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.

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.

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.

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].

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.

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.

Cholinergic input from the pedunculopontine nucleus to the cerebellum: implications for deep brain stimulation in Parkinson's disease

Deep brain stimulation（DBS）is a well established electrophysiological treatment initially applied to treat medication-refractory motor symptoms in Parkinson＇s disease（PD）,and is now being explored for several neurological and psychiatric disorders.The specific physiological mechanisms underlying the effectiveness of DBS are not fully understood.

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.

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 17q 12 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 gone.

Expression of estrogen receptor alpha,nerve growth factor,interleukin-2,and androgen receptor in the cerebellum of ovariectomized rats following soybean isoflavone treatment

BACKGROUND： Studies have shown that estrogen receptor alpha （ERα）, nerve growth factor （NGF）, interleukin-2 （IL-2）, and androgen receptor （AR） expression in the cerebellum decreases when estrogen levels decrease in vivo. Soybean isoflavone, a type of non-steroid estrogen with similar molecular structure and function to estradiol, exhibits estrogen-like characteristics. OBJECTIVE： To investigate the effects of various doses of soybean isoflavone on expression of ERa, NGF, IL-2, and AR in the cerebellum of ovariectomized rat, and to determine whether there is a dose-dependent effect.DESIGN, TIME AND SETTING： Controlled trial at the cellular and molecular level. The study was performed at the Experimental Animal Engineering Center, College of Veterinary Medicine, Sichuan Agricultural University from July 2006 to May 2008. MATERIALS： Soybean isoflavone, comprised of daidzin, genistein and isoflavone, was provided by Taiyuan Yuantai Biochemical Industry, China. The ERα, NGF, IL-2, and AR in situ hybridization kit, rabbit anti-rat ERa, NGF, IL-2, and AR monoclonal antibodies, and SABC kit were purchased from Wuhan Boster Biological Technology, China. METHODS： A total of 50 female, Sprague Dawley rats, aged 3 months, were randomly assigned to 5 groups, with 10 animals in each group. With the exception of the sham-operation group （abdominal cavity opening alone）, all rats underwent bilateral ovariectomy. At 14 days after surgery, rats in the high-, middle-, and low-dose soybean isoflavone groups were subcutaneously injected with 1.5, 1.0, and 0.5 mg/kg soybean isoflavone, respectively, every 2 days for 6 consecutive weeks. Rats in the sham-operation and ovariectomized groups were subcutaneously injected with absolute alcohol （0.5 mL/kg）. MAIN OUTCOME MEASURES： Expression levels and distribution of ERα, NGF, IL-2, and AR in the cerebellum were detected by immunohistochemistry and in situ hybridization. RESULTS： Compared with the sham-operation group, immunoreactive products and hybridization signals of ERa, NGF, IL-2, and AR were significantly decreased in the cerebellar cortex and nuclei of ovariectomized rats （P 〈 0.05 or P 〈 0.01）, but increased following soybean isoflavone treatment. In particular, levels of the high-dose soybean isoflavone group were almost restored to levels of the sham-operation group （P 〉 0.05）. The immunoreactive products were primarily located in the cytoplasm and neurites, and rarely in the cell membrane and nuclei. However, the hybridization signals were predominantly located in the nuclei, but rarely in the cytoplasm, cell membrane, or neurites. CONCLUSION： Soybean isoflavone upregulated ERα, NGF, IL-2, and AR protein and gene expression in a dose-dependent manner, and played an important role in sustaining and protecting structure and function of cerebellar neurons. Moreover, the similarity of expression patterns of these molecules indicated that they were mutually interactive during the regulation of soybean isoflavone to the cerebellum.

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 （KBrO3）, 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 KBrO3, group 3 received KBrO3 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 KBrO3-exposed mice. When investigating redox homeostasis in the cerebellum, we found that mice treated with KBrO3 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 KBrO3-treated mice. Microscopy revealed that KBrO3 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 KBrO3.Conclusion Our results demonstrate that vanillin is a potential therapeutic agent for oxidative stress associated with neurodegenerative diseases.

The Effect of Tryptophan on Serotonin-Like Neurons in Duck Cerebellum

Healthy Cherry Valley ducks were used in the present study. Different doses of tryptophan were injected intraperitoneally to them after being fasted 4 h （8：00 a.m.-12：00 a.m.）. One hour later, they were deeply anaesthetized and perfused. The cerebellum was removed to make serial paraffin longitudinal sections. The streptavidin-biotin-peroxidase complex （SABC） method was used to study the distribution of serotonin-like neurons in the cerebellum. All films were analysed by using a computer-assisted image analysis system. Serotonin-like neurons are only localized in cerebellar Purkinje cell layer. The optical density averages of serotonin-like neurons in 200 and 100 mg kg^-1 group are significantly higher than that of 0 mg kg^-1 group （P〈0.01）. These results show that serotonin-like neurons are distributed in Purkinje cell layer and that excessive tryptophan can affect the content of serotonin in cerebellum.

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

Using a combined microsphere retrograde transport with immunofluorescence technique,the glutamate-immunoreactive neurons in the medullary raphe nuclei that project to the cerebellar cortex were investigated in the present study.The cells double-labeled by glutamate-immunoresctivity and microspheres were found in all medullary raphe nuclei.Among all the cerebellar projection neurons in the medullary raphe nuclei,(49. 49±2.78)% (±)in pallidus (NRP),(62.02±3. 62) % in obscures (NRD),(3. 03±3. 03) % in magnus (NRM) were immunoreactive to glutamate.The results raise the possibility that the cerehellar vermal cortex (lobules Ⅴ-Ⅶ) may receive some excitatory input from medullary raphe nuclei to affect the function of the cerebellum.

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.

Study on the Location of the Activated Cerebellum Regions in Manual Movement Related to Handedness

The present study used functional magnetic resonance imaging （fMRI） to study the activated site in the cerebellum during bi-hand movement and uni-hand movement, and the lateralization of the cerebellum in hand movement. The coordinates of the peak activation in the CRB were compared using statistical tests, and the results in the primary motor cortex （PMC） were presented as comparison. The results showed a significant difference in cerebellum during bi-hand movement comparing the right-handed with the left-handed subjects. When comparing the right-handed subjects and left-handed subjects during right-hand movement, the significantly different coordinate in dorsal/ventral orientation was observed. The results also showed the different activated site during bi-hand movement and non-dominant hand movement. Our study took the point of view of the lateralization in cerebellum, and the results demonstrated the different site of the peak activation in cerebellum during bi-hand movement and uni-hand movement, which suggested that the handedness also existed in the cerebellum.

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.