Motor Coordination Dysfunction Research Articles

Presymptomatic Targeted Circuit Manipulation for Ameliorating Huntington's Disease Pathogenesis.

Early stages of Huntington's disease (HD) before the onset of motor and cognitive symptoms are characterized by imbalanced excitatory and inhibitory output from the cortex to striatal and subcortical structures. The window before the onset of symptoms presents an opportunity to adjust the firing rate within microcircuits with the goal of restoring the impaired E/I balance, thereby preventing or slowing down disease progression. Here, we investigated the effect of presymptomatic cell-type specific manipulation of activity of pyramidal neurons and parvalbumin interneurons in the M1 motor cortex on disease progression in the R6/2 HD mouse model. Our results show that dampening excitation of Emx1 pyramidal neurons or increasing activity of parvalbumin interneurons once daily for 3 weeks during the pre-symptomatic phase alleviated HD-related motor coordination dysfunction. Cell-type-specific modulation to normalize the net output of the cortex is a potential therapeutic avenue for HD and other neurodegenerative disorders.

Proprioception vs Motor Coordination of PFM: definitions and differential diagnoses

Background: Although fundamental for good PFM training, proprioception and motor coordination remain confusing terms for most health professionals. Aims: To clarify the theoretical differences between the concepts of proprioception and motor coordination in the context of MAP, and to provide practical tools for the differential kinesiologicalfunctional diagnosis between proprioception and motor coordination dysfunctions. Method: Electronic mini-review of the literature. Results: Proprioception can be defined as the ability to perceive body positions and movements and, for PFM, its dysfunction can be understood as the inability to move (contract/relax). Motor coordination can be defined as the ability to move parts of the body in a precise and harmonic way. In the context of PFM, its dysfunction could be defined when the movement of that musculature is not precise enough. Conclusion: The concepts of proprioception and motor coordination could be defined in the context of PFM, allowing the establishment of differential kinesiological-functional diagnoses for the two dysfunctions.

The Impact of Alpha-lipoic acid on the Monosodium Glutamate Induced Motor Coordination Dysfunction in Rats

The Impact of Alpha-lipoic acid on the Monosodium Glutamate Induced Motor Coordination Dysfunction in Rats

Genetic variations in DOCK4 contribute to schizophrenia susceptibility in a Chinese cohort: A genetic neuroimaging study

BackgroundEmerging evidence suggests that the DOCK4 gene increases susceptibility to schizophrenia. However, no study has hitherto repeated this association in Chinese, and further investigated the relationship between DOCK4 and clinical symptoms in schizophrenic patients using clinical scales and functional magnetic resonance imaging (fMRI). MethodsIn this study, we genotyped three single nucleotide polymorphisms (SNPs) (rs2074127, rs2217262, and rs2074130) within the DOCK4 gene using a case-control design (including 1289 healthy controls and 1351 patients with schizophrenia). 55 first-episode schizophrenia (FES) patients and 59 healthy participants were divided by the genotypes of rs2074130 into CC and CT+TT groups. We further investigated the association with clinical symptoms and neural characteristics (brain activation/connectivity and nodal network metrics). ResultsOur results showed significant associations between all selected SNPs and schizophrenia (all P < 0.05). In patients, letter fluency and motor speed scores of T allele carriers were significantly higher than the CC group (all P < 0.05). Interestingly, greater brain activity, functional connectivity, and betweenness centrality (BC) in language processing and motor coordination were also observed in the corresponding brain zones in patients with the T allele based on a two-way ANCOVA model. Moreover, a potential positive correlation was found between brain activity/connectivity of these brain regions and verbal fluency and motor speed. ConclusionOur findings suggest that the DOCK4 gene may contribute to the onset of schizophrenia and lead to language processing and motor coordination dysfunction in this patient population from China.

Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway.

Chronic and long-term methamphetamine (METH) abuse is bound to cause damages to multiple organs and systems, especially the central nervous system (CNS). Icariside II (ICS), a type of flavonoid and one of the main active ingredients of the traditional Chinese medicine Epimedium, exhibits a variety of biological and pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. However, whether ICS could protect against METH-induced neurotoxicity remains unknown. Based on a chronic METH abuse mouse model, we detected the neurotoxicity after METH exposure and determined the intervention effect of ICS and the potential mechanism of action. Here, we found that METH could trigger neurotoxicity, which was characterized by loss of dopaminergic neurons, depletion of dopamine (DA), activation of glial cells, upregulation of α-synuclein (α-syn), abnormal dendritic spine plasticity, and dysfunction of motor coordination and balance. ICS treatment, however, alleviated the above-mentioned neurotoxicity elicited by METH. Our data also indicated that when ICS combated METH-induced neurotoxicity, it was accompanied by partial correction of the abnormal Kelch 2 like ECH2 associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and oxidative stress response. In the presence of ML385, an inhibitor of Nrf2, ICS failed to activate the Nrf2-related protein expression and reduce the oxidative stress response. More importantly, ICS could not attenuate METH-induced dopaminergic neurotoxicity and behavioral damage when the Nrf2 was inhibited, suggesting that the neuroprotective effect of ICS on METH-induced neurotoxicity was dependent on activating the Keap1-Nrf2 pathway. Although further research is needed to dig deeper into the actual molecular targets of ICS, it is undeniable that the current results imply the potential value of ICS to reduce the neurotoxicity of METH abusers.

Lipoxin A4 Receptor Stimulation Attenuates Neuroinflammation in a Mouse Model of Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is caused by the rupture of blood vessels in the brain. The excessive activation of glial cells and the infiltration of numerous inflammatory cells are observed during bleeding. Thrombin is a key molecule that triggers neuroinflammation in the ICH brain. In this study, we focused on lipoxin A4 (LXA4), an arachidonic acid metabolite that has been reported to suppress inflammation and cell migration. LXA4 and BML-111, an agonist of the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2), suppressed microglial activation; LXA4 strongly inhibited the migration of neutrophil-like cells in vitro. ALX/FPR2 was expressed on neutrophils in the ICH mouse brain and the daily administration of BML-111 attenuated the motor coordination dysfunction and suppressed the production of proinflammatory cytokines in the ICH mouse brain. On the other hand, BML-111 did not show a significant reduction in the number of microglia and neutrophils. These results suggest that systemic administration of ALX/FPR2 agonists may suppress the neuroinflammatory response of microglia and neutrophils without a change in cell numbers. Additionally, their combination with molecules that reduce cell numbers, such as modulators of leukotriene B4 signaling, may be required in future studies.

Chronic Toxoplasma gondii Infection Potentiates Parkinson's Disease Course in Mice Model.

Background:Toxoplasma gondii is a neuroinvasive protozoa pathogen that could manipulate its intermediate host's behavior. However, the possible link between T. gondii infection and the development of neurodegenerative disorders such as Parkinson’s disease (PD) has been proposed, we tested the hypothesis that in chronic toxoplasmosis neuroinflammation, and molecular mediators potentiate behavioral-cognitive impairments in BALB/c mice with PD.Methods:To establish chronic toxoplasmosis by Tehran strain, cysts of T. gondii were injected intraperitoneally into BALB/c mice in Kerman, Iran in 2019. To induce the PD model, mice (BALB/c) were treated with Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The behavioral experiments such as anxiety and motor coordination were performed using the Open field and Rotarod tests. Additionally, we investigated the contribution of Toxoplasma-induced neuroinflammation, and behavioral-cognitive impairments in the PD mice model.Results:Chronic toxoplasmosis caused PD-like symptoms and induced various behavioral changes in infected BALB/c mice. In T. gondii infected+MPTP treated group, T. gondii infection could potentiate PD in infected mice receiving MPTP and caused remarkable dysfunction in motor coordination and change in anxiety and depression-like behaviors similar or more severe than PD group.Conclusion:Chronic T. gondii infection exacerbates pathological progression of PD in BALB/c mice brain by promoting neuroinflammation, and behavioral changes establishing.

Aberrant brain oscillatory coupling from the primary motor cortex in children with autism spectrum disorders

Autism spectrum disorder (ASD) often involves dysfunction in general motor control and motor coordination, in addition to core symptoms. However, the neural mechanisms underlying motor dysfunction in ASD are poorly understood. To elucidate this issue, we focused on brain oscillations and their coupling in the primary motor cortex (M1). We recorded magnetoencephalography in 18 children with ASD, aged 5 to 7 years, and 19 age- and IQ-matched typically-developing children while they pressed a button during a video-game-like motor task. The motor-related gamma (70 to 90 Hz) and pre-movement beta oscillations (15 to 25 Hz) were analyzed in the primary motor cortex using an inverse method. To determine the coupling between beta and gamma oscillations, we applied phase-amplitude coupling to calculate the statistical dependence between the amplitude of fast oscillations and the phase of slow oscillations. We observed a motor-related gamma increase and a pre-movement beta decrease in both groups. The ASD group exhibited a reduced motor-related gamma increase and enhanced pre-movement beta decrease in the ipsilateral primary motor cortex. We found phase-amplitude coupling, in which high-gamma activity was modulated by the beta rhythm in the primary motor cortex. Phase-amplitude coupling in the ipsilateral primary motor cortex was reduced in the ASD group compared with the control group. Using oscillatory changes and their couplings, linear discriminant analysis classified the ASD and control groups with high accuracy (area under the receiver operating characteristic curve: 97.1%). The current findings revealed alterations in oscillations and oscillatory coupling, reflecting the dysregulation of motor gating mechanisms in ASD. These results may be helpful for elucidating the neural mechanisms underlying motor dysfunction in ASD, suggesting the possibility of developing a biomarker for ASD diagnosis.

Modern principles of diagnosis and treatment of Kinsbourne encephalopathy (a clinical case)

Opsoclonus-myoclonus syndrome (OMS) or Kinsbourne encephalopathy is a unique, rare neurological disease that causes difficulties in diagnosis, examination and treatment tactics. This article presents some organizational clinical, psychological and rehabilitation issues.The aim of the study was to develop treatment tactics and means of preventing the recurrent development of neurological, behavioral and cognitive impairment in this pathology.Results. Diagnosis of the disease was carried out based on a detailed study of anamnestic, molecular genetic, scintigraphic, neuroimaging, ultrasound, lymphocytic and neurological (opsoclonus, myoclonus, ataxia, behavioral and sleep disorders) signs. The severity of a child condition was determined using the Pranzatelli M. and Matthay K. scales. The clinical picture was represented by specific involuntary, arrhythmic, chaotic, multidirectional saccadic eye movements with horizontal, vertical, torsional components, behavioral changes, sleep disturbances, motor coordination dysfunction, the presence of myoclonic seizures, myoclonic jerks in the limbs and trunk, cerebellar ataxia and tremor. Slight cerebrospinal fluid lymphocytic pleocytosis was noted in the child, as it was described in the literature. Due to the fact that Kinsbourne encephalopathy has a paraneoplastic etiology in most cases, the child underwent brain MRI and CT as well as laboratory and instrumental examinations of the internal organs. The neuroimaging examination of the child’s brain indicated no focal density changes.To rule out neuroblastoma, the child underwent ultrasound examination of the abdominal cavity organs and retroperitoneal space, a blood test for tumor markers, and measurements of catecholamine levels. To rule out parainfection and autoimmune processes, serum antibodies to various viruses were studied. Diagnosis of OMS was based on the analysis of the clinical picture, medical history and screening tests for oncopathology which was ruled out after a cytological study.The prolonged multiple use of a combination of glucocorticoid, immunosuppressive and immunoglobulin therapy has been the essence of successful treatment. Currently, relative improvements in the emotional-volitional sphere can be reported - age-appropriate intelligence and vocabulary skills, pulls himself up to stand and walks without support. Ocular opsoclonus rarely occurs – more often in jitteriness.Conclusions. The rare occurrence and anatomical and biological characteristics of this disease emphasize the importance of search for new specific methods of diagnosis and treatment to implement timely measures aimed at slowing the disease progression.

3-Nitro-Tyrosine as a Biomarker of Minimal Hepatic Encephalopathy in Patients with Liver Cirrhosis

Abstract Background hepatic encephalopathy (HE) is a common complication in patient with liver cirrhosis. It comprises of a broad spectrum of neuropsychiatric abnormalities of varying severity, and affected patients usually suffer from psychomotor, cognitive, emotional, behavioural, and motor coordination dysfunctions. Patients with minimal HE (MHE), a subclinical form of HE, usually have a normal mental and neurological status upon routine clinical examination. The subtle deficits in patients with MHE can only be elicited by specialized neuropsychological tests. Aim of the Work the aim of this study was to evaluate the role of 3-Nitro-Tyrosine as a biomarker of Minimal Hepatic Encephalopathy in patients with liver cirrhosis. Patients and Methods our conducted study was a prospective case control study carried on 60 adult patients and 30 age matched controls. All were recruited from Internal Medicine and Hepatology and Gastroenterology Department at Ain Shams University Hospitals in the period between September 2016 and June 2018. All patients enrolled in the study were subjected to detailed history taking, full physical examination, laboratory investigations, psychometric tests for detection of MHE using specially digit symbol test (DST), Trail making test A (TMT A), Trail making test B (TMT B), serial dotting test (SDT) and 3-Nitro-Tyrosine level (3NT). Results our study found that the serum levels of 3-nitro-tyrosine are a good predictor of the presence of MHE in patients with liver cirrhosis, with good sensitivity (90%) and specificity (93.33%) and positive and negative predictive values were 93.1% and 90.3% respectively at a cutoff of 14.8 ng. Conclusion determination of 3-nitro-tyrosine in serum is easy and is not time consuming. It only requires taking a serum sample from the patient and determining 3-nitro-tyrosine concentration. This procedure can be therefore easily added to the routine clinical determinations in patients with liver cirrhosis. This would also allow extending the diagnosis of MHE to most clinical settings, helping to identify patients with MHE.

The Influence of IQ Levels on Clinical Features of Developmental Coordination Disorder

Objective: There is no study exploring the correlation between motor coordination dysfunction and high cognitive functioning. We aim to explore the influence of IQ (≥120) on clinical features of DCD. Method: We collected data from 38 children (average age: 9 years old, 2.7 SD) with DCD based on criteria of DSM-5. Two matched groups of DCD were studied according to the IQ: 19 typical children (IQ = 90-110) and 19 HIQ-HIP children. Within this last group, we distinguished superior IQ (120-129) (HIQ), and very superior IQ (≥130) (HIP). All participants completed assessments of neuropsychological, neurovisual, and neuropsychomotor functions. Result: We displayed less Ideomotor (IM), Visio-Spatial/Constructive (VSC)-DCD and more Mixed (MX)-DCD in HIQ-HIP compared to typical children DCD. We showed significant correlations between IM-DCD and executive functions disorders (ρ=+0.519 [95% CI, 0.163 to 0.795], p=0.001), between visuo-constructional task and VSC-DCD subtype (ρ= -0.651 [95% CI, -0.899 to -0.406], p=0.006). A statistical difference between both groups was shown in adiadochokinesia and bimanual coordination disorder in favor of typical children. There is no significant difference between HIP and HIQ. More left-handed in functional laterality was found with IQ≥130, χ2 (1)=4.571, p=0.033, [95% CI, 0.052 to 0.061]. Conclusion: Both groups displayed similar clinical features of DCD. HIQ-HIP groups have better executive functions and visio-spatial functioning than typical children with DCD but worse auditory attention and memory, and more neurological soft signs related to the high rate of MX-DCD. The findings are useful for clinical decision-making processes.

Genetic and behavioral characterization of a Kmt2d mouse mutant, a new model for Kabuki Syndrome.

The recessive mutant mice bate palmas (bapa) - claps in Portuguese arose from N-ethyl-N-nitrosourea mutagenesis. A single nucleotide, T > C, change in exon 13, leading to a Thr1289 Ala substitution, was identified in the lysine (K)-specific methyltransferase 2D gene (Kmt2d) located on chromosome 15. Mutations with a loss-of-function in the KMT2D gene on chromosome 12 in humans are responsible for Kabuki syndrome (KS). Phenotypic characterization of the bapa mutant was performed using a behavioral test battery to evaluate the parameters related to general activity, the sensory nervous system, the psychomotor system, and the autonomous nervous system, as well as to measure motor function and spatial memory. Relative to BALB/cJ mice, the bapa mutant showed sensory and psychomotor impairments, such as hypotonia denoted by a surface righting reflex impairment and hindquarter fall, and a reduction in the auricular reflex, suggesting hearing impairment. Additionally, the enhanced general activity showed by the increased rearing and grooming frequency, distance traveled and average speed possibly presupposes the presence of hyperactivity of bapa mice compared with the control group. A slight motor coordination dysfunction was showed in bapa mice, which had a longer crossing time on the balance beam compared with BALB/cJ controls. Male bapa mice also showed spatial gait pattern changes, such as a shorter stride length and shorter step length. In conclusion, the bapa mouse may be a valuable animal model to study the mechanisms involved in psychomotor and behavior impairments, such as hypotonia, fine motor coordination and hyperactivity linked to the Kmt2d mutation.

Pathological changes in mice with long term cuprizone administration

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). In MS, a long disease duration is known to be a strong risk factor for converting the clinical course of the disease from relapse remitting MS to secondary progressing MS. There is a hypothesis that long sustained demyelination may exhaust neurons, however, pathological changes induced in neurons following demyelination remain unknown. Cuprizone administration can induce and sustain demyelination in the mouse CNS. We examined pathological changes in mice following long sustained demyelination caused by up to 34-week cuprizone administration. Twelve-week cuprizone administration induced severe demyelination in the cerebral cortex, corpus callosum and deep cerebellar nuclei. Demyelination persisted up to 34 weeks, as shown by myelin basic protein immunohistochemistry. In contrast, cuprizone administration developed demyelination in the striatum by week 34. In these demyelinated regions, no neuronal loss was observed. However, in the striatum and deep cerebellar nuclei, cuprizone-induced demyelination changed the intracellular distribution of parvalbumin (PV). Furthermore, in the striatum, there was an increase in PV in the demyelinated axons and most PV immunoreactivity did not co-localize with SMI32 immunoreactivity in mice with 34-week cuprizone administration. Further, mice with 34-week cuprizone administration showed motor coordination dysfunction in the balance beam test. However, 12-week withdrawal from the cuprizone diet induced remyelination in the regions and motor coordination dysfunction recovered. These results indicate that 34-week cuprizone administration induces and sustains demyelination and results in reversible motor coordination dysfunction. The change of intracellular PV distribution suggests that PV may protect demyelinated axons by Ca2+ buffering. This model may be useful to investigate pathological and behavioral changes following demyelination in the CNS.

Mutation in NADPH oxidase 3 (NOX3) impairs SHH signaling and increases cerebellar neural stem/progenitor cell proliferation

Abnormalities in cerebellar structure and function may cause ataxia, a neurological dysfunction of motor coordination. In the course of the present study, we characterized a mutant mouse lineage with an ataxia-like phenotype. We localized the mutation on chromosome 17 and mapped it to position 1534 of the Nox3 gene, resulting in p.Asn64Tyr change. The primary defect observed in Nox3eqlb mice was increased proliferation of cerebellar granule cell precursors (GCPs). cDNA microarray comparing Nox3eqlb and BALB/c neonatal cerebellum revealed changes in the expression of genes involved in the control of cell proliferation. Nox3eqlb GCPs and NSC produce higher amounts of reactive oxygen species (ROS) and upregulate the expression of SHH target genes, such as Gli1–3 and Ccnd1 (CyclinD1). We hypothesize that this new mutation is responsible for an increase in proliferation via stimulation of the SHH pathway. We suggest this mutant mouse lineage as a new model to investigate the role of ROS in neuronal precursor cell proliferation.

Autism, Joint Hypermobility-Related Disorders and Pain.

Autism Spectrum Disorder (ASD) and Joint Hypermobility-Related Disorders are blanket terms for two etiologically and clinically heterogeneous groups of pathologies that usually appears in childhood. These conditions are seen by different medical fields, such as psychiatry in the case of ASD, and musculoskeletal disciplines and genetics in the case of hypermobility-related disorders. Thus, a link between them is rarely established in clinical setting, despite a scarce but growing body of research suggesting that both conditions co-occur more often than expected by chance. Hypermobility is a frequent sign of hereditary disorders of connective tissue (e.g., Ehlers-Danlos syndromes, Marfan syndrome), in which the main characteristic is the multisystem fragility that prone to proprioceptive and motor coordination dysfunction and hence to trauma and chronic pain. Considering the high probability that pain remains disregarded and untreated in people with ASD due to communication and methodological difficulties, increasing awareness about the interconnection between ASD and hypermobility-related disorders is relevant, since it may help identify those ASD patients susceptible to chronic pain.

3-Nitro-Tyrosine as a Biomarker of Minimal Hepatic Encephalopathy in Patients with Liver Cirrhosis

Background: hepatic encephalopathy (HE) is a common complication in patient with liver cirrhosis. It comprises of a broad spectrum of neuropsychiatric abnormalities of varying severity, and affected patients usually suffer from psychomotor, cognitive, emotional, behavioural, and motor coordination dysfunctions. Patients with minimal HE (MHE), a subclinical form of HE, usually have a normal mental and neurological status upon routine clinical examination. The subtle deficits in patients with MHE can only be elicited by specialized neuropsychological tests. Aim of the Work: the aim of this study was to evaluate the role of 3-Nitro-Tyrosine as a biomarker of Minimal Hepatic Encephalopathy in patients with liver cirrhosis. Patients and Methods: our conducted study was a prospective case control study carried on 60 adult patients and 30 age matched controls. All were recruited from Internal Medicine and Hepatology and Gastroenterology Department at Ain Shams University Hospitals in the period between September 2016 and June 2018. All patients enrolled in the study were subjected to detailed history taking, full physical examination, laboratory investigations, psychometric tests for detection of MHE using specially digit symbol test (DST), Trail making test A (TMT A), Trail making test B (TMT B), serial dotting test (SDT) and 3-Nitro-Tyrosine level (3NT). Results: our study found that the serum levels of 3-nitro-tyrosine are a good predictor of the presence of MHE in patients with liver cirrhosis, with good sensitivity (90%) and specificity (93.33%) and positive and negative predictive values were 93.1% and 90.3% respectively at a cutoff of 14.8 ng. Conclusion: determination of 3-nitro-tyrosine in serum is easy and is not time consuming. It only requires taking a serum sample from the patient and determining 3-nitro-tyrosine concentration. This procedure can be therefore easily added to the routine clinical determinations in patients with liver cirrhosis. This would also allow extending the diagnosis of MHE to most clinical settings, helping to identify patients with MHE.

Chronic traffic noise stress accelerates brain impairment and cognitive decline in mice

Although traffic noise exposure is a well-known environmental pollutant whose negative health effect has been discussed in different aspects of the human life, only a few animal studies have tackled this issue as a cohort study, which is not feasible to be addressed in human studies. In addition to the deleterious impact of the daytime noise on well-being, chronic nocturnal noise can also disturb sleep and affects physical and mental health, but to date, little research has examined the neurobiological effects of light/dark cycles of traffic noise exposure. We investigated the effects of light/dark cycles and sex on the impact of chronic traffic noise exposure on mouse brain structure-function. The mice were randomly assigned to either one of two stress conditions or a control condition. Animals were exposed to traffic noise on either the light-cycle (LC) or dark-cycle (DC) for 30 days. Traffic noise exposure caused the hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, anxiety-like behavior, impairments in learning and memory, dysfunction in balance and motor coordination, and a reduction in variety of brain measures including a brain volume, medial prefrontal cortex (mPFC) area, cortical thickness, hippocampal volume, amygdala area, and the neural density in mPFC and dentate gyrus. All behavioral and brain measures revealed adverse effects of the chronic noise stress irrespective of the LC/DC exposure or sex. Our findings were a re-emphasis on the significance of noise prevention and mitigation strategies for public health.

Maternal iodine supplementation improves motor coordination in offspring by modulating the mGluR1 signaling pathway in mild iodine deficiency-induced hypothyroxinemia rats

Iodine is an essential component for thyroid hormone synthesis. Epidemiological investigations have demonstrated that maternal mild iodine deficiency (ID)-induced hypothyroxinemia can affect intellectual and behavioral function in offspring. There is no definitive evidence demonstrating the effects of maternal iodine supplementation on neurobehavioral function in regional areas with mild ID. Thus, we aimed to clarify the effects of maternal mild ID and iodine supplementation on motor coordination in offspring and illuminate the underlying molecular mechanisms. Animal models of maternal mild ID and iodine supplementation were generated by providing Wistar rats an iodine-deficient diet and deionized water supplemented with potassium iodide during pregnancy and lactation. We found that mild ID-induced hypothyroxinemia led to a shorter latent time before falling down from the rotarod, a longer time to traverse the balance beam and poorer wire grip of the forelimbs, which imply motor coordination dysfunction. However, these impairments in the offspring were improved by iodine supplementation during pregnancy and lactation. We further observed that the ultrastructure and dendritic tree morphology of cerebellar Purkinje cells were altered in mild ID-induced hypothyroxinemia but that these changes could be reversed by iodine supplementation. Maternal mild ID and iodine supplementation also affected expression of the mGluR1 signaling pathway in offspring. Together, iodine supplementation during pregnancy and lactation can improve motor coordination in offspring by modulating the mGluR1 signaling pathway in mild ID-induced hypothyroxinemia rats.

Down-regulation of ghrelin receptors on dopaminergic neurons in the substantia nigra contributes to Parkinson\u2019s disease-like motor dysfunction

Ghrelin exerts a wide range of physiological actions throughout the body and appears to be a promising target for disease therapy. Endogenous ghrelin receptors (GHSRs) are present in extrahypothalamic sites including the substantia nigra pars compacta (SNc), which is related to phenotypic dysregulation or frank degeneration in Parkinson’s disease (PD). Here we found a dramatic decrease in the expression of GHSR in PD-specific induced pluripotent stem cell (iPSC)-derived dopaminergic (DAnergic) neurons generated from patients carrying parkin gene (PARK2) mutations compared to those from healthy controls. Consistently, a significant decrease in the expression of GHSR was found in DAnergic neurons of isogenic PARK2-iPSC lines that mimicked loss of function of the PARK2 gene through CRISPR Cas9 technology. Furthermore, either intracerebroventricular injection or microinjection into the SNc of the selective GHSR1a antagonist [D-Lys3]-GHRP6 in normal mice produced cataleptic behaviors related to dysfunction of motor coordination. These findings suggest that the down-regulation of GHSRs in SNc-DA neurons induced the initial dysfunction of DA neurons, leading to extrapyramidal disorder under PD.

Disorganization of Oligodendrocyte Development in the Layer II/III of the Sensorimotor Cortex Causes Motor Coordination Dysfunction in a Model of White Matter Injury in Neonatal Rats

We previously established neonatal white matter injury (WMI) model rat that is made by right common carotid artery dissection at postnatal day 3, followed by 6% hypoxia for 60min. This model has fewer oligodendrocyte progenitor cells and reduced myelin basic protein (MBP) positive areas in the sensorimotor cortex, but shows no apparent neuronal loss. However, how motor deficits are induced in this model is unclear. To elucidate the relationship between myelination disturbance and concomitant motor deficits, we first performed motor function tests (gait analysis, grip test, horizontal ladder test) and then analyzed myelination patterns in the sensorimotor cortex using transmission electron microscopy (TEM) and Contactin associated protein 1 (Caspr) staining in the neonatal WMI rats in adulthood. Behavioral tests revealed imbalanced motor coordination in this model. Motor deficit scores were higher in the neonatal WMI model, while hindlimb ladder stepping scores and forelimb grasping force were comparable to controls. Prolonged forelimb swing times and decreased hindlimb paw angles on the injured side were revealed by gait analysis. TEM revealed no change in myelinated axon number and the area g-ratio in the layer II/III of the cortex. Electromyographical durations and latencies in the gluteus maximus in response to electrical stimulation of the brain area were unchanged in the model. Caspr staining revealed fewer positive dots in layers II/III of the WMI cortex, indicating fewer and/or longer myelin sheath. These data suggest that disorganization of oligodendrocyte development in layers II/III of the sensorimotor cortex relates to imbalanced motor coordination in the neonatal WMI model rat.