindin D-28k and ephexin-1 immunoreactivities gradually increased in developing canine cerebellum. When compared to the calbindin D-28k immunoreactivities, belated ephexin-1 immunolocalization was observed in the Purkinje cells which aligned a single layer during cerebellar development. These results suggest that ephexin-1 might play an important role in the development of the Purkinje cells during the first two postnatal weeks based on its immunolocalization in the present study.

Volume and shape analysis of the human fetal cerebellum during the early second trimester

The cerebellum,resided in the posterior cranialfossa,is a critical structure.The development of the cerebellum spans a long period and undergoes a dramatic change in its morphological structure.The protracted cerebellar development makes it particularly vulnerable to a wide range of pathologic injuries,especially during the early fetal period.This study characterizes the growth of human fetal cerebellum during the early second trimester.Using 7.0T high-resolution MR images,we manually segmented the fetal cerebellum of 35 specimens with gestational ages ranging from 15 to 22 weeks.V olume measurements and shape analysis were performed to quantitatively evaluate the global and regional cerebellar growth.

Motor Learning Based on the Cooperation of Cerebellum and Basal Ganglia for a Self-Balancing Two-Wheeled Robot

A novel motor learning method is present based on the cooperation of the cerebellum and basal ganglia for the behavior learning of agent. The motor learning method derives from the principle of CNS and operant learning mechanism and it depends on the interactions between the basal ganglia and cerebellum. The whole learning system is composed of evaluation mechanism, action selection mechanism, tropism mechanism. The learning signals come from not only the Inferior Olive but also the Substantia Nigra in the beginning. The speed of learning is increased as well as the failure time is reduced with the cerebellum as a supervisor. Convergence can be guaranteed in the sense of entropy. With the proposed motor learning method, a motor learning system for the self-balancing two-wheeled robot has been built using the RBF neural networks as the actor and evaluation function approximator. The simulation experiments showed that the proposed motor learning system achieved a better learning effect, so the motor learning based on the coordination of cerebellum and basal ganglia is effective.

Liponeurocytoma of the Cerebellum with Myoid Features

We report an extremely rare tumor presenting with myoid features in the left cerebellum lobe in a 62-year-old man. This tumor consisted of medium to large round cells with focal lipomatous and myoid differentiation. Immunohistochemically, the tumor cells expressed synaptophysin, GFAP (glial fibrillary acidic protein) and focally desmin. From these findings, we concluded that this tumor was a liponeurocytoma with myoid features. To our knowledge, this is the second report of liponeurocytoma with myoid differentiation in the cerebellum.

Deciphering the Role of Klf10 in the Cerebellum

Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tissues that are highly reliant on optimal mitochondrial function such as the cerebellum and to decipher the role of Klf10 in the functional and structural properties of this brain region. In vivo (magnetic resonance imaging and localized spectroscopy, behavior analysis) and in vitro (histology, spectroscopy analysis, enzymatic activity) techniques were applied to comprehensively assess the cerebellum of wild type (WT) and Klf10 knockout (KO) mice. Histology analysis and assessment of locomotion revealed no significant difference in Klf10 KO mice. Diffusion and texture results obtained using MRI revealed structural changes in KO mice characterized as defects in the organization of axons. These modifications may be explained by differences in the levels of specific metabolites (myo-inositol, lactate) within the KO cerebellum. Loss of Klf10 expression also led to changes in mitochondrial activity as reflected by a significant increase in the activity of citrate synthase, complexes I and IV. In summary, this study has provided evidence that Klf10 plays an important role in energy production and mitochondrial function in the cerebellum.

STUDY ON THE GROWTH OF CEREBELLUMIN NEWBORN INFANTS

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Effects of lead exposure on histological structure and antioxidant capacity in the cerebellum of 30-day-old mice

The current study sought to observe the effects of lead on histological structure and antioxidant capacity in 30-day-old mice.Spectrophotometry was used to detect the activities of superoxide dismutase,catalase,alkaline phosphatase,acid phosphatase and the malondialdehyde content.The results revealed that Purkinje cells in the lead-exposed group exhibited obvious pyknosis,atrophy and a decrease in overall number.Granular cells exhibited a disorderly arrangement,and were reduced in number.Administration of lead decreased the activities of superoxide dismutase,catalase,alkaline phosphatase and acid phosphatase,while malondialdehyde content increased.Two-way analysis of variance indicated that dose contributed more to lead-induced cerebellum damage than treatment time.The present study demonstrated that lead exerted strong effects on histological structure and inhibited antioxidant capacity of the cerebellum in 30-day-old mice.

Non invasive blood flow measurement in cerebellum detects minimal hepatic encephalopathy earlier than psychometric tests

AIM: To assess whether non invasive blood flow measurement by arterial spin labeling in several brain regions detects minimal hepatic encephalopathy. METHODS: Blood flow(BF) was analyzed by arterial spin labeling(ASL) in different brain areas of 14 controls, 24 cirrhotic patients without and 16 cirrhotic patients with minimal hepatic encephalopathy(MHE). Images were collected using a 3 Tesla MR scanner(Achieva 3T-TX, Philips, Netherlands). Pulsed ASL was performed. Patients showing MHE were detected using the battery Psychometric Hepatic Encephalopathy Score(PHES) consisting of five tests. Different cognitive and motor functions were also assessed: alterations in selective attention were evaluated using the Stroop test. Patients and controls also performed visuo-motor and bimanual coordination tests. Several biochemical parameters were measured: serum pro-inflammatory interleukins(IL-6 and IL-18), 3-nitrotyrosine, cGMP and nitrates+nitrites in plasma, and blood ammonia. Bivariate correlations were evaluated.RESULTS: In patients with MHE, BF was increased in cerebellar hemisphere(P = 0.03) and vermis(P = 0.012) and reduced in occipital lobe(P = 0.017). BF in cerebellar hemisphere was also increased in patients without MHE(P = 0.02). Bimanual coordination was impaired in patients without MHE(P = 0.05) and much more in patients with MHE(P < 0.0001). Visuo-motor coordination was impaired only in patients with MHE(P < 0.0001). Attention was slightly affected in patients without MHE and more strongly in patients with MHE(P< 0.0001). BF in cerebellar hemisphere and vermis correlated with performance in most tests of PHES [(number connection tests A(NCT-A), B(NCT-B)and line tracing test] and in the congruent task of Stroop test. BF in frontal lobe correlated with NCT-A. Performance in bimanual and visuomotor coordination tests correlated only with BF in cerebellar hemisphere. BF in occipital lobe correlates with performance in the PHES battery and with CFF. BF in cerebellar hemisphere correlates with plasma cGMP and nitric oxide(NO) metabolites. BF in vermis cerebellar also correlates with NO metabolites and with 3-nitrotyrosine. IL-18 in plasma correlates with BF in thalamus and occipital lobe.CONCLUSION: Non invasive BF determination in cerebellum using ASL may detect MHE earlier than the PHES. Altered NO-cGMP pathway seems to be associated to altered BF in cerebellum.

Pilomyxoid Astrocytoma in Cerebellum

Pilomyxoid astrocytoma is a new identified variant type of pilocytic astrocytoma,and typically locates in the hypothalamic and chiasmatic region.Herein,we reported a nine-year-old boy with pilomyxoid astrocytoma in the cerebellum.MRI scanning showed a tumor involved the cerebellar vermis,tonsil,the forth ventricle and brainstem.It was homogeneous isointensity on T1WI,relative hyper-intensity on T2WI,hyper-intensity on fluid attenuated inversion recovery (FLAIR) images,and uniform enhancement on contrast T1WI.The tumor was sub-totally removed and was proved histologically to be pilomyxoid astrocytoma.Follow-up at the 5th month,MRI showed the residual tumor enlarged at the brainstem.The patient survived 10 months after the operation,and finally died of respiration failure resulting from brainstem dysfunction.

Cerebellum and neurodegenerative diseases:Beyond conventional magnetic resonance imaging

The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases.While conventional magnetic resonance imaging(MRI) is widely used for brain and cerebellar morphologic evaluation,advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics.Volumetry,voxel-based morphometry,diffusion MRI based fiber tractography,resting state and task related functional MRI,perfusion,and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum.In the present review,after providing a brief description of each technique's advantages and limitations,we focus on their application to the study of cerebellar injury in major neurodegenerative diseases,such as multiple sclerosis,Parkinson's and Alzheimer's disease and hereditary ataxia.A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease,followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance.

Effects of Estrogen on ER, NGF, and ChAT Expression in Cerebellum of Aging Female Sprague-Dawley Rat

This article discusses the effects of estrogen on the expression of estrogen receptor (ER), nerve growth factor (NGF), and choline acetyltransferase (ChAT) in the cerebellum of rats. The model of aging female rat was established to study the expression and distribution of ER, NGF, and ChAT in the cerebellum following 17β-estradiol treatment using the technique of immunohistochemical ultrasensitive SP in sprague-dawley rat. The immunoreactive productions were distributed in stratum Purkinje cell, nucleus dentatus, nucleus interpositus, and nucleus fastigii of cerebellum, and the ER positive production was mainly located in the plasma, cytoplasmic membrane, and neurite, and also existed in nucleus. The general tendency of the expression of ER, NGF, and ChAT positive production in the cerebellum cortex and nuclei of aging rat significantly decreases, while the intensity and quantity of the immunoreactive production ascends predominantly after 17β-estradiol treatment. Simultaneously, the positive neurite of Purkinje cell shows a similar tendency. The above- mentioned results suggest that the estrogen upregulates the expression of NGF and ChAT, and plays a vital role in sustaining and protecting the structure and function of cerebellum neurons. Furthermore, the similarity of their changing tendency implies that they were correlated and cooperated during the course in effect of estrogen on cerebellum. It also showed that the action of estrogen in cerebellum could be via genomic and nongenomic mechanism.

Expression of estrogen receptor (ER) -α and -βtranscripts in the neonatal and adult rat cerebral cortex, cerebellum, and olfactory bulb

In the present study expression of estrogen receptor subtype -α(ERα) and -β (ERβ) in the cerebral cortex, cerebellum, and olfactory bulb was investigated and compared between neonatal (1～3-days-old) and adult (250～350g) rats, using reverse transcription-polymerase chain reaction (RT- PCR). No ERα transcripts were detectable in the adult cerebellum and olfactory bulb, whereas very weak expression of ERα was present in the adult cerebral cortex. No significant difference in ERβ transcripts was detectable between the neonatal and adult rats. While transcripts for both ER subtypes were co-expressed in these brain areas of neonatal rats, although ERα expression was significantly weaker than ERβ. Even in the cerebral cortex known to contain both ER subtypes in adult rats, ERα transcripts in neonatal rats were much higher than in adult. These observations provide evidence for the existence of different expression patterns of ERcα/ERβ transcripts in these three brain areas between the neonatal and adult rats, suggesting that each ER subtype may play a distinct role in the regulation of differentiation, development, and functions of the brain by estrogen.

Seizure-related 6,a brain-specific expression gene,is highly expressed in the human cerebellum

Epilepsy is a complex, Mendelian disease, and most cases are sporadic. Genomic comparisons of tissue from identified monogenic epilepsies with multigenic and acquired syndromes could ultimately reveal crucial molecular neuropathology for an epileptic phenotype. In the present study, a novel gene, human seizure-related (hSEZ)-6, was isolated from a human brain cDNA library. hSEZ-6 comprises 17 exons and spans a region of at least 55.6 kb, which was localized to 17q12 by radiation hybridization. hSEZ-6 exhibits two isoform types, hSEZ-6A and hSEZ-6B, which encode 996 and 995 amino acids, respectively. The two putative hSEZ-6 proteins contain similar motifs and share 82% and 84% identity with mouse SEZ-6A protein, whose expression level increased in mouse cerebral cortex-derived cells treated with a convulsant drug, pentylentetrazole. Northern blot analysis demonstrated that hSEZ-6 is expressed highly in the cerebellum and in nucleus of the extrapyramidal system, such as the caudate nucleus and putamen. Reverse transcription polymerase chain reaction revealed that hSEZ-6 is expressed in neurons rather than gliocytes, which suggests that hSEZ-6 is a seizure-related gene.

Potassium Bromate-induced Changes in the Adult Mouse Cerebellum Are Ameliorated by Vanillin

Objective The current study aimed to elucidate the effect of vanillin on behavioral changes, oxidative stress, and histopathological changes induced by potassium bromate(KBrO_3), an environmental pollutant, in the cerebellum of adult mice. Methods The animals were divided into four groups: group 1 served as a control, group 2 received KBrO 3, group 3 received KBrO_3 and vanillin, and group 4 received only vanillin. We then measured behavioral changes, oxidative stress, and molecular and histological changes in the cerebellum. Results We observed significant behavioral changes in KBrO_3-exposed mice. When investigating redox homeostasis in the cerebellum, we found that mice treated with KBrO_3 had increased lipid peroxidation and protein oxidation in the cerebellum. These effects were accompanied by decreased Na+-K+ and Mg2+ ATPase activity and antioxidant enzyme gene expression when compared to the control group. Additionally, there was a significant increase in cytokine gene expression in KBrO 3-treated mice. Microscopy revealed that KBrO_3 intoxication resulted in numerous degenerative changes in the cerebellum that were substantially ameliorated by vanillin supplementation. Co-administration of vanillin blocked the biochemical and molecular anomalies induced by KBrO_3. Conclusion Our results demonstrate that vanillin is a potential therapeutic agent for oxidative stress associated with neurodegenerative diseases.