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.

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.

Exploring cerebral structural and functional abnormalities in a mouse model of post-traumatic headache induced by mild traumatic brain injury

Mild traumatic brain injury(mTBI)-induced post-traumatic headache(PTH)is a pressing public health concern and leading cause of disability worldwide.Although PTH is often accompanied by neurological disorders,the exact underlying mechanism remains largely unknown.Identifying potential biomarkers may prompt the diagnosis and development of effective treatments for mTBI-induced PTH.In this study,a mouse model of mTBI-induced PTH was established to investigate its effects on cerebral structure and function during short-term recovery.Results indicated that mice with mTBI-induced PTH exhibited balance deficits during the early post-injury stage.Metabolic kinetics revealed that variations in neurotransmitters were most prominent in the cerebellum,temporal lobe/cortex,and hippocampal regions during the early stages of PTH.Additionally,variations in brain functional activities and connectivity were further detected in the early stage of PTH,particularly in the cerebellum and temporal cortex,suggesting that these regions play central roles in the mechanism underlying PTH.Moreover,our results suggested that GABA and glutamate may serve as potential diagnostic or prognostic biomarkers for PTH.Future studies should explore the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex,with these two regions potentially utilized as targets for non-invasive stimulation in future clinical treatment.

Probiotic microorganisms affect the reproductive and nervous systems of male rats treated with acrylamide

Objective:To evaluate the protective effects of probiotic microorganisms on the reproductive and nervous systems of male rats treated with acrylamide.Methods:Thirty-two rats were randomly divided into 4 groups and received normal saline through gavage(control),acrylamide 20 mg/kg body weight,acrylamide plus probiotic microorganisms(Lactobacillus acidophilus,Lactobacillus casei,Lactobacillus bulgaricus,Lactobacillus rhamnosus,Bifidobacterium breve,Bifidobacterium infantis,Streptococcus thermophilus and fructooligosaccharides,all mixed in sachets)20 or 200 mg/kg body weight,respectively.After 30 days,the testis,prostate,seminal vesicle and cerebellum were removed,fixed and stained with hematoxylin-eosin(H&E).The Johnsen score was used to classify spermatogenesis.Cavalieri's principle method was used to evaluate the total volume(in mm3)of the testes.The number of each intratubular cell type as well as intertubular Leydig cells in whole samples was measured using the physical dissector counting techniques.Stereological analysis and the grids were used to determine the volume of cerebellar layers as well as the Purkinje cell number.Results:The testis weight decreased significantly in the acrylamide-treated group compared to the other groups(P<0.001).The number of spermatogonia,spermatocytes,spermatids and Leydig cells in the acrylamide-treated group were significantly less compared to the control group(P<0.05),while they were increased significantly in the acrylamide+200 mg/kg probiotic group(P<0.05;P<0.01).The mean Johnsen score in the acrylamide-treated group was lower than in the control group(P<0.001).Acrylamide-induced changes including congestion,vacuolization in the secretory epithelial cells,and epithelial rupture were observed in the prostate and seminal vesicle.The volumes of cerebellar layers were decreased in the acrylamide group compared to the control group while recovered in both probiotic treated groups.Conclusions:Probiotic microorganisms alleviate acrylamide-induced toxicities against the reproductive and cerebellar tissues in rats.

Distinct and Additive Effects of Alcohol and Thiamine Deficiency in the Developing Brain: Relevance to Fetal Alcohol Spectrum Disorder

Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse effects were likely due to neurotoxicity and the activation of apoptosis cascades. The findings suggest that FASD severity may be reduced by thiamine supplementation, but without additional support for insulin/IGF signaling networks, FASD would not be prevented.

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.

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.

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.

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 -alpha (ERalpha) and -beta (ERbeta) in the cerebral cortex, cerebellum, and olfactory bulb was investigated and compared between neonatal (1 to approximately 3-days-old) and adult (250 to approximately 350 g) rats, using reverse transcription-polymerase chain reaction (RT-PCR). No ERalpha transcripts were detectable in the adult cerebellum and olfactory bulb, whereas very weak expression of ERalpha was present in the adult cerebral cortex. No significant difference in ERbeta 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 ERalpha expression was significantly weaker than ERbeta. Even in the cerebral cortex known to contain both ER subtypes in adult rats, ERalpha transcripts in neonatal rats were much higher than in adult. These observations provide evidence for the existence of different expression patterns of ERalpha/ERbeta 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.

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 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.

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.

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.

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.

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.

Electro-Acupuncture for Treatment of Dysequillibrium Due to Cerebellum or Brain Stem Infarction

The authors treated 26 cases of dysequillibrium due tocerebellum or brain stem infarction byelectro-acupuncture from Aug 2000 - April 2002. Theresults were quite satisfactory and reported as follows.

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.