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Sample records for motor neurons

  1. Neurons other than motor neurons in motor neuron disease.

    PubMed

    Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

  2. Motor neurone disease.

    PubMed

    2016-03-23

    Essential facts Motor neurone disease describes a group of related diseases, affecting the neurones in the brain and spinal cord. Progressive, incurable and life-limiting, MND is rare, with about 1,100 people developing it each year in the UK and up to 5,000 people affected at any one time. One third of people will die within a year of diagnosis and more than half within two years. About 5% to 10% are alive at ten years.

  3. Pain in motor neuron disease.

    PubMed Central

    Newrick, P G; Langton-Hewer, R

    1985-01-01

    Twenty-seven of 42 patients with motor neuron disease had significant pain. The nature and duration of the pain are described along with an illustrative case-report. The aetiology and most effective treatment of this common complication of motor neuron disease remain unclear. PMID:4031936

  4. Motor neuropathies and lower motor neuron syndromes.

    PubMed

    Verschueren, A

    2017-05-01

    Motor or motor-predominant neuropathies may arise from disease processes affecting the motor axon and/or its surrounding myelin. Lower motor neuron syndrome (LMNS) arises from a disease process affecting the spinal motor neuron itself. The term LMNS is more generally used, rather than motor neuronopathy, although both entities are clinically similar. Common features are muscle weakness (distal or proximal) with atrophy and hyporeflexia, but no sensory involvement. They can be acquired or hereditary. Immune-mediated neuropathies (multifocal motor neuropathy, motor-predominant chronic inflammatory demyelinating polyneuropathy) are important to identify, as effective treatments are available. Other acquired neuropathies, such as infectious, paraneoplastic and radiation-induced neuropathies are also well known. Focal LMNS is an amyotrophic lateral sclerosis (ALS)-mimicking syndrome especially affecting young adults. The main hereditary LMNSs in adulthood are Kennedy's disease, late-onset spinal muscular atrophy and distal hereditary motor neuropathies. Motor neuropathies and LMNS are all clinical entities that should be better known, despite being rare diseases. They can sometimes be difficult to differentially diagnose from other diseases, particularly from the more frequent ALS in its pure LMN form. Nevertheless, correct identification of these syndromes is important because their treatment and prognoses are definitely different. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Motor neurone disease: an overview.

    PubMed

    Kent, Anna

    Motor neurone disease (MND) is a relatively rare, progressive and incurable neurological condition affecting patients' speech, mobility and respiratory function. Care of patients with MND is complex and involves various healthcare professionals and services. There is a need to discuss symptom management and promote palliative and end of life care from the point of diagnosis to ensure appropriate holistic care is provided.

  6. Differentiating lower motor neuron syndromes.

    PubMed

    Garg, Nidhi; Park, Susanna B; Vucic, Steve; Yiannikas, Con; Spies, Judy; Howells, James; Huynh, William; Matamala, José M; Krishnan, Arun V; Pollard, John D; Cornblath, David R; Reilly, Mary M; Kiernan, Matthew C

    2017-06-01

    Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  7. Quo vadis motor neuron disease?

    PubMed Central

    Balendra, Rubika; Patani, Rickie

    2016-01-01

    Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The aetio-pathogenesis of MND remains unresolved and no effective treatments exist. The only Food and Drug Administration approved disease modifying therapy is riluzole, a glutamate antagonist, which prolongs survival by up to 3 mo. Current management is largely symptomatic/supportive. There is therefore a desperate and unmet clinical need for discovery of disease mechanisms to guide novel therapeutic strategy. In this review, we start by introducing the organizational anatomy of the motor system, before providing a clinical overview of its dysfunction specifically in MND. We then summarize insights gained from pathological, genetic and animal models and conclude by speculating on optimal strategies to drive the step change in discovery, which is so desperately needed in this arena. PMID:27019797

  8. Motor neuron dysfunction in frontotemporal dementia.

    PubMed

    Burrell, James R; Kiernan, Matthew C; Vucic, Steve; Hodges, John R

    2011-09-01

    Frontotemporal dementia and motor neuron disease share clinical, genetic and pathological characteristics. Motor neuron disease develops in a proportion of patients with frontotemporal dementia, but the incidence, severity and functional significance of motor system dysfunction in patients with frontotemporal dementia has not been determined. Neurophysiological biomarkers have been developed to document motor system dysfunction including: short-interval intracortical inhibition, a marker of corticospinal motor neuron dysfunction and the neurophysiological index, a marker of lower motor neuron dysfunction. The present study performed detailed clinical and neurophysiological assessments on 108 participants including 40 consecutive patients with frontotemporal dementia, 42 age- and gender-matched patients with motor neuron disease and 26 control subjects. Of the 40 patients with frontotemporal dementia, 12.5% had concomitant motor neuron disease. A further 27.3% of the patients with frontotemporal dementia had clinical evidence of minor motor system dysfunction such as occasional fasciculations, mild wasting or weakness. Biomarkers of motor system function were abnormal in frontotemporal dementia. Average short-interval intracortical inhibition was reduced in frontotemporal dementia (4.3 ± 1.7%) compared with controls (9.1 ± 1.1%, P < 0.05). Short-interval intracortical inhibition was particularly reduced in the progressive non-fluent aphasia subgroup, but was normal in patients with behavioural variant frontotemporal dementia and semantic dementia. The neurophysiological index was reduced in frontotemporal dementia (1.1) compared with controls (1.9, P < 0.001), indicating a degree of lower motor neuron dysfunction, although remained relatively preserved when compared with motor neuron disease (0.7, P < 0.05). Motor system dysfunction in frontotemporal dementia may result from pathological involvement of the primary motor cortex, with secondary

  9. Advances in motor neurone disease.

    PubMed

    Bäumer, Dirk; Talbot, Kevin; Turner, Martin R

    2014-01-01

    Motor neurone disease (MND), the commonest clinical presentation of which is amyotrophic lateral sclerosis (ALS), is regarded as the most devastating of adult-onset neurodegenerative disorders. The last decade has seen major improvements in patient care, but also rapid scientific advances, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS is strikingly heterogeneous in both its presentation, with an average one-year delay from first symptoms to diagnosis, and subsequent rate of clinical progression. Although half of patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. Although an apparently sporadic disorder for most patients, without clear environmental triggers, recent genetic studies have identified disease-causing mutations in genes in several seemingly disparate functional pathways, so that motor neuron degeneration may need to be understood as a common final pathway with a number of upstream causes. This apparent aetiological and clinical heterogeneity suggests that therapeutic studies should include detailed biomarker profiling, and consider genetic as well as clinical stratification. The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein degradation pathways in the core of ALS pathogenesis. A major gap remains in understanding how such fundamental processes appear to function without obvious deficit in the decades prior to symptom emergence, and the study of pre-symptomatic gene carriers is an important new initiative.

  10. Multidisciplinary Interventions in Motor Neuron Disease

    PubMed Central

    Williams, U. E.; Philip-Ephraim, E. E.; Oparah, S. K.

    2014-01-01

    Motor neuron disease is a neurodegenerative disease characterized by loss of upper motor neuron in the motor cortex and lower motor neurons in the brain stem and spinal cord. Death occurs 2–4 years after the onset of the disease. A complex interplay of cellular processes such as mitochondrial dysfunction, oxidative stress, excitotoxicity, and impaired axonal transport are proposed pathogenetic processes underlying neuronal cell loss. Currently evidence exists for the use of riluzole as a disease modifying drug; multidisciplinary team care approach to patient management; noninvasive ventilation for respiratory management; botulinum toxin B for sialorrhoea treatment; palliative care throughout the course of the disease; and Modafinil use for fatigue treatment. Further research is needed in management of dysphagia, bronchial secretion, pseudobulbar affect, spasticity, cramps, insomnia, cognitive impairment, and communication in motor neuron disease. PMID:26317009

  11. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

    PubMed

    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

  12. Motor neurons and the generation of spinal motor neuron diversity

    PubMed Central

    Stifani, Nicolas

    2014-01-01

    Motor neurons (MNs) are neuronal cells located in the central nervous system (CNS) controlling a variety of downstream targets. This function infers the existence of MN subtypes matching the identity of the targets they innervate. To illustrate the mechanism involved in the generation of cellular diversity and the acquisition of specific identity, this review will focus on spinal MNs (SpMNs) that have been the core of significant work and discoveries during the last decades. SpMNs are responsible for the contraction of effector muscles in the periphery. Humans possess more than 500 different skeletal muscles capable to work in a precise time and space coordination to generate complex movements such as walking or grasping. To ensure such refined coordination, SpMNs must retain the identity of the muscle they innervate. Within the last two decades, scientists around the world have produced considerable efforts to elucidate several critical steps of SpMNs differentiation. During development, SpMNs emerge from dividing progenitor cells located in the medial portion of the ventral neural tube. MN identities are established by patterning cues working in cooperation with intrinsic sets of transcription factors. As the embryo develop, MNs further differentiate in a stepwise manner to form compact anatomical groups termed pools connecting to a unique muscle target. MN pools are not homogeneous and comprise subtypes according to the muscle fibers they innervate. This article aims to provide a global view of MN classification as well as an up-to-date review of the molecular mechanisms involved in the generation of SpMN diversity. Remaining conundrums will be discussed since a complete understanding of those mechanisms constitutes the foundation required for the elaboration of prospective MN regeneration therapies. PMID:25346659

  13. Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss.

    PubMed

    Wyatt, Tanya J; Rossi, Sharyn L; Siegenthaler, Monica M; Frame, Jennifer; Robles, Rockelle; Nistor, Gabriel; Keirstead, Hans S

    2011-01-01

    Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN), ALS (SOD1 G93A), and spinal cord injury (SCI). The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

  14. Trophic Factor Expression in Phrenic Motor Neurons

    PubMed Central

    Mantilla, Carlos B.; Sieck, Gary C.

    2008-01-01

    The function of a motor neuron and the muscle fibers it innervates (i.e., a motor unit) determines neuromotor output. Unlike other skeletal muscles, respiratory muscles (e.g., the diaphragm, DIAm) must function from birth onwards in sustaining ventilation. DIAm motor units are capable of both ventilatory and non-ventilatory behaviors, including expulsive behaviors important for airway clearance. There is significant diversity in motor unit properties across different types of motor units in the DIAm. The mechanisms underlying the development and maintenance of motor unit diversity in respiratory muscles (including the DIAm) are not well understood. Recent studies suggest that trophic factor influences contribute to this diversity. Remarkably little is known about the expression of trophic factors and their receptors in phrenic motor neurons. This review will focus on the contribution of trophic factors to the establishment and maintenance of motor unit diversity in the DIAm, during development and in response to injury or disease. PMID:18708170

  15. Delayed focal involvement of upper motor neurons in the Madras pattern of motor neuron disease.

    PubMed

    Massa, R; Scalise, A; Iani, C; Palmieri, M G; Bernardi, G

    1998-12-01

    We report the case of a young man from the south of India, initially presenting the typical signs of benign monomelic amyotrophy (BMA) in the left upper limb. After several years, the involvement of other limbs and the appearance of bulbar signs suggested the possible diagnosis of the Madras pattern of motor neuron disease (MMND). Serial motor evoked potential (MEP) recordings allowed detection of the onset of a focal involvement of upper motor neurons (UMN) controlling innervation in the originally amyotrophic limb. Therefore, serial MEP recordings can be useful for the early detection of sub-clinical UMN damage in motor neuron disease presenting with pure lower motor neuron (LMN) signs.

  16. Protein phosphorylation networks in motor neuron death.

    PubMed

    Hu, Jie Hong; Krieger, Charles

    2002-01-01

    The disorder amyotrophic lateral sclerosis (ALS) is characterized by the death of specific groups of neurons, especially motor neurons, which innervate skeletal muscle, and neurons connecting the cerebral cortex with motor neurons, such as corticospinal tract neurons. There have been numerous attempts to elucidate why there is selective involvement of motor neurons in ALS. Recent observations have demonstrated altered activities and protein levels of diverse kinases in the brain and spinal cord of transgenic mice that overexpress a mutant superoxide dismutase (mSOD) gene that is found in patients with the familial form of ALS, as well as in patients who have died with ALS. These results suggest that the alteration of protein phosphorylation may be involved in the pathogenesis of ALS. The changes in protein kinase and phosphatase expression and activity can affect the activation of important neuronal neurotransmitter receptors such as NMDA receptors or other signaling proteins and can trigger, or modify, the process producing neuronal loss in ALS. These various kinases, phosphatases and signaling proteins are involved in many signaling pathways; however, they have close interactions with each other. Therefore, an understanding of the role of protein kinases and protein phosphatases and the molecular organization of protein phosphorylation networks are useful to determine the mechanisms of selective motor neuron death.

  17. A computational model of motor neuron degeneration.

    PubMed

    Le Masson, Gwendal; Przedborski, Serge; Abbott, L F

    2014-08-20

    To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. A COMPUTATIONAL MODEL OF MOTOR NEURON DEGENERATION

    PubMed Central

    Le Masson, Gwendal; Przedborski, Serge; Abbott, L.F.

    2014-01-01

    SUMMARY To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. PMID:25088365

  19. Heavy metals in locus ceruleus and motor neurons in motor neuron disease

    PubMed Central

    2013-01-01

    Background The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Results Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Conclusions Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons. PMID:24330485

  20. Heavy metals in locus ceruleus and motor neurons in motor neuron disease.

    PubMed

    Pamphlett, Roger; Kum Jew, Stephen

    2013-12-12

    The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons.

  1. Motor neurons controlling fluid ingestion in Drosophila.

    PubMed

    Manzo, Andrea; Silies, Marion; Gohl, Daryl M; Scott, Kristin

    2012-04-17

    Rhythmic motor behaviors such as feeding are driven by neural networks that can be modulated by external stimuli and internal states. In Drosophila, ingestion is accomplished by a pump that draws fluid into the esophagus. Here we examine how pumping is regulated and characterize motor neurons innervating the pump. Frequency of pumping is not affected by sucrose concentration or hunger but is altered by fluid viscosity. Inactivating motor neurons disrupts pumping and ingestion, whereas activating them elicits arrhythmic pumping. These motor neurons respond to taste stimuli and show prolonged activity to palatable substances. This work describes an important component of the neural circuit for feeding in Drosophila and is a step toward understanding the rhythmic activity producing ingestion.

  2. Lower motor neuron dysfunction in ALS.

    PubMed

    de Carvalho, Mamede; Swash, Michael

    2016-07-01

    In the motor system there is a complex interplay between cortical structures and spinal cord lower motor neurons (LMN). In this system both inhibitory and excitatory neurons have relevant roles. LMN loss is a marker of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Conventional needle electromyography (EMG) does not allow LMN loss to be quantified. Measurement of compound muscle action potential (CMAP) amplitude or area, and the neurophysiological index, provide a surrogate estimate of the number of functional motor units. Increased motor neuronal excitability is a neurophysiological marker of ALS in the context of a suspected clinical and electrophysiological diagnosis. In the LMN system, fasciculation potentials (FPs) are the earliest changes observed in affected muscles, a feature of LMN hyperexcitability. Reinnervation is best investigated by needle EMG although other methods can be explored. Moreover needle EMG give information about the temporal profile of the reinnervation process, important ancillary data. Quantitative motor unit potential analysis is a valuable method of evaluating reinnervation. The importance of FPs has been recognized in the Awaji criteria for the electrodiagnosis of ALS, criteria that are a sensitive adjunct to the revised El Escorial criteria. Finally, functionality of LMN's, and perhaps excitability studies in motor nerves, aids understanding of the disease process, allowing measurement of potential treatment effects in clinical trials. Other investigational techniques, such as electrical impedance myography, muscle and nerve ultrasound, and spinal cord imaging methods may prove useful in future. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  3. Atypical motor neuron disease and related motor syndromes.

    PubMed

    Verma, A; Bradley, W G

    2001-06-01

    There is an imperative need for the early diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) in the current era of emerging treatments. When evaluating the patient with ALS/MND, the neurologist must consider a number of other motor neuron disorders and related motor syndromes that may have clinical features resembling ALS/MND. The revised Airlie House-El Escorial diagnostic criteria have been established through the consensus of experts meeting at workshops. However, by definition, using these criteria a patient is likely to have fairly advanced disease at the time of a definitive ALS/MND diagnosis. The reasons for the difficulty in making an early ALS/MND diagnosis are several. No surrogate diagnostic marker currently exists for ALS/MND. ALS/MND at its onset is heterogeneous in clinical presentation, its clinical course is variable, and several clinical variants are recognized. In addition, certain motor syndromes, such as monomelic amyotrophy, postpolio muscular atrophy, and multifocal motor neuropathy, can clinically mimic ALS/MND. Therefore, not only may the diagnosis of ALS/MND be clinically missed in the early stages, but worse, the patient may be wrongly labeled as having ALS/MND. The diagnosis of ALS/MND requires a combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Motor syndromes in which the deficit is restricted to the UMN or LMN through the entire course of the disease are described as atypical MND in this review. Approximately 5% of patients with ALS/MND have overt dementia with a characteristic frontal affect. ALS/MND with parkinsonism and dementia is rare outside the western Pacific region. The clinical course of motor disorder in these overlap syndromes does not differ from that in typical ALS/MND.

  4. Lower Motor Neuron Findings after Upper Motor Neuron Injury: Insights from Postoperative Supplementary Motor Area Syndrome

    PubMed Central

    Florman, Jeffrey E.; Duffau, Hugues; Rughani, Anand I.

    2013-01-01

    Hypertonia and hyperreflexia are classically described responses to upper motor neuron injury. However, acute hypotonia and areflexia with motor deficit are hallmark findings after many central nervous system insults such as acute stroke and spinal shock. Historic theories to explain these contradictory findings have implicated a number of potential mechanisms mostly relying on the loss of descending corticospinal input as the underlying etiology. Unfortunately, these simple descriptions consistently fail to adequately explain the pathophysiology and connectivity leading to acute hyporeflexia and delayed hyperreflexia that result from such insult. This article highlights the common observation of acute hyporeflexia after central nervous system insults and explores the underlying anatomy and physiology. Further, evidence for the underlying connectivity is presented and implicates the dominant role of supraspinal inhibitory influence originating in the supplementary motor area descending through the corticospinal tracts. Unlike traditional explanations, this theory more adequately explains the findings of postoperative supplementary motor area syndrome in which hyporeflexia motor deficit is observed acutely in the face of intact primary motor cortex connections to the spinal cord. Further, the proposed connectivity can be generalized to help explain other insults including stroke, atonic seizures, and spinal shock. PMID:23508473

  5. [Dropped head syndrome in motor neuron disease].

    PubMed

    Lorenzoni, Paulo José; Lange, Marcos Christiano; Kay, Cláudia S K; Almeida, Luiz G M P de; Teive, Hélio A G; Scola, Rosana H; Werneck, Lineu C

    2006-03-01

    Dropped head is a syndrome caused by weakness of the neck extensor muscles found in different kinds of neuromuscular disorders and also in amyotrophic lateral sclerosis. This is a cases report of three women with motor neuron disease with beginning of dysphagia and cervical weakness that it evolved with dropped head. The investigation showed normal magnetic resonance imaging of brain and cervical column. Needle electromyography showed active and chronic denervation in bulbar muscles and cervical, thoracic and lumbosacral segments. We discuss the characteristic of disease, specially the clinical manifestations and electromyography features, with emphasis at the clinical evaluation of dropped head in the suspicion of motor neuron disease.

  6. Neuropathology and omics in motor neuron diseases.

    PubMed

    Tanaka, Fumiaki; Ikenaka, Kensuke; Yamamoto, Masahiko; Sobue, Gen

    2012-08-01

    Motor neuron diseases, including amyotrophic lateral sclerosis (ALS), are devastating disorders and effective therapies have not yet been established. One of the reasons for this lack of therapeutics, especially in sporadic ALS (SALS), is attributed to the absence of excellent disease models reflecting its pathology. For this purpose, identifying important key molecules for ALS pathomechanisms and developing disease models is crucial, and omics approaches, including genomics, transcriptomics and proteomics, have been employed. In particular, transcriptome analysis using cDNA microarray is the most popular omics approach and we have previously identified dynactin-1 as an important molecule downregulated in the motor neurons of SALS patients from the early stage of the disease. Dynactin-1 is also known as a causative gene in familial ALS (FALS). Dynactin-1 is a major component of the dynein/dynactin motor protein complex functioning in retrograde axonal transport. In motor neuron diseases as well as other neurodegenerative diseases, the role of axonal transport dysfunction in their pathogenesis always draws attention, but its precise mechanisms remain to be fully elucidated. In this article, we review our previous omics approach to SALS and the role of dynactin-1 in the pathogenesis of ALS. Finally, we emphasize the need for creating novel SALS disease models based on the results of omics analysis, especially based on the observation that dynactin-1 gene expression was downregulated in SALS motor neurons.

  7. Generation of motor neurons from pluripotent stem cells.

    PubMed

    Chipman, Peter H; Toma, Jeremy S; Rafuse, Victor F

    2012-01-01

    Alpha motor neurons (also known as lower or skeletal motor neurons) have been studied extensively for over 100 years. Motor neurons control the contraction of skeletal muscles and thus are the final common pathway in the nervous system responsible for motor behavior. Muscles become paralyzed when their innervating motor neurons die because of injury or disease. Motor neuron diseases (MNDs), such as Amyotrophic Lateral Sclerosis, progressively destroy motor neurons until those inflicted succumb to the illness due to respiratory failure. One strategy being explored to study and treat muscle paralysis due to motor neuron loss involves deriving surrogate motor neurons from pluripotent stem cells. Guided by decades of research on the development of the spinal cord, recent advances in neurobiology have shown that functional motor neurons can be derived from mouse and human embryonic stem (ES) cells. Furthermore, ES cell-derived motor neurons restore motor behavior when transplanted into animal models of motor dysfunction. The recent discovery that mouse and human motor neurons can be derived from induced pluripotent stem (iPS) cells (i.e., somatic cells converted to pluripotency) has set the stage for the development of patient-specific therapies designed to treat movement disorders. Indeed, there is now hope within the scientific community that motor neurons derived from pluripotent stem cells will be used to treat MNDs through cell transplantation and/or to screen molecules that will prevent motor neuron death. In this chapter, we review the journey that led to the generation of motor neurons from ES and iPS cells, how stem cell-derived motor neurons have been used to treat/study motor dysfunction, and where the technology will likely lead to in the future.

  8. Synaptic Circuit Organization of Motor Corticothalamic Neurons

    PubMed Central

    Yamawaki, Naoki

    2015-01-01

    Corticothalamic (CT) neurons in layer 6 constitute a large but enigmatic class of cortical projection neurons. How they are integrated into intracortical and thalamo-cortico-thalamic circuits is incompletely understood, especially outside of sensory cortex. Here, we investigated CT circuits in mouse forelimb motor cortex (M1) using multiple circuit-analysis methods. Stimulating and recording from CT, intratelencephalic (IT), and pyramidal tract (PT) projection neurons, we found strong CT↔ CT and CT↔ IT connections; however, CT→IT connections were limited to IT neurons in layer 6, not 5B. There was strikingly little CT↔ PT excitatory connectivity. Disynaptic inhibition systematically accompanied excitation in these pathways, scaling with the amplitude of excitation according to both presynaptic (class-specific) and postsynaptic (cell-by-cell) factors. In particular, CT neurons evoked proportionally more inhibition relative to excitation (I/E ratio) than IT neurons. Furthermore, the amplitude of inhibition was tuned to match the amount of excitation at the level of individual neurons; in the extreme, neurons receiving no excitation received no inhibition either. Extending these studies to dissect the connectivity between cortex and thalamus, we found that M1-CT neurons and thalamocortical neurons in the ventrolateral (VL) nucleus were remarkably unconnected in either direction. Instead, VL axons in the cortex excited both IT and PT neurons, and CT axons in the thalamus excited other thalamic neurons, including those in the posterior nucleus, which additionally received PT excitation. These findings, which contrast in several ways with previous observations in sensory areas, illuminate the basic circuit organization of CT neurons within M1 and between M1 and thalamus. PMID:25653383

  9. Motor neuron death in ALS – programmed by astrocytes?

    PubMed Central

    Pirooznia, Sheila K.; Dawson, Valina L.; Dawson, Ted M.

    2014-01-01

    Motor neurons in ALS die via cell-autonomous and non-cell autonomous mechanisms. Using adult human astrocytes and motor neurons, Re et al (2014) discover that familial and sporadic ALS derived human adult astrocytes secrete neurotoxic factors that selectively kill motor neurons through necroptosis, suggesting a new therapeutic avenue. PMID:24607221

  10. The central nervous system in motor neurone disease

    PubMed Central

    Brownell, Betty; Oppenheimer, D. R.; Hughes, J. Trevor

    1970-01-01

    Forty-five necropsied cases with primary degeneration of lower motor neurones are described and discussed. Of these, 36 are considered to be `typical' cases of motor neurone disease, eight of which showed no upper motor neurone lesions. The relation of the nine `atypical' cases to the remainder is discussed. It is concluded that motor neurone disease constitutes an ill-defined band in a broad spectrum of multiple system atrophies. The authors have found no evidence suggesting a causal relation between motor neurone disease and either vascular or malignant diseases. They point out suggestive analogies with various subacute encephalomyelopathies in man and other animals. Images PMID:5431724

  11. The frontotemporal dementia-motor neuron disease continuum.

    PubMed

    Burrell, James R; Halliday, Glenda M; Kril, Jillian J; Ittner, Lars M; Götz, Jürgen; Kiernan, Matthew C; Hodges, John R

    2016-08-27

    Early reports of cognitive and behavioural deficits in motor neuron disease might have been overlooked initially, but the concept of a frontotemporal dementia-motor neuron disease continuum has emerged during the past decade. Frontotemporal dementia-motor neuron disease is now recognised as an important dementia syndrome, which presents substantial challenges for diagnosis and management. Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum. Indeed, the C9orf72 repeat expansion provides important clues to disease pathogenesis and suggests potential therapeutic targets. Variable diagnostic criteria identify motor, cognitive, and behavioural deficits, but further refinement is needed to define the clinical syndromes encountered in frontotemporal dementia-motor neuron disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron.

    PubMed

    Xiao, Qingpin; Hu, Xiaohui; Wei, Zhiyi; Tam, Kin Yip

    2016-01-01

    Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons.

  13. Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron

    PubMed Central

    Xiao, Qingpin; Hu, Xiaohui; Wei, Zhiyi; Tam, Kin Yip

    2016-01-01

    Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons. PMID:27570482

  14. Mimics and chameleons in motor neurone disease

    PubMed Central

    Turner, Martin R; Talbot, Kevin

    2013-01-01

    The progression of motor neurone disease (MND) is currently irreversible, and the grave implications of diagnosis naturally fuels concern among neurologists over missing a potential mimic disorder. There is no diagnostic test for MND but in reality there are few plausible mimics in routine clinical practice. In the presence of a progressive pure motor disorder, signs such as florid fasciculations, bilateral tongue wasting, the ‘split hand’, head drop, emotionality, and cognitive or behavioural impairment carry high positive predictive value. MND is clinically heterogeneous, however, with some important chameleon-like presentations and considerable variation in clinical course. Lack of confidence about the scope of such variation, or an approach to diagnosis emphasising investigations over clinical common sense, has the potential to exacerbate diagnostic delay in MND and impede timely planning of the care which is essential to maximising quality of life. PMID:23616620

  15. Mimics and chameleons in motor neurone disease.

    PubMed

    Turner, Martin R; Talbot, Kevin

    2013-06-01

    The progression of motor neurone disease (MND) is currently irreversible, and the grave implications of diagnosis naturally fuels concern among neurologists over missing a potential mimic disorder. There is no diagnostic test for MND but in reality there are few plausible mimics in routine clinical practice. In the presence of a progressive pure motor disorder, signs such as florid fasciculations, bilateral tongue wasting, the 'split hand', head drop, emotionality, and cognitive or behavioural impairment carry high positive predictive value. MND is clinically heterogeneous, however, with some important chameleon-like presentations and considerable variation in clinical course. Lack of confidence about the scope of such variation, or an approach to diagnosis emphasising investigations over clinical common sense, has the potential to exacerbate diagnostic delay in MND and impede timely planning of the care which is essential to maximising quality of life.

  16. Motor neurone disease presenting as polycythaemia.

    PubMed

    Santana-Vaz, Natasha; Bwika, Jumaa; Morley, Kirstie; Mukherjee, Rahul

    2014-04-28

    Motor neurone disease (MND) is a chronic, progressive and currently incurable neurodegenerative disorder. This case report discusses an instance of MND presenting initially as polycythaemia, caused via insidious respiratory failure through ventilatory insufficiency. This case aims to improve clinicians' awareness of this atypical presentation and highlights the need for a high index of suspicion of respiratory failure in any patient with polycythaemia. Finally it demonstrates an improvement in quality of life associated with the use of non-invasive ventilation (NIV) in a patient with MND.

  17. Pathological involvement of the motor neuron system and hippocampal formation in motor neuron disease-inclusion dementia.

    PubMed

    Toyoshima, Yasuko; Piao, Yue-Shan; Tan, Chun-Feng; Morita, Masahiro; Tanaka, Masaharu; Oyanagi, Kiyomitsu; Okamoto, Koichi; Takahashi, Hitoshi

    2003-07-01

    We report two patients with motor neuron disease-inclusion dementia, with special reference to the pathology of the motor neuron system and hippocampal formation. The ages of the patients at death were 55 and 62 years, and the disease durations were 8 and 3 years, respectively. The two patients exhibited progressive frontotemporal dementia in the absence of motor neuron signs. At autopsy, both cases exhibited frontotemporal lobar atrophy with ubiquitin-positive, and tau- and alpha-synuclein-negative neuronal inclusions. As expected from the clinical signs, in both cases, the upper and lower motor neuron systems were well preserved: no Bunina bodies or ubiquitinated inclusions were detected in the motor neurons. However, of great importance was that when visualized immunohistochemically, the Golgi apparatus and trans-Golgi network often exhibited fragmentation in the lower motor neurons (the spinal anterior horn cells). In one of the cases, a decrease in the amount of Golgi apparatus was also a frequent feature in the upper motor neurons (Betz cells in the motor cortex). Moreover, in both cases, circumscribed degeneration affecting the CA1-subiculum border zone was evident in the hippocampal formation. These findings further strengthen the idea that, pathologically, motor neuron disease-inclusion dementia is a rare phenotype of amyotrophic lateral sclerosis.

  18. Is developmental neuropathology of the motor neurons the key to resolving the mystery in motor neuron diseases?

    PubMed

    Hayashi, Masaharu

    2010-04-01

    Recently, genetic analyses on motor neurons diseases have advanced leaps and bounds, but mysteries still remain in the pathogenesis of amyotrophic lateral sclerosis and spinal muscular atrophy. Three papers in this issue of Brain and Development presented intriguing topics on the developmental neuropathology of motor neurons in the spinal cord and brainstem. Neonatal asphyxia experiments in rats indicated the modification of brainstem monoaminergic neuron systems in the development and repair of spinal motor neurons. In the victims of sudden perinatal and infant death, population changes in motor neurons and interneurons in the hypoglossal nucleus were shown to be involved in the disturbed maturation of the respiratory network in the brainstem. The coexistence of hypoglossal hypoplasia and hyperplasia of the area postrema was reported in a case of perinatal hypoxic ischemic encephalopathy. These findings are likely to be a key to resolving the undetermined pathological mechanisms of motor neuron diseases. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  19. Transcriptional regulation of mouse hypoglossal motor neuron somatotopic map formation.

    PubMed

    Chen, Xin; Wang, Jae Woong; Salin-Cantegrel, Adele; Dali, Rola; Stifani, Stefano

    2016-11-01

    Somatic motor neurons in the hypoglossal nucleus innervate tongue muscles controlling vital functions such as chewing, swallowing and respiration. Formation of functional hypoglossal nerve circuits depends on the establishment of precise hypoglossal motor neuron maps correlating with specific tongue muscle innervations. Little is known about the molecular mechanisms controlling mammalian hypoglossal motor neuron topographic map formation. Here we show that combinatorial expression of transcription factors Runx1, SCIP and FoxP1 defines separate mouse hypoglossal motor neuron groups with different topological, neurotransmitter and calcium-buffering phenotypes. Runx1 and SCIP are coexpressed in ventromedial hypoglossal motor neurons involved in control of tongue protrusion whereas FoxP1 is expressed in dorsomedial motor neurons associated with tongue retraction. Establishment of separate hypoglossal motor neuron maps depends in part on Runx1-mediated suppression of ventrolateral and dorsomedial motor neuron phenotypes and regulation of FoxP1 expression pattern. These findings suggest that combinatorial actions of Runx1, SCIP and FoxP1 are important for mouse hypoglossal nucleus somatotopic map formation.

  20. GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling.

    PubMed

    Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin; Rao, Meenakshi; Sockanathan, Shanthini

    2011-09-22

    The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons.

  1. GDE2 regulates subtype specific motor neuron generation through inhibition of Notch signaling

    PubMed Central

    Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin; Rao, Meenakshi; Sockanathan, Shanthini

    2011-01-01

    The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here, we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons. PMID:21943603

  2. Motor neurone disease: progress and challenges.

    PubMed

    Dharmadasa, Thanuja; Henderson, Robert D; Talman, Paul S; Macdonell, Richard Al; Mathers, Susan; Schultz, David W; Needham, Merrillee; Zoing, Margaret; Vucic, Steve; Kiernan, Matthew C

    2017-05-01

    Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.

  3. Accelerated neuronal differentiation toward motor neuron lineage from human embryonic stem cell line (H9).

    PubMed

    Lu, David; Chen, Eric Y T; Lee, Philip; Wang, Yung-Chen; Ching, Wendy; Markey, Christopher; Gulstrom, Chase; Chen, Li-Ching; Nguyen, Thien; Chin, Wei-Chun

    2015-03-01

    Motor neurons loss plays a pivotal role in the pathoetiology of various debilitating diseases such as, but not limited to, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, and spinal muscular atrophy. However, advancement in motor neuron replacement therapy has been significantly constrained by the difficulties in large-scale production at a cost-effective manner. Current methods to derive motor neuron heavily rely on biochemical stimulation, chemical biological screening, and complex physical cues. These existing methods are seriously challenged by extensive time requirements and poor yields. An innovative approach that overcomes prior hurdles and enhances the rate of successful motor neuron transplantation in patients is of critical demand. Iron, a trace element, is indispensable for the normal development and function of the central nervous system. Whether ferric ions promote neuronal differentiation and subsequently promote motor neuron lineage has never been considered. Here, we demonstrate that elevated iron concentration can drastically accelerate the differentiation of human embryonic stem cells (hESCs) toward motor neuron lineage potentially via a transferrin mediated pathway. HB9 expression in 500 nM iron-treated hESCs is approximately twofold higher than the control. Moreover, iron treatment generated more matured and functional motor neuron-like cells that are ∼1.5 times more sensitive to depolarization when compared to the control. Our methodology renders an expedited approach to harvest motor neuron-like cells for disease, traumatic injury regeneration, and drug screening.

  4. Mesodermal and neuronal retinoids regulate the induction and maintenance of limb innervating spinal motor neurons.

    PubMed

    Ji, Sheng-Jian; Zhuang, BinQuan; Falco, Crystal; Schneider, André; Schuster-Gossler, Karin; Gossler, Achim; Sockanathan, Shanthini

    2006-09-01

    During embryonic development, the generation, diversification and maintenance of spinal motor neurons depend upon extrinsic signals that are tightly regulated. Retinoic acid (RA) is necessary for specifying the fates of forelimb-innervating motor neurons of the Lateral Motor Column (LMC), and the specification of LMC neurons into medial and lateral subtypes. Previous studies implicate motor neurons as the relevant source of RA for specifying lateral LMC fates at forelimb levels. However, at the time of LMC diversification, a significant amount of retinoids in the spinal cord originates from the adjacent paraxial mesoderm. Here we employ mouse genetics to show that RA derived from the paraxial mesoderm is required for lateral LMC induction at forelimb and hindlimb levels, demonstrating that mesodermally synthesized RA functions as a second source of signals to specify lateral LMC identity. Furthermore, reduced RA levels in postmitotic motor neurons result in a decrease of medial and lateral LMC neurons, and abnormal axonal projections in the limb; invoking additional roles for neuronally synthesized RA in motor neuron maintenance and survival. These findings suggest that during embryogenesis, mesodermal and neuronal retinoids act coordinately to establish and maintain appropriate cohorts of spinal motor neurons that innervate target muscles in the limb.

  5. Insm1a Regulates Motor Neuron Development in Zebrafish.

    PubMed

    Gong, Jie; Wang, Xin; Zhu, Chenwen; Dong, Xiaohua; Zhang, Qinxin; Wang, Xiaoning; Duan, Xuchu; Qian, Fuping; Shi, Yunwei; Gao, Yu; Zhao, Qingshun; Chai, Renjie; Liu, Dong

    2017-01-01

    Insulinoma-associated1a (insm1a) is a zinc-finger transcription factor playing a series of functions in cell formation and differentiation of vertebrate central and peripheral nervous systems and neuroendocrine system. However, its roles on the development of motor neuron have still remained uncovered. Here, we provided evidences that insm1a was a vital regulator of motor neuron development, and provided a mechanistic understanding of how it contributes to this process. Firstly, we showed the localization of insm1a in spinal cord, and primary motor neurons (PMNs) of zebrafish embryos by in situ hybridization, and imaging analysis of transgenic reporter line Tg(insm1a: mCherry)(ntu805) . Then we demonstrated that the deficiency of insm1a in zebrafish larvae lead to the defects of PMNs development, including the reduction of caudal primary motor neurons (CaP), and middle primary motor neurons (MiP), the excessive branching of motor axons, and the disorganized distance between adjacent CaPs. Additionally, knockout of insm1 impaired motor neuron differentiation in the spinal cord. Locomotion analysis showed that swimming activity was significantly reduced in the insm1a-null zebrafish. Furthermore, we showed that the insm1a loss of function significantly decreased the transcript levels of both olig2 and nkx6.1. Microinjection of olig2 and nkx6.1 mRNA rescued the motor neuron defects in insm1a deficient embryos. Taken together, these data indicated that insm1a regulated the motor neuron development, at least in part, through modulation of the expressions of olig2 and nkx6.1.

  6. Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease.

    PubMed

    Fisher, Karen M; Zaaimi, Boubker; Williams, Timothy L; Baker, Stuart N; Baker, Mark R

    2012-09-01

    In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15-30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15-30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control

  7. Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease

    PubMed Central

    Fisher, Karen M.; Zaaimi, Boubker; Williams, Timothy L.; Baker, Stuart N.

    2012-01-01

    In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15–30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15–30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control

  8. Diverse role of survival motor neuron protein.

    PubMed

    Singh, Ravindra N; Howell, Matthew D; Ottesen, Eric W; Singh, Natalia N

    2017-03-01

    The multifunctional Survival Motor Neuron (SMN) protein is required for the survival of all organisms of the animal kingdom. SMN impacts various aspects of RNA metabolism through the formation and/or interaction with ribonucleoprotein (RNP) complexes. SMN regulates biogenesis of small nuclear RNPs, small nucleolar RNPs, small Cajal body-associated RNPs, signal recognition particles and telomerase. SMN also plays an important role in DNA repair, transcription, pre-mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance. The tissue-specific requirement of SMN is dictated by the variety and the abundance of its interacting partners. Reduced expression of SMN causes spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA displays a broad spectrum ranging from embryonic lethality to an adult onset. Aberrant expression and/or localization of SMN has also been associated with male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. This review provides a summary of various SMN functions with implications to a better understanding of SMA and other pathological conditions.

  9. Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

    ClinicalTrials.gov

    2015-08-24

    Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

  10. Motor neurone disease presenting as postoperative respiratory failure.

    PubMed

    Walker, H C; Dinsdale, D; Abernethy, D A

    2006-02-01

    We present the case of a woman who developed respiratory failure in the postoperative period secondary to previously unsuspected motor neurone disease. This case highlights the difficulty in detecting subtle neuromuscular weakness during anaesthetic pre-assessment.

  11. Gli function is essential for motor neuron induction in zebrafish.

    PubMed

    Vanderlaan, Gary; Tyurina, Oksana V; Karlstrom, Rolf O; Chandrasekhar, Anand

    2005-06-15

    The Gli family of zinc-finger transcription factors mediates Hedgehog (Hh) signaling in all vertebrates. However, their roles in ventral neural tube patterning, in particular motor neuron induction, appear to have diverged across species. For instance, cranial motor neurons are essentially lost in zebrafish detour (gli1(-)) mutants, whereas motor neuron development is unaffected in mouse single gli and some double gli knockouts. Interestingly, the expression of some Hh-regulated genes (ptc1, net1a, gli1) is mostly unaffected in the detour mutant hindbrain, suggesting that other Gli transcriptional activators may be involved. To better define the roles of the zebrafish gli genes in motor neuron induction and in Hh-regulated gene expression, we examined these processes in you-too (yot) mutants, which encode dominant repressor forms of Gli2 (Gli2(DR)), and following morpholino-mediated knockdown of gli1, gli2, and gli3 function. Motor neuron induction at all axial levels was reduced in yot (gli2(DR)) mutant embryos. In addition, Hh target gene expression at all axial levels except in rhombomere 4 was also reduced, suggesting an interference with the function of other Glis. Indeed, morpholino-mediated knockdown of Gli2(DR) protein in yot mutants led to a suppression of the defective motor neuron phenotype. However, gli2 knockdown in wild-type embryos generated no discernable motor neuron phenotype, while gli3 knockdown reduced motor neuron induction in the hindbrain and spinal cord. Significantly, gli2 or gli3 knockdown in detour (gli1(-)) mutants revealed roles for Gli2 and Gli3 activator functions in ptc1 expression and spinal motor neuron induction. Similarly, gli1 or gli3 knockdown in yot (gli2(DR)) mutants resulted in severe or complete loss of motor neurons, and of ptc1 and net1a expression, in the hindbrain and spinal cord. In addition, gli1 expression was greatly reduced in yot mutants following gli3, but not gli1, knockdown, suggesting that Gli3 activator

  12. Discussing sexuality with patients in a motor neurone disease clinic.

    PubMed

    Marsden, Rachael; Botell, Rachel

    Sexual relationships remain an important aspect of life for people living with motor neurone disease. This article explores the use of the Extended-PLISSIT model when discussing relationships and sexual function with patients and their partners in a motor neurone disease clinic. The model provides a structured approach to assist discussions with patients as well as promoting reflection and exchange of knowledge in the multidisciplinary team. It is a useful model when addressing issues that are sometimes difficult to discuss.

  13. Selective disruption of acetylcholine synthesis in subsets of motor neurons: a new model of late-onset motor neuron disease.

    PubMed

    Lecomte, Marie-José; Bertolus, Chloé; Santamaria, Julie; Bauchet, Anne-Laure; Herbin, Marc; Saurini, Françoise; Misawa, Hidemi; Maisonobe, Thierry; Pradat, Pierre-François; Nosten-Bertrand, Marika; Mallet, Jacques; Berrard, Sylvie

    2014-05-01

    Motor neuron diseases are characterized by the selective chronic dysfunction of a subset of motor neurons and the subsequent impairment of neuromuscular function. To reproduce in the mouse these hallmarks of diseases affecting motor neurons, we generated a mouse line in which ~40% of motor neurons in the spinal cord and the brainstem become unable to sustain neuromuscular transmission. These mice were obtained by conditional knockout of the gene encoding choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine. The mutant mice are viable and spontaneously display abnormal phenotypes that worsen with age including hunched back, reduced lifespan, weight loss, as well as striking deficits in muscle strength and motor function. This slowly progressive neuromuscular dysfunction is accompanied by muscle fiber histopathological features characteristic of neurogenic diseases. Unexpectedly, most changes appeared with a 6-month delay relative to the onset of reduction in ChAT levels, suggesting that compensatory mechanisms preserve muscular function for several months and then are overwhelmed. Deterioration of mouse phenotype after ChAT gene disruption is a specific aging process reminiscent of human pathological situations, particularly among survivors of paralytic poliomyelitis. These mutant mice may represent an invaluable tool to determine the sequence of events that follow the loss of function of a motor neuron subset as the disease progresses, and to evaluate therapeutic strategies. They also offer the opportunity to explore fundamental issues of motor neuron biology.

  14. The in vivo contribution of motor neuron TrkB receptors to mutant SOD1 motor neuron disease.

    PubMed

    Zhai, Jinbin; Zhou, Weiguo; Li, Jian; Hayworth, Christopher R; Zhang, Lei; Misawa, Hidemi; Klein, Rudiger; Scherer, Steven S; Balice-Gordon, Rita J; Kalb, Robert Gordon

    2011-11-01

    Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are widely expressed in the vertebrate nervous system and play a central role in mature neuronal function. In vitro BDNF/TrkB signaling promotes neuronal survival and can help neurons resist toxic insults. Paradoxically, BDNF/TrkB signaling has also been shown, under certain in vitro circumstances, to render neurons vulnerable to insults. We show here that in vivo conditional deletion of TrkB from mature motor neurons attenuates mutant superoxide dismutase 1 (SOD1) toxicity. Mutant SOD1 mice lacking motor neuron TrkB live a month longer than controls and retain motor function for a longer period, particularly in the early phase of the disease. These effects are subserved by slowed motor neuron loss, persistence of neuromuscular junction integrity and reduced astrocytic and microglial reactivity within the spinal cord. These results suggest that manipulation of BDNF/TrkB signaling might have therapeutic efficacy in motor neuron diseases.

  15. Intrinsic Membrane Hyperexcitability of ALS Patient-Derived Motor Neurons

    PubMed Central

    Wainger, Brian J.; Kiskinis, Evangelos; Mellin, Cassidy; Wiskow, Ole; Han, Steve S.W.; Sandoe, Jackson; Perez, Numa P.; Williams, Luis A.; Lee, Seungkyu; Boulting, Gabriella; Berry, James D.; Brown, Robert H.; Cudkowicz, Merit E.; Bean, Bruce P.; Eggan, Kevin; Woolf, Clifford J.

    2014-01-01

    SUMMARY Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multi-electrode array and patch clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72 and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected, but otherwise isogenic, SOD1+/+ stem cell line do not display the hyperexcitability phenotype. SOD1A4V/+ ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates. PMID:24703839

  16. Motor neuron mitochondrial dysfunction in spinal muscular atrophy

    PubMed Central

    Miller, Nimrod; Shi, Han; Zelikovich, Aaron S.; Ma, Yong-Chao

    2016-01-01

    Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased basal and maximal mitochondrial respiration in motor neurons from SMA mice. Using a reduction-oxidation sensitive GFP and fluorescence sensors specifically targeted to mitochondria, we found increased oxidative stress level and impaired mitochondrial membrane potential in motor neurons affected by SMA. In addition, mitochondrial mobility was impaired in SMA disease conditions, with decreased retrograde transport but no effect on anterograde transport. We also found significantly increased fragmentation of the mitochondrial network in primary motor neurons from SMA mice, with no change in mitochondria density. Electron microscopy study of SMA mouse spinal cord revealed mitochondria fragmentation, edema and concentric lamellar inclusions in motor neurons affected by the disease. Intriguingly, these functional and structural deficiencies in the SMA mouse model occur during the presymptomatic stage of disease, suggesting a role in initiating SMA. Altogether, our findings reveal a critical role for mitochondrial defects in SMA pathogenesis and suggest a novel target for improving tissue health in the disease. PMID:27488123

  17. Extracellularly Identifying Motor Neurons for a Muscle Motor Pool in Aplysia californica

    PubMed Central

    Lu, Hui; McManus, Jeffrey M.; Chiel, Hillel J.

    2013-01-01

    In animals with large identified neurons (e.g. mollusks), analysis of motor pools is done using intracellular techniques1,2,3,4. Recently, we developed a technique to extracellularly stimulate and record individual neurons in Aplysia californica5. We now describe a protocol for using this technique to uniquely identify and characterize motor neurons within a motor pool. This extracellular technique has advantages. First, extracellular electrodes can stimulate and record neurons through the sheath5, so it does not need to be removed. Thus, neurons will be healthier in extracellular experiments than in intracellular ones. Second, if ganglia are rotated by appropriate pinning of the sheath, extracellular electrodes can access neurons on both sides of the ganglion, which makes it easier and more efficient to identify multiple neurons in the same preparation. Third, extracellular electrodes do not need to penetrate cells, and thus can be easily moved back and forth among neurons, causing less damage to them. This is especially useful when one tries to record multiple neurons during repeating motor patterns that may only persist for minutes. Fourth, extracellular electrodes are more flexible than intracellular ones during muscle movements. Intracellular electrodes may pull out and damage neurons during muscle contractions. In contrast, since extracellular electrodes are gently pressed onto the sheath above neurons, they usually stay above the same neuron during muscle contractions, and thus can be used in more intact preparations. To uniquely identify motor neurons for a motor pool (in particular, the I1/I3 muscle in Aplysia) using extracellular electrodes, one can use features that do not require intracellular measurements as criteria: soma size and location, axonal projection, and muscle innervation4,6,7. For the particular motor pool used to illustrate the technique, we recorded from buccal nerves 2 and 3 to measure axonal projections, and measured the contraction

  18. Extracellularly identifying motor neurons for a muscle motor pool in Aplysia californica.

    PubMed

    Lu, Hui; McManus, Jeffrey M; Chiel, Hillel J

    2013-03-25

    In animals with large identified neurons (e.g. mollusks), analysis of motor pools is done using intracellular techniques. Recently, we developed a technique to extracellularly stimulate and record individual neurons in Aplysia californica. We now describe a protocol for using this technique to uniquely identify and characterize motor neurons within a motor pool. This extracellular technique has advantages. First, extracellular electrodes can stimulate and record neurons through the sheath, so it does not need to be removed. Thus, neurons will be healthier in extracellular experiments than in intracellular ones. Second, if ganglia are rotated by appropriate pinning of the sheath, extracellular electrodes can access neurons on both sides of the ganglion, which makes it easier and more efficient to identify multiple neurons in the same preparation. Third, extracellular electrodes do not need to penetrate cells, and thus can be easily moved back and forth among neurons, causing less damage to them. This is especially useful when one tries to record multiple neurons during repeating motor patterns that may only persist for minutes. Fourth, extracellular electrodes are more flexible than intracellular ones during muscle movements. Intracellular electrodes may pull out and damage neurons during muscle contractions. In contrast, since extracellular electrodes are gently pressed onto the sheath above neurons, they usually stay above the same neuron during muscle contractions, and thus can be used in more intact preparations. To uniquely identify motor neurons for a motor pool (in particular, the I1/I3 muscle in Aplysia) using extracellular electrodes, one can use features that do not require intracellular measurements as criteria: soma size and location, axonal projection, and muscle innervation. For the particular motor pool used to illustrate the technique, we recorded from buccal nerves 2 and 3 to measure axonal projections, and measured the contraction forces of the I1

  19. British motor neuron disease twin study.

    PubMed Central

    Graham, A J; Macdonald, A M; Hawkes, C H

    1997-01-01

    OBJECTIVES: To investigate the cause of sporadic motor neuron disease (MND) by twin study, so allowing (1) estimation of the genetic contribution, and (2) collection of matched pairs for a case-control study of possible environmental factors. METHODS: 10872 death certificates bearing the diagnosis MND were collected from 1979 to 1989 inclusive. Inspection of individual birth entries allowed identification of potential twins. The status of each co-twin was determined and contact made through the National Health Service Central Register (NHS-CR) and their general practitioner (GP). The diagnosis of MND was verified via the co-twin and relatives, and medical records where available. Zygosity was assessed using a recognised questionnaire. Details concerning environmental exposures and health were gathered by interview of cotwin and relatives using a semistructured questionnaire. Heritability (h2) of MND was estimated, and the environmental information was analysed by conditional logistic regression modelling. RESULTS: Seventy seven probands were identified, of whom 26 were monozygotic and 51 dizygotic. Four monozygotic probands were concordant, but two probands came from a family known to have familial MND. The estimated heritability was between 0.38 and 0.85. Most environmental risk factors were not significant. Regular vehicle maintenance (odds ratio (OR) = 7.0; 95% confidence interval (95% CI) 1.3-89.9) and occupational paint usage (OR = 3.75; 95% CI 1.0-17.1), however, occurred significantly more often in the affected cases. CONCLUSIONS: This "death discordant" method for twin collection has proved to be viable, and has allowed the ascertainment of a large population sample in a rare disease. The genetic role in sporadic MND is substantial, and higher than expected. Exposure to industrial chemicals, particularly constituents of petrochemicals and paints, may contribute to the aetiology of MND. PMID:9219739

  20. The Effects of Motor Neurone Disease on Language: Further Evidence

    ERIC Educational Resources Information Center

    Bak, Thomas H.; Hodges, John R.

    2004-01-01

    It might sound surprising that Motor Neurone Disease (MND), regarded still by many as the very example of a neurodegenerative disease affecting selectively the motor system and sparing the sensory functions as well as cognition, can have a significant influence on language. In this article we hope to demonstrate that language dysfunction is not…

  1. The Effects of Motor Neurone Disease on Language: Further Evidence

    ERIC Educational Resources Information Center

    Bak, Thomas H.; Hodges, John R.

    2004-01-01

    It might sound surprising that Motor Neurone Disease (MND), regarded still by many as the very example of a neurodegenerative disease affecting selectively the motor system and sparing the sensory functions as well as cognition, can have a significant influence on language. In this article we hope to demonstrate that language dysfunction is not…

  2. Reconstruction of phrenic neuron identity in embryonic stem cell-derived motor neurons.

    PubMed

    Machado, Carolina Barcellos; Kanning, Kevin C; Kreis, Patricia; Stevenson, Danielle; Crossley, Martin; Nowak, Magdalena; Iacovino, Michelina; Kyba, Michael; Chambers, David; Blanc, Eric; Lieberam, Ivo

    2014-02-01

    Air breathing is an essential motor function for vertebrates living on land. The rhythm that drives breathing is generated within the central nervous system and relayed via specialised subsets of spinal motor neurons to muscles that regulate lung volume. In mammals, a key respiratory muscle is the diaphragm, which is innervated by motor neurons in the phrenic nucleus. Remarkably, relatively little is known about how this crucial subtype of motor neuron is generated during embryogenesis. Here, we used direct differentiation of motor neurons from mouse embryonic stem cells as a tool to identify genes that direct phrenic neuron identity. We find that three determinants, Pou3f1, Hoxa5 and Notch, act in combination to promote a phrenic neuron molecular identity. We show that Notch signalling induces Pou3f1 in developing motor neurons in vitro and in vivo. This suggests that the phrenic neuron lineage is established through a local source of Notch ligand at mid-cervical levels. Furthermore, we find that the cadherins Pcdh10, which is regulated by Pou3f1 and Hoxa5, and Cdh10, which is controlled by Pou3f1, are both mediators of like-like clustering of motor neuron cell bodies. This specific Pcdh10/Cdh10 activity might provide the means by which phrenic neurons are assembled into a distinct nucleus. Our study provides a framework for understanding how phrenic neuron identity is conferred and will help to generate this rare and inaccessible yet vital neuronal subtype directly from pluripotent stem cells, thus facilitating subsequent functional investigations.

  3. Reconstruction of phrenic neuron identity in embryonic stem cell-derived motor neurons

    PubMed Central

    Machado, Carolina Barcellos; Kanning, Kevin C.; Kreis, Patricia; Stevenson, Danielle; Crossley, Martin; Nowak, Magdalena; Iacovino, Michelina; Kyba, Michael; Chambers, David; Blanc, Eric; Lieberam, Ivo

    2014-01-01

    Air breathing is an essential motor function for vertebrates living on land. The rhythm that drives breathing is generated within the central nervous system and relayed via specialised subsets of spinal motor neurons to muscles that regulate lung volume. In mammals, a key respiratory muscle is the diaphragm, which is innervated by motor neurons in the phrenic nucleus. Remarkably, relatively little is known about how this crucial subtype of motor neuron is generated during embryogenesis. Here, we used direct differentiation of motor neurons from mouse embryonic stem cells as a tool to identify genes that direct phrenic neuron identity. We find that three determinants, Pou3f1, Hoxa5 and Notch, act in combination to promote a phrenic neuron molecular identity. We show that Notch signalling induces Pou3f1 in developing motor neurons in vitro and in vivo. This suggests that the phrenic neuron lineage is established through a local source of Notch ligand at mid-cervical levels. Furthermore, we find that the cadherins Pcdh10, which is regulated by Pou3f1 and Hoxa5, and Cdh10, which is controlled by Pou3f1, are both mediators of like-like clustering of motor neuron cell bodies. This specific Pcdh10/Cdh10 activity might provide the means by which phrenic neurons are assembled into a distinct nucleus. Our study provides a framework for understanding how phrenic neuron identity is conferred and will help to generate this rare and inaccessible yet vital neuronal subtype directly from pluripotent stem cells, thus facilitating subsequent functional investigations. PMID:24496616

  4. A Supranuclear Disorder of Ocular Motility as a Rare Initial Presentation of Motor Neurone Disease.

    PubMed

    Yu-Wai-Man, C; Petheram, K; Davidson, A W; Williams, T; Griffiths, P G

    2011-01-01

    A case is described of motor neurone disease presenting with an ocular motor disorder characterised by saccadic intrusions, impaired horizontal and vertical saccades, and apraxia of eyelid opening. The occurrence of eye movement abnormalities in motor neurone disease is discussed.

  5. Experience-dependent development of spinal motor neurons

    NASA Technical Reports Server (NTRS)

    Inglis, F. M.; Zuckerman, K. E.; Kalb, R. G.; Walton, K. D. (Principal Investigator)

    2000-01-01

    Locomotor activity in many species undergoes pronounced alterations in early postnatal life, and environmental cues may be responsible for modifying this process. To determine how these events are reflected in the nervous system, we studied rats reared under two different conditions-the presence or absence of gravity-in which the performance of motor operations differed. We found a significant effect of rearing environment on the size and complexity of dendritic architecture of spinal motor neurons, particularly those that are likely to participate in postural control. These results provide evidence that neurons subserving motor function undergo activity-dependent maturation in early postnatal life in a manner analogous to sensory systems.

  6. Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

    PubMed Central

    Sampaio, Hugo; Mowat, David; Roscioli, Tony

    2017-01-01

    Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis. PMID:28634552

  7. Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

    PubMed

    Powis, Rachael A; Gillingwater, Thomas H

    2016-03-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

  8. Proprioceptive coupling within motor neurons drives C. elegans forward locomotion

    PubMed Central

    Wen, Quan; Po, Michelle; Hulme, Elizabeth; Chen, Sway; Liu, Xinyu; Kwok, Sen Wai; Gershow, Marc; Leifer, Andrew M; Butler, Victoria; Fang-Yen, Christopher; Kawano, Taizo; Schafer, William R; Whitesides, George

    2012-01-01

    Summary Locomotion requires coordinated motor activity throughout an animal’s body. In both vertebrates and invertebrates, chains of coupled Central Pattern Generators (CPGs) are commonly evoked to explain local rhythmic behaviors. In C. elegans, we report that proprioception within the motor circuit is responsible for propagating and coordinating rhythmic undulatory waves from head to tail during forward movement. Proprioceptive coupling between adjacent body regions transduces rhythmic movement initiated near the head into bending waves driven along the body by a chain of reflexes. Using optogenetics and calcium imaging to manipulate and monitor motor circuit activity of moving C. elegans held in microfluidic devices, we found that the B-type cholinergic motor neurons transduce the proprioceptive signal. In C. elegans, a sensorimotor feedback loop operating within a specific type of motor neuron both drives and organizes body movement. PMID:23177960

  9. A quantitative electrophysiological study of motor neurone disease.

    PubMed Central

    Hansen, S; Ballantyne, J P

    1978-01-01

    Thirty-two patients with motor neurone disease were investigated using quantitative electrophysiological techniques. Estimates of the number of surviving motor units in the extensor digitorum brevis muscle and measurements of the electrophysiological parameters of these units are present along with the values for motor nerve conduction velocities. The results indicate that reinnervation in motor neurone disease is sufficient to compensate completely for the loss of up to 50% of the motor neurone pool supplying the muscle. The capacity for reinnervation is greater than we have found in a number of neuropathies but the efficiency of reinnervation decreases as the number of surviving motor units falls. Reinnervation appears to cease when 5% or less of the motor units remain viable. There is no electrophysiological evidence of a preferential loss of fast conducting axons, of pathological slowing of conduction nor of a dying-back process affecting the motor axon. Comparison of the electrophysiological parameters in progressive muscular atrophy and amyotrophic lateral sclerosis shows no significant differences. The underlying pathophysiological mechanisms are discussed in terms of the results. PMID:690647

  10. Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice.

    PubMed

    Turner, Bradley J; Alfazema, Neza; Sheean, Rebecca K; Sleigh, James N; Davies, Kay E; Horne, Malcolm K; Talbot, Kevin

    2014-04-01

    Spinal muscular atrophy results from diminished levels of survival motor neuron (SMN) protein in spinal motor neurons. Low levels of SMN also occur in models of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1) and genetic reduction of SMN levels exacerbates the phenotype of transgenic SOD1(G93A) mice. Here, we demonstrate that SMN protein is significantly reduced in the spinal cords of patients with sporadic ALS. To test the potential of SMN as a modifier of ALS, we overexpressed SMN in 2 different strains of SOD1(G93A) mice. Neuronal overexpression of SMN significantly preserved locomotor function, rescued motor neurons, and attenuated astrogliosis in spinal cords of SOD1(G93A) mice. Despite this, survival was not prolonged, most likely resulting from SMN mislocalization and depletion of gems in motor neurons of symptomatic mice. Our results reveal that SMN upregulation slows locomotor deficit onset and motor neuron loss in this mouse model of ALS. However, disruption of SMN nuclear complexes by high levels of mutant SOD1, even in the presence of SMN overexpression, might limit its survival promoting effects in this specific mouse model. Studies in emerging mouse models of ALS are therefore warranted to further explore the potential of SMN as a modifier of ALS. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Motor imagery muscle contraction strength influences spinal motor neuron excitability and cardiac sympathetic nerve activity.

    PubMed

    Bunno, Yoshibumi; Suzuki, Toshiaki; Iwatsuki, Hiroyasu

    2015-12-01

    [Purpose] The aim of this study was to investigate the changes in spinal motor neuron excitability and autonomic nervous system activity during motor imagery of isometric thenar muscle activity at 10% and 50% maximal voluntary contraction (MVC). [Methods] The F-waves and low frequency/high frequency (LF/HF) ratio were recorded at rest, during motor imagery, and post-trial. For motor imagery trials, subjects were instructed to imagine thenar muscle activity at 10% and 50% MVC while holding the sensor of a pinch meter for 5 min. [Results] The F-waves and LF/HF ratio during motor imagery at 50% MVC were significantly increased compared with those at rest, whereas those during motor imagery at 10% MVC were not significantly different from those at rest. The relative values of the F/M amplitude ratio during motor imagery at 50% MVC were significantly higher than those at 10% MVC. The relative values of persistence and the LF/HF ratio during motor imagery were similar during motor imagery at the two muscle contraction strengths. [Conclusion] Motor imagery can increase the spinal motor neuron excitability and cardiac sympathetic nerve activity. Motor imagery at 50% MVC may be more effective than motor imagery at 10% MVC.

  12. ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation.

    PubMed

    Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C; Chen, Adam; Tamrazian, Eric; Babaniyi, Olusegun; Selig, Martin; Hynynen, Meri; Woolf, Clifford J; Brown, Robert H

    2014-01-28

    ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1(G93A) ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1(G93A) mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.

  13. ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

    PubMed Central

    Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C.; Chen, Adam; Tamrazian, Eric; Babaniyi, Olusegun; Selig, Martin; Hynynen, Meri; Woolf, Clifford J.; Brown, Robert H.

    2014-01-01

    ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1G93A ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1G93A mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1G93A mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways. PMID:24474789

  14. Amyotrophic lateral sclerosis and other motor neuron diseases.

    PubMed

    Krivickas, Lisa S

    2003-05-01

    The anterior horn cell diseases, with the exception of polio, are progressive degenerative diseases of the motor neurons. These disorders include SMA types I to III in children and familial and sporadic ALS and its variants (PMA, PLS, and PBP), Kennedy's disease, and SMA type IV in adults. The electrodiagnostic study is a crucial step in the diagnostic process for all of these disorders. In general, motor NCS may be normal or reveal low CMAP amplitudes with relatively normal conduction velocities. Sensory NCS, except in the case of Kennedy's disease, are normal. The NEE is notable for the often abundant presence of abnormal spontaneous activity, including fibrillation potentials and positive sharp waves, fasciculation potentials, and complex repetitive discharges. Motor unit morphology is abnormal, with polyphasic motor units and large amplitude and duration MUAPs when the disease is slowly progressive. Recruitment in affected muscles is reduced with abnormally rapidly firing motor units. To diagnose a widespread disorder of the motor neurons, abnormalities must be present in multiple muscles with different nerve root and peripheral nerve innervation in multiple limbs. The Lambert Criteria and the El Escorial Criteria are the two most widely accepted sets of electrodiagnostic criteria for ALS. The electrodiagnostic diagnosis must be supported by appropriate history and physical examination findings and the exclusion, via neuroimaging and laboratory testing, of other diseases that may mimic a generalized disorder of the motor neurons.

  15. Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.

    PubMed

    Tu, Wen-Yo; Simpson, Julie E; Highley, J Robin; Heath, Paul R

    2017-02-02

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets.

  16. Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms.

    PubMed

    Curtis, R; Tonra, J R; Stark, J L; Adryan, K M; Park, J S; Cliffer, K D; Lindsay, R M; DiStefano, P S

    1998-10-01

    We investigated the retrograde axonal transport of 125I-labeled neurotrophins (NGF, BDNF, NT-3, and NT-4) from the sciatic nerve to dorsal root ganglion (DRG) sensory neurons and spinal motor neurons in normal rats or after neuronal injury. DRG neurons showed increased transport of all neurotrophins following crush injury to the sciatic nerve. This was maximal 1 day after sciatic nerve crush and returned to control levels after 7 days. 125I-BDNF transport from sciatic nerve was elevated with injection either proximal to the lesion or directly into the crush site and after transection of the dorsal roots. All neurotrophin transport was receptor-mediated and consistent with neurotrophin binding to the low-affinity neurotrophin receptor (LNR) or Trk receptors. However, transport of 125I-labeled wheat germ agglutinin also increased 1 day after sciatic nerve crush, showing that increased uptake and transport is a generalized response to injury in DRG sensory neurons. Spinal cord motor neurons also showed increased neurotrophin transport following sciatic nerve injury, although this was maximal after 3 days. The transport of 125I-NGF depended on the expression of LNR by injured motor neurons, as demonstrated by competition experiments with unlabeled neurotrophins. The absence of TrkA in normal motor neurons or after axotomy was confirmed by immunostaining and in situ hybridization. Thus, increased transport of neurotrophic factors after neuronal injury is due to multiple receptor-mediated mechanisms including general increases in axonal transport capacity. Copyright 1998 Academic Press.

  17. Motor neuron mitochondrial dysfunction in spinal muscular atrophy.

    PubMed

    Miller, Nimrod; Shi, Han; Zelikovich, Aaron S; Ma, Yong-Chao

    2016-08-15

    Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased basal and maximal mitochondrial respiration in motor neurons from SMA mice. Using a reduction-oxidation sensitive GFP and fluorescence sensors specifically targeted to mitochondria, we found increased oxidative stress level and impaired mitochondrial membrane potential in motor neurons affected by SMA. In addition, mitochondrial mobility was impaired in SMA disease conditions, with decreased retrograde transport but no effect on anterograde transport. We also found significantly increased fragmentation of the mitochondrial network in primary motor neurons from SMA mice, with no change in mitochondria density. Electron microscopy study of SMA mouse spinal cord revealed mitochondria fragmentation, edema and concentric lamellar inclusions in motor neurons affected by the disease. Intriguingly, these functional and structural deficiencies in the SMA mouse model occur during the presymptomatic stage of disease, suggesting a role in initiating SMA. Altogether, our findings reveal a critical role for mitochondrial defects in SMA pathogenesis and suggest a novel target for improving tissue health in the disease. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  18. Maturation of Spinal Motor Neurons Derived from Human Embryonic Stem Cells

    PubMed Central

    Takazawa, Tomonori; Croft, Gist F.; Amoroso, Mackenzie W.; Studer, Lorenz; Wichterle, Hynek; MacDermott, Amy B.

    2012-01-01

    Our understanding of motor neuron biology in humans is derived mainly from investigation of human postmortem tissue and more indirectly from live animal models such as rodents. Thus generation of motor neurons from human embryonic stem cells and human induced pluripotent stem cells is an important new approach to model motor neuron function. To be useful models of human motor neuron function, cells generated in vitro should develop mature properties that are the hallmarks of motor neurons in vivo such as elaborated neuronal processes and mature electrophysiological characteristics. Here we have investigated changes in morphological and electrophysiological properties associated with maturation of neurons differentiated from human embryonic stem cells expressing GFP driven by a motor neuron specific reporter (Hb9::GFP) in culture. We observed maturation in cellular morphology seen as more complex neurite outgrowth and increased soma area over time. Electrophysiological changes included decreasing input resistance and increasing action potential firing frequency over 13 days in vitro. Furthermore, these human embryonic stem cell derived motor neurons acquired two physiological characteristics that are thought to underpin motor neuron integrated function in motor circuits; spike frequency adaptation and rebound action potential firing. These findings show that human embryonic stem cell derived motor neurons develop functional characteristics typical of spinal motor neurons in vivo and suggest that they are a relevant and useful platform for studying motor neuron development and function and for modeling motor neuron diseases. PMID:22802953

  19. Motor conduction block and high titres of anti-GM1 ganglioside antibodies: pathological evidence of a motor neuropathy in a patient with lower motor neuron syndrome.

    PubMed Central

    Adams, D; Kuntzer, T; Steck, A J; Lobrinus, A; Janzer, R C; Regli, F

    1993-01-01

    A patient with a progressive lower motor neuron syndrome and neurophysiological evidence of motor axon loss, multifocal proximal motor nerve conduction block, and high titres of anti-ganglioside GM1 antibodies. Neuropathological findings included a predominantly proximal motor radiculoneuropathy with multifocal IgG and IgM deposits on nerve fibres associated with a loss of spinal motor neurons. These findings support an autoimmune origin of this lower motor neuron syndrome with retrograde degeneration of spinal motor neurons and severe neurogenic muscular atrophy. Images PMID:8410039

  20. Motor neuron 'bistability'. A pathogenetic mechanism for cramps and myokymia.

    PubMed

    Baldissera, F; Cavallari, P; Dworzak, F

    1994-10-01

    In three patients suffering from chronic muscle cramps, spasms and myokymia, these involuntary contractions were triggered in the triceps surae, quadriceps, flexor carpi radialis or flexor digitorum by means of single or short-train stimulation of homonymous Ia afferents, elicited by electrical means or tendon taps. In some cases cramp was induced by the first afferent volleys; more often, however, continued stimulation produced stepwise recruitment of motor units (whose rhythmic firing was visible as myokymia in the muscle) until cramp developed. Cramps and myokymic discharges could usually be terminated by a single maximal stimulus to the motor axons (producing antidromic invasion and Renshaw inhibition of the motor neurons), or by short trains of volleys in inhibitory pathways from the skin. The fact that it was possible to induce myokymia and cramps by brief synaptic excitation and terminate them by antidromic invasion or synaptic inhibition, suggests that the mechanism generating these disturbances is intrinsic to alpha-motor neuron somata. Similar on-off switching of self-sustained motor discharges has been observed in the decerebrate cat and is known to depend on 'bistability' of the motor neuron membrane. We propose that a similar mechanism is responsible for discharges that produce cramp.

  1. Expression of the mitotic motor protein Eg5 in postmitotic neurons: implications for neuronal development.

    PubMed

    Ferhat, L; Cook, C; Chauviere, M; Harper, M; Kress, M; Lyons, G E; Baas, P W

    1998-10-01

    It is well established that the microtubules of the mitotic spindle are organized by a variety of motor proteins, and it appears that the same motors or closely related variants organize microtubules in the postmitotic neuron. Specifically, cytoplasmic dynein and the kinesin-related motor known as CHO1/MKLP1 are used within the mitotic spindle, and recent studies suggest that they are also essential for the establishment of the axonal and dendritic microtubule arrays of the neuron. Other motors are required to tightly regulate microtubule behaviors in the mitotic spindle, and it is attractive to speculate that these motors might also help to regulate microtubule behaviors in the neuron. Here we show that a homolog of the mitotic kinesin-related motor known as Eg5 continues to be expressed in rodent neurons well after their terminal mitotic division. In neurons, Eg5 is directly associated with the microtubule array and is enriched within the distal regions of developing processes. This distal enrichment is transient, and typically lost after a process has been clearly defined as an axon or a dendrite. Strong expression can resume later in development, and if so, the protein concentrates within newly forming sprouts at the distal tips of dendrites. We suggest that Eg5 generates forces that help to regulate microtubule behaviors within the distal tips of developing axons and dendrites.

  2. Communications Technology and Motor Neuron Disease: An Australian Survey of People With Motor Neuron Disease.

    PubMed

    Mackenzie, Lynette; Bhuta, Prarthna; Rusten, Kim; Devine, Janet; Love, Anna; Waterson, Penny

    2016-01-25

    People with Motor Neuron Disease (MND), of which amyotrophic lateral sclerosis (ALS) is the most common form in adults, typically experience difficulties with communication and disabilities associated with movement. Assistive technology is essential to facilitate everyday activities, promote social support and enhance quality of life. This study aimed to explore the types of mainstream and commonly available communication technology used by people with MND including software and hardware, to identify the levels of confidence and skill that people with MND reported in using technology, to determine perceived barriers to the use of technology for communication, and to investigate the willingness of people with MND to adopt alternative modes of communication. An on-line survey was distributed to members of the New South Wales Motor Neuron Disease Association (MND NSW). Descriptive techniques were used to summarize frequencies of responses and cross tabulate data. Free-text responses to survey items and verbal comments from participants who chose to undertake the survey by telephone were analyzed using thematic analysis. Responses from 79 MND NSW members indicated that 15-21% had difficulty with speaking, writing and/or using a keyboard. Commonly used devices were desktop computers, laptops, tablets and mobile phones. Most participants (84%) were connected to the Internet and used it for email (91%), to find out more about MND (59%), to follow the news (50%) or for on-line shopping (46%). A third of respondents used Skype or its equivalent, but few used this to interact with health professionals. People with MND need greater awareness of technology options to access the most appropriate solutions. The timing for people with MND to make decisions about technology is critical. Health professionals need skills and knowledge about the application of technology to be able to work with people with MND to select the best communication technology options as early as possible

  3. Communications Technology and Motor Neuron Disease: An Australian Survey of People With Motor Neuron Disease

    PubMed Central

    2016-01-01

    Background People with Motor Neuron Disease (MND), of which amyotrophic lateral sclerosis (ALS) is the most common form in adults, typically experience difficulties with communication and disabilities associated with movement. Assistive technology is essential to facilitate everyday activities, promote social support and enhance quality of life. Objective This study aimed to explore the types of mainstream and commonly available communication technology used by people with MND including software and hardware, to identify the levels of confidence and skill that people with MND reported in using technology, to determine perceived barriers to the use of technology for communication, and to investigate the willingness of people with MND to adopt alternative modes of communication. Methods An on-line survey was distributed to members of the New South Wales Motor Neuron Disease Association (MND NSW). Descriptive techniques were used to summarize frequencies of responses and cross tabulate data. Free-text responses to survey items and verbal comments from participants who chose to undertake the survey by telephone were analyzed using thematic analysis. Results Responses from 79 MND NSW members indicated that 15-21% had difficulty with speaking, writing and/or using a keyboard. Commonly used devices were desktop computers, laptops, tablets and mobile phones. Most participants (84%) were connected to the Internet and used it for email (91%), to find out more about MND (59%), to follow the news (50%) or for on-line shopping (46%). A third of respondents used Skype or its equivalent, but few used this to interact with health professionals. Conclusions People with MND need greater awareness of technology options to access the most appropriate solutions. The timing for people with MND to make decisions about technology is critical. Health professionals need skills and knowledge about the application of technology to be able to work with people with MND to select the best

  4. Multiple neuropeptides in cholinergic motor neurons of Aplysia: evidence for modulation intrinsic to the motor circuit

    SciTech Connect

    Cropper, E.C.; Lloyd, P.E.; Reed, W.; Tenenbaum, R.; Kupfermann, I.; Weiss, K.R.

    1987-05-01

    Changes in Aplysia biting responses during food arousal are partially mediated by the serotonergic metacerebral cells (MCCs). The MCCs potentiate contractions of a muscle utilized in biting, the accessory radula closer (ARCM), when contractions are elicited by stimulation of either of the two cholinergic motor neurons B15 or B16 that innervate the muscle. The authors have now shown that ARCM contractions may also be potentiated by peptide cotransmitters in the ARCM motor neurons. They found that motor neuron B15 contains small cardioactive peptides A and B (SCP/sub A/ and SCP/sub B/) i.e., whole B15 neurons were bioactive on the SCP-sensitive Helix heart, as were reverse-phase HPLC fractions of B15 neurons that eluted like synthetic SCP/sub A/ and SCP/sub B/. Furthermore, (/sup 35/S)methionine-labeled B15 peptides precisely coeluted with synthetic SCP/sub A/ and SCP/sub B/. SCP/sub B/-like immunoreactivity was associated with dense-core vesicles in the soma of B15 and in neuritic varicosities and terminals in the ARCM. B16 motor neurons did not contain SCP/sub A/ or SCP/sub B/ but contained an unidentified bioactive peptide. RP-HPLC of (/sup 35/S)methionine-labeled B16s resulted in one major peak of radioactivity that did not coelute with either SCP and which, when subject to Edman degradation, yielded (/sup 35/S)methionine in positions where there is no methionine in the SCPs. Exogenously applied B16 peptide potentiated ARCM contractions elicited by stimulation of B15 or B16 neurons. Thus, in this system there appear to be two types of modulation; one type arises from the MCCs and is extrinsic to the motor system, whereas the second type arises from the motor neurons themselves and hence is intrinsic.

  5. Epigenetic regulation of motor neuron cell death through DNA methylation.

    PubMed

    Chestnut, Barry A; Chang, Qing; Price, Ann; Lesuisse, Catherine; Wong, Margaret; Martin, Lee J

    2011-11-16

    DNA methylation is an epigenetic mechanism for gene silencing engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to cytosine residues in gene-regulatory regions. It is unknown whether aberrant DNA methylation can cause neurodegeneration. We tested the hypothesis that Dnmts can mediate neuronal cell death. Enforced expression of Dnmt3a induced degeneration of cultured NSC34 cells. During apoptosis of NSC34 cells induced by camptothecin, levels of Dnmt1 and Dnmt3a increased fivefold and twofold, respectively, and 5-methylcytosine accumulated in nuclei. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocked apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with RG108 and procainamide protected cultured neurons from excessive DNA methylation and apoptosis. In vivo, Dnmt1 and Dnmt3a are expressed differentially during mouse brain and spinal cord maturation and in adulthood when Dnmt3a is abundant in synapses and mitochondria. Dnmt1 and Dnmt3a are expressed in motor neurons of adult mouse spinal cord, and, during their apoptosis induced by sciatic nerve avulsion, nuclear and cytoplasmic 5-methylcytosine immunoreactivity, Dnmt3a protein levels and Dnmt enzyme activity increased preapoptotically. Inhibition of Dnmts with RG108 blocked completely the increase in 5-methycytosine and the apoptosis of motor neurons in mice. In human amyotrophic lateral sclerosis (ALS), motor neurons showed changes in Dnmt1, Dnmt3a, and 5-methylcytosine similar to experimental models. Thus, motor neurons can engage epigenetic mechanisms to drive apoptosis, involving Dnmt upregulation and increased DNA methylation. These cellular mechanisms could be relevant to human ALS pathobiology and disease treatment.

  6. Neuronal mechanisms of motor learning and motor memory consolidation in healthy old adults.

    PubMed

    Berghuis, K M M; Veldman, M P; Solnik, S; Koch, G; Zijdewind, I; Hortobágyi, T

    2015-06-01

    It is controversial whether or not old adults are capable of learning new motor skills and consolidate the performance gains into motor memory in the offline period. The underlying neuronal mechanisms are equally unclear. We determined the magnitude of motor learning and motor memory consolidation in healthy old adults and examined if specific metrics of neuronal excitability measured by magnetic brain stimulation mediate the practice and retention effects. Eleven healthy old adults practiced a wrist extension-flexion visuomotor skill for 20 min (MP, 71.3 years), while a second group only watched the templates without movements (attentional control, AC, n = 11, 70.5 years). There was 40 % motor learning in MP but none in AC (interaction, p < 0.001) with the skill retained 24 h later in MP and a 16 % improvement in AC. Corticospinal excitability at rest and during task did not change, but when measured during contraction at 20 % of maximal force, it strongly increased in MP and decreased in AC (interaction, p = 0.002). Intracortical inhibition at rest and during the task decreased and facilitation at rest increased in MP, but these metrics changed in the opposite direction in AC. These neuronal changes were especially profound at retention. Healthy old adults can learn a new motor skill and consolidate the learned skill into motor memory, processes that are most likely mediated by disinhibitory mechanisms. These results are relevant for the increasing number of old adults who need to learn and relearn movements during motor rehabilitation.

  7. Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS

    PubMed Central

    Lalancette-Hebert, Melanie; Sharma, Aarti; Lyashchenko, Alexander K.; Shneider, Neil A.

    2016-01-01

    The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (IA) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced IA activation by targeted reduction of γ-MNs in SOD1G93A mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS. PMID:27930290

  8. Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS.

    PubMed

    Lalancette-Hebert, Melanie; Sharma, Aarti; Lyashchenko, Alexander K; Shneider, Neil A

    2016-12-20

    The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (IA) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced IA activation by targeted reduction of γ-MNs in SOD1(G93A) mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.

  9. Lower motor neuron facial palsy in cerebral venous sinus thrombosis

    PubMed Central

    Kulkarni, Girish Baburao; Ravi, Yadav; Nagaraja, Dindigur; Veerendrakumar, Mustare

    2013-01-01

    With advances in the neuro-imaging modalities, diverse manifestations of the cerebral venous sinus thrombosis (CVT) are being recognized. There are very few reports of isolated cranial nerve palsies in CVT. In this case report, we describe a patient of lower motor neuron facial palsy with CVT who was successfully treated with anticoagulation, highlighting the atypical manifestation of the disease. PMID:23914113

  10. Equine motor neuron disease in 2 horses from Saskatchewan

    PubMed Central

    Husulak, Michelle L.; Lohmann, Katharina L.; Gabadage, Kamal; Wojnarowicz, Chris; Marqués, Fernando J.

    2016-01-01

    Two horses from Saskatchewan were presented with signs of sweating, muscle fasciculations, weight loss, and generalized weakness. The horses were diagnosed with equine motor neuron disease (EMND), by histological assessment of a spinal accessory nerve or sacrocaudalis dorsalis medialis muscle biopsy. This is the first report of EMND in western Canada. PMID:27429468

  11. Assessment of the upper motor neuron in amyotrophic lateral sclerosis.

    PubMed

    Huynh, William; Simon, Neil G; Grosskreutz, Julian; Turner, Martin R; Vucic, Steve; Kiernan, Matthew C

    2016-07-01

    Clinical signs of upper motor neuron (UMN) involvement are an important component in supporting the diagnosis of amyotrophic lateral sclerosis (ALS), but are often not easily appreciated in a limb that is concurrently affected by muscle wasting and lower motor neuron degeneration, particularly in the early symptomatic stages of ALS. Whilst recent criteria have been proposed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains essentially clinical. As a result, there is often a significant diagnostic delay that in turn may impact institution of disease-modifying therapy and access to other optimal patient management. Biomarkers of pathological UMN involvement are also required to ensure patients with suspected ALS have timely access to appropriate therapeutic trials. The present review provides an analysis of current and recently developed assessment techniques, including novel imaging and electrophysiological approaches used to study corticomotoneuronal pathology in ALS. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  12. Dysarthria of Motor Neuron Disease: Clinician Judgments of Severity.

    ERIC Educational Resources Information Center

    Seikel, J. Anthony; And Others

    1990-01-01

    This study investigated the relationship between the temporal-acoustic parameters of the speech of 15 adults with motor neuron disease. Differences in predictions of the progression of the disease and clinician judgments of dysarthria severity were found to relate to the linguistic systems of both speaker and judge. (Author/JDD)

  13. Decreased function of survival motor neuron protein impairs endocytic pathways

    PubMed Central

    Dimitriadi, Maria; Derdowski, Aaron; Kalloo, Geetika; Maginnis, Melissa S.; O’Hern, Patrick; Bliska, Bryn; Sorkaç, Altar; Nguyen, Ken C. Q.; Cook, Steven J.; Poulogiannis, George; Atwood, Walter J.; Hall, David H.; Hart, Anne C.

    2016-01-01

    Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death. PMID:27402754

  14. Equine motor neuron disease in 2 horses from Saskatchewan.

    PubMed

    Husulak, Michelle L; Lohmann, Katharina L; Gabadage, Kamal; Wojnarowicz, Chris; Marqués, Fernando J

    2016-07-01

    Two horses from Saskatchewan were presented with signs of sweating, muscle fasciculations, weight loss, and generalized weakness. The horses were diagnosed with equine motor neuron disease (EMND), by histological assessment of a spinal accessory nerve or sacrocaudalis dorsalis medialis muscle biopsy. This is the first report of EMND in western Canada.

  15. Calcineurin inhibition enhances motor neuron survival following injury

    PubMed Central

    Hui, Kelvin KW; Liadis, Nicole; Robertson, Jennifer; Kanungo, Anish; Henderson, Jeffrey T

    2010-01-01

    Abstract The immunosuppressive agents cyclosporin A (CsA) and FK-506 have previously been shown to exhibit neurotrophic and neuroprotective properties in vivo. Given that significant clinical expertise exists for both drugs, they represent an attractive starting point for treatment of acute neural injuries. One putative mechanism for neuroprotection by these drugs relates to inhibition of calcineurin activity. However each drug–immunophilin complex can potentially influence additional signal transduction pathways. Furthermore, several non-immunosuppressive immunophilin ligands have been described as possessing neuroprotective properties, suggesting that neuroprotection may be separable from calcineurin inhibition. In the present study, we examined the mechanism of this neuroprotection in facial motor neurons following axotomy-induced injury. Similar to previous studies in rats, CsA and FK-506 enhanced motor neuron survival in mice following acute injury. To examine the mechanism responsible for neuroprotection by these agents, pharmacologic inhibitors of several potential alternate signalling pathways (17-(allylamino)-17-demethoxygeldanamycin, rapamycin, cypermethrin) were evaluated with respect to neuroprotection. Of these, only cypermethrin, a direct calcineurin inhibitor not previously associated with neuronal survival properties, was observed to significantly enhance motor neuron survival following injury. The results demonstrate for the first time that direct inhibition of calcineurin is neuroprotective in vivo. These data support a model in which calcineurin inhibition promotes neuronal survival, distinct from effects upon neurite outgrowth. PMID:19243469

  16. Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction

    PubMed Central

    Gogliotti, Rocky G.; Quinlan, Katharina A.; Barlow, Courtenay B.; Heier, Christopher R.; Heckman, C. J.

    2012-01-01

    The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using an Hb9-Cre allele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. MN rescue also corrects hyperexcitability in SMA motor neurons and prevents sensory-motor synaptic stripping. Survival in MN-rescued SMA mice is extended by only 5 d, due in part to failed autonomic innervation of the heart. Collectively, this work demonstrates that the SMA phenotype autonomously originates in MNs and that sensory-motor synapse loss is a consequence, not a cause, of MN dysfunction. PMID:22423102

  17. Spasticity: the misunderstood part of the upper motor neuron syndrome.

    PubMed

    Ivanhoe, Cindy B; Reistetter, Timothy A

    2004-10-01

    Spasticity is a sensorimotor phenomenon related to the integration of the nervous system motor responses to sensory input. Although most commonly considered a velocity-dependent increase to tonic stretch, it is related to hypersensitivity of the reflex arc and changes that occur within the central nervous system, most notably, the spinal cord. Injury to the central nervous system results in loss of descending inhibition, allowing for the clinical manifestation of abnormal impulses. Muscle activity becomes overactive. This is mediated at several areas of the stretch-reflex pathway. Although spasticity is part of the upper motor neuron syndrome, it is frequently tied to the other presentations of the said syndrome. Contracture, hypertonia, weakness, and movement disorders can all coexist as a result of the upper motor neuron syndrome. Although basic science descriptions of spasticity are being elucidated, clinically, confusion exists.

  18. Functional diversity of ES cell derived motor neuron subtypes revealed through intraspinal transplantation

    PubMed Central

    Peljto, Mirza; Dasen, Jeremy S.; Mazzoni, Esteban O.; Jessell, Thomas M.; Wichterle, Hynek

    2010-01-01

    Summary Cultured ES cells can form different classes of neurons, but whether these neurons can acquire specialized subtype features typical of neurons in vivo remains unclear. We show here that mouse ES cells can be directed to form highly specific motor neuron subtypes in the absence of added factors, through a differentiation program that relies on endogenous Wnts, FGFs, and Hh – mimicking the normal program of motor neuron subtype differentiation. Molecular markers that characterize motor neuron subtypes anticipate the functional properties of these neurons in vivo: ES motor neurons grafted isochronically into chick spinal cord settle in appropriate columnar domains and select axonal trajectories with a fidelity that matches that of their in vivo generated counterparts. ES motor neurons can therefore be programmed in a predictive manner to acquire molecular and functional properties that characterize one of the many dozens of specialized motor neuron subtypes that exist in vivo. PMID:20804971

  19. Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

    PubMed

    Schwab, Andrew J; Ebert, Allison D

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

  20. Neurons in Primary Motor Cortex Engaged During Action Observation

    PubMed Central

    Dushanova, Juliana; Donoghue, John

    2010-01-01

    Neurons in higher cortical areas appear to become active during action observation, either by mirroring observed actions (termed mirror neurons) or by eliciting mental rehearsal of observed motor acts. We report the existence of neurons in primary motor cortex (MI) responding to viewed actions, an area generally considered to initiate and guide movement performance. Multielectrode recordings in monkeys performing or observing a well-learned step tracking task showed that approximately half of MI neurons, active when monkeys performed the task, were also active when they observed the action being performed by a human. These ‘view’ neurons were spatially intermingled with ‘do’ neurons, active only during movement performance. Simultaneously recorded, ‘view’ neurons comprised two groups: ∼38% retained the same preferred direction (PD) and timing during performance and viewing, while the remainder (62%) changed their PDs and time lag during viewing compared with performance. Nevertheless, population activity during viewing was sufficient to predict the direction and trajectory of viewed movements as action unfolded, although less accurately than during performance. ‘View’ neurons became less active and contained poorer representations of action when viewing only sub-components of the task. MI ‘view’ neurons thus appear to reflect the aspects of a learned movement when observed in others and form part of a broadly engaged set of cortical areas routinely responding to learned behaviors. These findings suggest that viewing a learned action elicits replay of aspects of MI activity needed to perform the observed action and could additionally reflect processing related to understanding, learning or mentally rehearsing action. PMID:20074212

  1. Genetic deficiency of GABA differentially regulates respiratory and non-respiratory motor neuron development.

    PubMed

    Fogarty, Matthew J; Smallcombe, Karen L; Yanagawa, Yuchio; Obata, Kunihiko; Bellingham, Mark C; Noakes, Peter G

    2013-01-01

    Central nervous system GABAergic and glycinergic synaptic activity switches from postsynaptic excitation to inhibition during the stage when motor neuron numbers are being reduced, and when synaptic connections are being established onto and by motor neurons. In mice this occurs between embryonic (E) day 13 and birth (postnatal day 0). Our previous work on mice lacking glycinergic transmission suggested that altered motor neuron activity levels correspondingly regulated motor neuron survival and muscle innervation for all respiratory and non respiratory motor neuron pools, during this period of development [1]. To determine if GABAergic transmission plays a similar role, we quantified motor neuron number and the extent of muscle innervation in four distinct regions of the brain stem and spinal cord; hypoglossal, phrenic, brachial and lumbar motor pools, in mice lacking the enzyme GAD67. These mice display a 90% drop in CNS GABA levels ( [2]; this study). For respiratory-based motor neurons (hypoglossal and phrenic motor pools), we have observed significant drops in motor neuron number (17% decline for hypoglossal and 23% decline for phrenic) and muscle innervations (55% decrease). By contrast for non-respiratory motor neurons of the brachial lateral motor column, we have observed an increase in motor neuron number (43% increase) and muscle innervations (99% increase); however for more caudally located motor neurons within the lumbar lateral motor column, we observed no change in either neuron number or muscle innervation. These results show in mice lacking physiological levels of GABA, there are distinct regional changes in motor neuron number and muscle innervation, which appear to be linked to their physiological function and to their rostral-caudal position within the developing spinal cord. Our results also suggest that for more caudal (lumbar) regions of the spinal cord, the effect of GABA is less influential on motor neuron development compared to that of

  2. Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Have Reduced Expression of Proteins Important in Neuronal Development

    PubMed Central

    Fuller, Heidi R.; Mandefro, Berhan; Shirran, Sally L.; Gross, Andrew R.; Kaus, Anjoscha S.; Botting, Catherine H.; Morris, Glenn E.; Sareen, Dhruv

    2016-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease primarily characterized by degeneration of spinal motor neurons, and caused by reduced levels of the SMN protein. Previous studies to understand the proteomic consequences of reduced SMN have mostly utilized patient fibroblasts and animal models. We have derived human motor neurons from type I SMA and healthy controls by creating their induced pluripotent stem cells (iPSCs). Quantitative mass spectrometry of these cells revealed increased expression of 63 proteins in control motor neurons compared to respective fibroblasts, whereas 30 proteins were increased in SMA motor neurons vs. their fibroblasts. Notably, UBA1 was significantly decreased in SMA motor neurons, supporting evidence for ubiquitin pathway defects. Subcellular distribution of UBA1 was predominantly cytoplasmic in SMA motor neurons in contrast to nuclear in control motor neurons; suggestive of neurodevelopmental abnormalities. Many of the proteins that were decreased in SMA motor neurons, including beta III-tubulin and UCHL1, were associated with neurodevelopment and differentiation. These neuron-specific consequences of SMN depletion were not evident in fibroblasts, highlighting the importance of iPSC technology. The proteomic profiles identified here provide a useful resource to explore the molecular consequences of reduced SMN in motor neurons, and for the identification of novel biomarker and therapeutic targets for SMA. PMID:26793058

  3. Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: implications for human motor neuron disease.

    PubMed

    Palmisano, Ralf; Golfi, Panagiota; Heimann, Peter; Shaw, Christopher; Troakes, Claire; Schmitt-John, Thomas; Bartsch, Jörg W

    2011-03-07

    The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown but hypotheses about disease mechanisms include oxidative stress, defective axonal transport, mitochondrial dysfunction and disrupted RNA processing. Whereas familial ALS is well represented by transgenic mutant SOD1 mouse models, the mouse mutant wobbler (WR) develops progressive motor neuron degeneration due to a point mutation in the Vps54 gene, and provides an animal model for sporadic ALS. VPS54 protein as a component of a protein complex is involved in vesicular Golgi trafficking; impaired vesicle trafficking might also be mechanistic in the pathogenesis of human ALS. In motor neurons of homozygous symptomatic WR mice, a massive number of endosomal vesicles significantly enlarged (up to 3 μm in diameter) were subjected to ultrastructural analysis and immunohistochemistry for the endosome-specific small GTPase protein Rab7 and for amyloid precursor protein (APP). Enlarged vesicles were neither detected in heterozygous WR nor in transgenic SOD1(G93A) mice; in WR motor neurons, numerous APP/Rab7-positive vesicles were observed which were mostly LC3-negative, suggesting they are not autophagosomes. We conclude that endosomal APP/Rab7 staining reflects impaired vesicle trafficking in WR mouse motor neurons. Based on these findings human ALS tissues were analysed for APP in enlarged vesicles and were detected in spinal cord motor neurons in six out of fourteen sporadic ALS cases. These enlarged vesicles were not detected in any of the familial ALS cases. Thus our study provides the first evidence for wobbler-like aetiologies in human ALS and suggests that the genes encoding proteins involved in vesicle trafficking should be screened for pathogenic mutations.

  4. Identification of motor neurons and a mechanosensitive sensory neuron in the defecation circuitry of Drosophila larvae.

    PubMed

    Zhang, Wei; Yan, Zhiqiang; Li, Bingxue; Jan, Lily Yeh; Jan, Yuh Nung

    2014-10-30

    Defecation allows the body to eliminate waste, an essential step in food processing for animal survival. In contrast to the extensive studies of feeding, its obligate counterpart, defecation, has received much less attention until recently. In this study, we report our characterizations of the defecation behavior of Drosophila larvae and its neural basis. Drosophila larvae display defecation cycles of stereotypic frequency, involving sequential contraction of hindgut and anal sphincter. The defecation behavior requires two groups of motor neurons that innervate hindgut and anal sphincter, respectively, and can excite gut muscles directly. These two groups of motor neurons fire sequentially with the same periodicity as the defecation behavior, as revealed by in vivo Ca(2+) imaging. Moreover, we identified a single mechanosensitive sensory neuron that innervates the anal slit and senses the opening of the intestine terminus. This anus sensory neuron relies on the TRP channel NOMPC but not on INACTIVE, NANCHUNG, or PIEZO for mechanotransduction.

  5. Axonal Regeneration and Motor Neuron Survival after Microsurgical Nerve Reconstruction

    PubMed Central

    Fox, Ida K.; Brenner, Michael J.; Johnson, Philip J.; Hunter, Daniel A.; Mackinnon, Susan E.

    2014-01-01

    Rodent models are used extensively for studying nerve regeneration, but little is known about how sprouting and pruning influence peripheral nerve fiber counts and motor neuron pools. The purpose of this study was to identify fluctuations in nerve regeneration and neuronal survival over time. One hundred and forty-four Lewis rats were randomized to end-to-end repair or nerve grafting (1.5 cm graft) after sciatic nerve transection. Quantitative histomorphometry and retrograde labeling of motor neurons were performed at 1, 3, 6, 9, 12, and 24 months and supplemented by electron microscopy. Fiber counts and motor neuron counts increased between 1 and 3 months, followed by plateau. End-to-end repair resulted in persistently higher fiber counts compared to the grafting for all time points (P < 0.05). Percent neural tissue and myelin width increased with time while fibrin debris dissipated. In conclusion, these data detail the natural history of regeneration and demonstrate that overall fiber counts may remain stable despite pruning. PMID:22806696

  6. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases

    PubMed Central

    Kaifer, Kevin A.; Osman, Erkan Y.; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L.

    2017-01-01

    The term “motor neuron disease” encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic

  7. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

    PubMed

    Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

    2017-03-31

    The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

  8. Cholestenoic acids regulate motor neuron survival via liver X receptors

    PubMed Central

    Theofilopoulos, Spyridon; Griffiths, William J.; Crick, Peter J.; Yang, Shanzheng; Meljon, Anna; Ogundare, Michael; Kitambi, Satish Srinivas; Lockhart, Andrew; Tuschl, Karin; Clayton, Peter T.; Morris, Andrew A.; Martinez, Adelaida; Reddy, M. Ashwin; Martinuzzi, Andrea; Bassi, Maria T.; Honda, Akira; Mizuochi, Tatsuki; Kimura, Akihiko; Nittono, Hiroshi; De Michele, Giuseppe; Carbone, Rosa; Criscuolo, Chiara; Yau, Joyce L.; Seckl, Jonathan R.; Schüle, Rebecca; Schöls, Ludger; Sailer, Andreas W.; Kuhle, Jens; Fraidakis, Matthew J.; Gustafsson, Jan-Åke; Steffensen, Knut R.; Björkhem, Ingemar; Ernfors, Patrik; Sjövall, Jan; Arenas, Ernest; Wang, Yuqin

    2014-01-01

    Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3β-hydroxy-7-oxocholest-5-en-26-oic acid (3βH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3β,7α-diHCA and 3βH,7O-CA, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3β-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3β,7α-diHCA. Moreover, 3β,7α-diHCA prevented the loss of motor neurons induced by 3β-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death. PMID:25271621

  9. Human endogenous retrovirus-K contributes to motor neuron disease.

    PubMed

    Li, Wenxue; Lee, Myoung-Hwa; Henderson, Lisa; Tyagi, Richa; Bachani, Muzna; Steiner, Joseph; Campanac, Emilie; Hoffman, Dax A; von Geldern, Gloria; Johnson, Kory; Maric, Dragan; Morris, H Douglas; Lentz, Margaret; Pak, Katherine; Mammen, Andrew; Ostrow, Lyle; Rothstein, Jeffrey; Nath, Avindra

    2015-09-30

    The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis. Copyright © 2015, American Association for the Advancement of Science.

  10. Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

    PubMed

    Statland, Jeffrey M; Barohn, Richard J; McVey, April L; Katz, Jonathan S; Dimachkie, Mazen M

    2015-11-01

    When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Neuronal cell sheet of cortical motor neuron phenotype derived from human iPS cells.

    PubMed

    Suzuki, Noboru; Arimitsu, Nagisa; Shimizu, Jun; Takai, Kenji; Hirotsu, Chieko; Takada, Erika; Ueda, Yuji; Wakisaka, Sueshige; Fujiwara, Naruyoshi; Suzuki, Tomoko

    2017-03-17

    Transplantation of stem cells which differentiate into more mature neural cells brings about functional improvement in pre-clinical studies of stroke. Previous transplant approaches in diseased brain have utilized injection of the cells in a cell suspension. In addition, neural stem cells were preferentially used as graft. However, these cells had no specific relationship to the damaged tissue of stroke patients and brain injury. The injection of cells in a suspension destroyed the cell-cell interactions that are suggested to be important for promoting functional integrity as cortical motor neurons.

    In order to obtain suitable cell types for grafting patients with stroke and brain damage, we have modified a protocol for differentiating human iPS cells to cells phenotypically related to cortical motor neurons. Moreover, we applied cell sheet technology to neural cell transplantation due to the idea in which keeping cell-cell communications was regarded as important for the repair of host brain architecture.

    Accordingly, we developed neuronal cell sheets being positive for FEZ family zinc finger 2 (Fezf2), COUP-TF-interacting protein 2 (CTIP2), insulin-like growth factor-binding protein 4 (Igfbp4), cysteine-rich motor neuron 1 protein precursor (CRIM1) and forkhead box p2 (Foxp2). These markers are associated with cortical motoneuron which is appropriate for the transplant location in the lesions. The sheets allowed preservation of cell-cell interactions shown by synapsin1 staining after transplantation to damaged mouse brain. The sheet transplantation brought about structural restoration partly and improvement of motor functions in hemiplegic mice.

    Collectively, the cell sheets were transplanted to damaged motor cortex in a way of a novel neuronal cell sheet that maintained cell-cell interactions and improved motor functions of the hemiplegic model mice. The motoneuron cell sheets are possibly applicable for stroke patients and patients with

  12. Selective vulnerability of spinal and cortical motor neuron subpopulations in delta7 SMA mice.

    PubMed

    d'Errico, Paolo; Boido, Marina; Piras, Antonio; Valsecchi, Valeria; De Amicis, Elena; Locatelli, Denise; Capra, Silvia; Vagni, Francesco; Vercelli, Alessandro; Battaglia, Giorgio

    2013-01-01

    Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients.

  13. Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS.

    PubMed

    Comley, L; Allodi, I; Nichterwitz, S; Nizzardo, M; Simone, C; Corti, S; Hedlund, E

    2015-04-16

    The lethal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons. However, not all motor neurons are equally vulnerable to disease; certain groups are spared, including those in the oculomotor nucleus controlling eye movement. The reasons for this differential vulnerability remain unknown. Here we have identified a protein signature for resistant oculomotor motor neurons and vulnerable hypoglossal and spinal motor neurons in mouse and man and in health and ALS with the aim of understanding motor neuron resistance. Several proteins with implications for motor neuron resistance, including GABAA receptor α1, guanylate cyclase soluble subunit alpha-3 and parvalbumin were persistently expressed in oculomotor neurons in man and mouse. Vulnerable motor neurons displayed higher protein levels of dynein, peripherin and GABAA receptor α2, which play roles in retrograde transport and excitability, respectively. These were dynamically regulated during disease and thus could place motor neurons at an increased risk. From our analysis is it evident that oculomotor motor neurons have a distinct protein signature compared to vulnerable motor neurons in brain stem and spinal cord, which could in part explain their resistance to degeneration in ALS. Our comparison of human and mouse shows the relative conservation of signals across species and infers that transgenic SOD1G93A mice could be used to predict mechanisms of neuronal vulnerability in man.

  14. Motor Neuron Diseases Accompanying Spinal Stenosis: A Case Study.

    PubMed

    Shin, HyeonJu; Park, Sun Kyung; HaeJin, Suh; Choi, Yun Suk

    2016-03-01

    A 75-year-old man, who was healthy, visited the hospital because of shooting pain and numbness in both lower limbs (right > left). The patient had an L4/5 moderate right foraminal stenosis and right subarticular disc protrusion and received a lumbar epidural block. The patient experienced severe weakness in the right lower limb after 2 days. Lumbar and cervical magnetic resonance images were taken and electromyography and a nerve conduction study were performed to arrive at the diagnosis of a motor neuron disease. The patient expired 4 months later with respiratory failure due to motor neuron disease. This case suggests that any abnormal neurological symptoms that occur after an epidural block should be examined thoroughly via testing and consultations to identify the cause of the symptoms.

  15. Brain-wide neuronal dynamics during motor adaptation in zebrafish.

    PubMed

    Ahrens, Misha B; Li, Jennifer M; Orger, Michael B; Robson, Drew N; Schier, Alexander F; Engert, Florian; Portugues, Ruben

    2012-05-09

    A fundamental question in neuroscience is how entire neural circuits generate behaviour and adapt it to changes in sensory feedback. Here we use two-photon calcium imaging to record the activity of large populations of neurons at the cellular level, throughout the brain of larval zebrafish expressing a genetically encoded calcium sensor, while the paralysed animals interact fictively with a virtual environment and rapidly adapt their motor output to changes in visual feedback. We decompose the network dynamics involved in adaptive locomotion into four types of neuronal response properties, and provide anatomical maps of the corresponding sites. A subset of these signals occurred during behavioural adjustments and are candidates for the functional elements that drive motor learning. Lesions to the inferior olive indicate a specific functional role for olivocerebellar circuitry in adaptive locomotion. This study enables the analysis of brain-wide dynamics at single-cell resolution during behaviour.

  16. Madras pattern of motor neuron disease in South India.

    PubMed Central

    Gourie-Devi, M; Suresh, T G

    1988-01-01

    This paper presents the clinical features in 12 patients with the Madras pattern of motor neuron disease (MMND) seen over a period of 10 years. Ten of the patients were from other parts of South India, outside Madras. Young age at onset, sporadic occurrence, sensorineural deafness, bulbar palsy, diffuse atrophy with weakness of limbs and progressive but benign course were the striking features. Electromyography revealed chronic partial denervation. MMND formed 3.7% of all forms of motor neuron disease. Although isolated cases have been seen elsewhere in India, this is the first report of a large number of patients of MMND seen outside Madras (Tamil Nadu). Recognition of this clinical syndrome is of importance for prognostication and as well for search of possible aetiological factors. Images PMID:3404185

  17. Motor neuron disease: current management and future prospects.

    PubMed

    Simon, N G; Huynh, W; Vucic, S; Talbot, K; Kiernan, M C

    2015-10-01

    Motor neuron disease (MND) is characterised by progressive neurological deterioration and coexistence of upper and lower motor neuron signs. Over the past decade, evidence has emerged of unique pathophysiological processes, including glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the recently discovered C9orf72 gene, have radically changed the pathological mindset, from MND being classified as a neuromuscular disease to one that MND forms a continuum with other primary neurodegenerative disorders, including frontotemporal dementia. The present review will highlight the improvements that have occurred in clinical care, in conjunction with recent scientific developments. © 2015 Royal Australasian College of Physicians.

  18. Motor neuron disease: biomarker development for an expanding cerebral syndrome.

    PubMed

    Turner, Martin R

    2016-12-01

    Descriptions of motor neuron disease (MND) documented more than a century ago remain instantly recognisable to the physician. The muscle weakness, typically with signs of upper and lower motor neuron dysfunction, is uniquely relentless. Over the last 30 years, a wider cerebral pathology has emerged, despite the lack of overt cognitive impairment in the majority of patients. From the initial linkage of a small number of cases to mutations in SOD1, diverse cellular pathways have been implicated in pathogenesis. An increasingly complex clinical heterogeneity has emerged around a significant variability in survival. Defining a cellular signature of aggregated TDP-43 common to nearly all MND and a large proportion of frontotemporal dementia (FTD), has placed MND alongside more traditional cerebral neurodegeneration. With new genetic causes, most notably a hexanucleotide expansion in C9orf72 associated with both MND and FTD, the development of biomarkers against which to test therapeutic candidates is a priority.

  19. GPs have key role in managing motor neurone disease.

    PubMed

    Orrell, Richard W

    2011-09-01

    Motor neurone disease (MND) is a rapidly progressive neurodegenerative condition. It affects people of all ages, but is more common with increasing age (especially over 50 years) and men are affected twice as often as women. The causes remain unknown, although around 5% of cases have a genetic basis. Survival is usually only three to five years from diagnosis. MND affects both upper and lower motor neurones, with variable contributions. The nerve involvement in MND usually has a focal onset, is asymmetrical, but tends to spread to adjacent regions of the body. If the affected region is in the legs, a common presenting feature is tripping, falls or foot drop. If it is in the arms there may be difficulty with fine tasks such as fastening buttons, or raising an arm, and if the cranial nerves are affected there may be slurring of speech, or difficulty swallowing. Key to the diagnosis is evidence of progression, and this may lead to some delay in considering and also confirming the diagnosis. When examining the patient, evidence of more widespread neuromuscular involvement should be looked for. In a patient with foot drop, and fasciculation of the tongue, MND would be a likely diagnosis. Upper motor neurone involvement may be readily determined by examining the reflexes. Brisk reflexes, in the arms, legs or jaw, in the context of features of lower motor neurone denervation are highly suggestive of MND. Suspicion of MND should lead to referral for a neurology opinion. The most useful investigation is likely to be EMG with nerve conduction studies, and probably MRI scan of relevant areas. Blood tests are arranged to screen for any other causative condition. Riluzole is a disease modifying drug licensed to extend the life of patients with MND. There is no treatment that will reverse, or halt, progression of the disease.

  20. TDP-43/FUS in motor neuron disease: Complexity and challenges.

    PubMed

    Guerrero, Erika N; Wang, Haibo; Mitra, Joy; Hegde, Pavana M; Stowell, Sara E; Liachko, Nicole F; Kraemer, Brian C; Garruto, Ralph M; Rao, K S; Hegde, Muralidhar L

    Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. GPNMB ameliorates mutant TDP-43-induced motor neuron cell death.

    PubMed

    Nagahara, Yuki; Shimazawa, Masamitsu; Ohuchi, Kazuki; Ito, Junko; Takahashi, Hitoshi; Tsuruma, Kazuhiro; Kakita, Akiyoshi; Hara, Hideaki

    2017-08-01

    Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. Motor neurone disease presenting with raised serum Troponin T.

    PubMed

    Mamo, Jonathan P

    2015-05-01

    Myocardial damage indicated by a rise in cardiac Troponin may not necessarily be due to a cardiac event. Many diseases such as sepsis, pulmonary embolism, heart and renal failure can also be associated with an elevated cardiac Troponin level. This brief report discusses the rare event of a patient with motor neurone disease, where the possible diagnosis of acute myocardial infarction arose due to an elevated cardiac Troponin. A 69-year-old gentleman presented with a history of a central chest ache of mild intensity, lasting a total of 2 h prior to complete resolution. Multiple cardiac Troponin assays were elevated, and echocardiography did not show any acute changes of myocardial damage. His electrocardiogram was also normal. This patient's raised cardiac Troponin was therefore explained on the basis of his active motor neurone disease. This rare case outlines the importance of considering motor neurone disease as a cause of elevated cardiac Troponin in the absence of clinical evidence of an acute coronary event.

  3. Hereditary spastic paraplegia: More than an upper motor neuron disease.

    PubMed

    Parodi, L; Fenu, S; Stevanin, G; Durr, A

    2017-05-01

    Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurological diseases characterized by extreme heterogeneity in both their clinical manifestations and genetic backgrounds. Based on symptoms, HSPs can be divided into pure forms, presenting with pyramidal signs leading to lower-limb spasticity, and complex forms, when additional neurological or extraneurological symptoms are detected. The clinical diversity of HSPs partially reflects their underlying genetic backgrounds. To date, 76 loci and 58 corresponding genes [spastic paraplegia genes (SPGs)] have been linked to HSPs. The genetic diagnosis is further complicated by the fact that causative mutations of HSP can be inherited through all possible modes of transmission (autosomal-dominant and -recessive, X-linked, maternal), with some genes showing multiple inheritance patterns. The pathogenic mutations of SPGs primarily lead to progressive degeneration of the upper motor neurons (UMNs) comprising corticospinal tracts. However, it is possible to observe lower-limb muscle atrophy and fasciculations on clinical examination that are clear signs of lower motor neuron (LMN) involvement. The purpose of this review is to classify HSPs based on their degree of motor neuron involvement, distinguishing forms in which only UMNs are affected from those involving both UMN and LMN degeneration, and to describe their differential diagnosis from diseases such as amyotrophic lateral sclerosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Vitamin E deficiency and risk of equine motor neuron disease.

    PubMed

    Mohammed, Hussni O; Divers, Thomas J; Summers, Brian A; de Lahunta, Alexander

    2007-07-02

    Equine motor neuron disease (EMND) is a spontaneous neurologic disorder of adult horses which results from the degeneration of motor neurons in the spinal cord and brain stem. Clinical manifestations, pathological findings, and epidemiologic attributes resemble those of human motor neuron disease (MND). As in MND the etiology of the disease is not known. We evaluated the predisposition role of vitamin E deficiency on the risk of EMND. Eleven horses at risk of EMND were identified and enrolled in a field trial at different times. The horses were maintained on a diet deficient in vitamin E and monitored periodically for levels of antioxidants--alpha-tocopherols, vitamins A, C, beta-carotene, glutathione peroxidase (GSH-Px), and erythrocytic superoxide dismutase (SOD1). In addition to the self-control another parallel control group was included. Survival analysis was used to assess the probability of developing EMND past a specific period of time. There was large variability in the levels of vitamins A and C, beta-carotene, GSH-Px, and SOD1. Plasma vitamin E levels dropped significantly over time. Ten horses developed EMND within 44 months of enrollment. The median time to develop EMND was 38.5 months. None of the controls developed EMND. The study elucidated the role of vitamin E deficiency on the risk of EMND. Reproducing this disease in a natural animal model for the first time will enable us to carry out studies to test specific hypotheses regarding the mechanism by which the disease occurs.

  5. Apoptosis of limb innervating motor neurons and erosion of motor pool identity upon lineage specific dicer inactivation.

    PubMed

    Chen, Jun-An; Wichterle, Hynek

    2012-01-01

    Diversification of mammalian spinal motor neurons into hundreds of subtypes is critical for the maintenance of body posture and coordination of complex movements. Motor neuron differentiation is controlled by extrinsic signals that regulate intrinsic genetic programs specifying and consolidating motor neuron subtype identity. While transcription factors have been recognized as principal regulators of the intrinsic program, the role of posttranscriptional regulations has not been systematically tested. MicroRNAs produced by Dicer mediated cleavage of RNA hairpins contribute to gene regulation by posttranscriptional silencing. Here we used Olig2-cre conditional deletion of Dicer gene in motor neuron progenitors to examine effects of miRNA biogenesis disruption on postmitotic spinal motor neurons. We report that despite the initial increase in the number of motor neuron progenitors, disruption of Dicer function results in a loss of many limb- and sympathetic ganglia-innervating spinal motor neurons. Furthermore, it leads to defects in motor pool identity specification. Thus, our results indicate that miRNAs are an integral part of the genetic program controlling motor neuron survival and acquisition of subtype specific properties.

  6. Apoptosis of Limb Innervating Motor Neurons and Erosion of Motor Pool Identity Upon Lineage Specific Dicer Inactivation

    PubMed Central

    Chen, Jun-An; Wichterle, Hynek

    2012-01-01

    Diversification of mammalian spinal motor neurons into hundreds of subtypes is critical for the maintenance of body posture and coordination of complex movements. Motor neuron differentiation is controlled by extrinsic signals that regulate intrinsic genetic programs specifying and consolidating motor neuron subtype identity. While transcription factors have been recognized as principal regulators of the intrinsic program, the role of posttranscriptional regulations has not been systematically tested. MicroRNAs produced by Dicer mediated cleavage of RNA hairpins contribute to gene regulation by posttranscriptional silencing. Here we used Olig2-cre conditional deletion of Dicer gene in motor neuron progenitors to examine effects of miRNA biogenesis disruption on postmitotic spinal motor neurons. We report that despite the initial increase in the number of motor neuron progenitors, disruption of Dicer function results in a loss of many limb- and sympathetic ganglia-innervating spinal motor neurons. Furthermore, it leads to defects in motor pool identity specification. Thus, our results indicate that miRNAs are an integral part of the genetic program controlling motor neuron survival and acquisition of subtype specific properties. PMID:22629237

  7. Increased neuronal Rab5 immunoreactive endosomes do not colocalize with TDP-43 in motor neuron disease.

    PubMed

    Matej, Radoslav; Botond, Gergö; László, Lajos; Kopitar-Jerala, Natasa; Rusina, Robert; Budka, Herbert; Kovacs, Gabor G

    2010-09-01

    Sporadic motor neuron disease (MND) is characterized by progressive degeneration of motor neurons and intraneuronal cytoplasmic translocation and deposition of the nuclear protein TDP-43. There is a paucity of data on the subcellular mechanisms of the nuclear-cytoplasmic trafficking of TDP-43, particularly about the precise role of the endosomal-lysosomal system (ELS). In the present study, using a neuron-specific morphometric approach, we examined the expression of the early endosomal marker Rab5 and lysosomal cathepsins B, D, F, and L as well as PAS-stained structures in the anterior horn cells in 11 individuals affected by sporadic MND and 5 age-matched controls. This was compared with the expression of ubiquitin, p62 and TDP-43 and its phosphorylated form. The principal finding was the increased expression of the endosomal marker Rab5 and lysosomal cathepsin D, and of PAS-positive structures in motor neurons of MND cases. Furthermore, the area-portion of Rab5 immunoreactivity correlated well with the intracellular accumulation of ubiquitin, p62 and (phosphorylated) TDP-43. However, double immunolabelling and immunogold electron microscopy excluded colocalization of phosphorylated TDP-43 with the ELS. These data contrast with observations on neuronal cytopathology in Alzheimer's or prion diseases where the disease-specific proteins are processed within endosomes, and suggest a distinct role of the ELS in MND.

  8. Gaskell revisited: new insights into spinal autonomics necessitate a revised motor neuron nomenclature.

    PubMed

    Fritzsch, Bernd; Elliott, Karen L; Glover, Joel C

    2017-08-31

    Several concepts developed in the nineteenth century have formed the basis of much of our neuroanatomical teaching today. Not all of these were based on solid evidence nor have withstood the test of time. Recent evidence on the evolution and development of the autonomic nervous system, combined with molecular insights into the development and diversification of motor neurons, challenges some of the ideas held for over 100 years about the organization of autonomic motor outflow. This review provides an overview of the original ideas and quality of supporting data and contrasts this with a more accurate and in depth insight provided by studies using modern techniques. Several lines of data demonstrate that branchial motor neurons are a distinct motor neuron population within the vertebrate brainstem, from which parasympathetic visceral motor neurons of the brainstem evolved. The lack of an autonomic nervous system in jawless vertebrates implies that spinal visceral motor neurons evolved out of spinal somatic motor neurons. Consistent with the evolutionary origin of brainstem parasympathetic motor neurons out of branchial motor neurons and spinal sympathetic motor neurons out of spinal motor neurons is the recent revision of the organization of the autonomic nervous system into a cranial parasympathetic and a spinal sympathetic division (e.g., there is no sacral parasympathetic division). We propose a new nomenclature that takes all of these new insights into account and avoids the conceptual misunderstandings and incorrect interpretation of limited and technically inferior data inherent in the old nomenclature.

  9. SMN in motor neurons determines synaptic integrity in spinal muscular atrophy

    PubMed Central

    Martinez, Tara L.; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A.; Crowder, Melissa E.; Van Meerbeke, James P.; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J.; Lutz, Cathleen M.; Rich, Mark. M.; Sumner, Charlotte J.

    2012-01-01

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power. PMID:22723710

  10. The structure and function of serially homologous leg motor neurons in the locust. I. Anatomy.

    PubMed

    Wilson, J A

    1979-01-01

    Twenty-one prothoracic and 17 mesothoracic motor neurons innervating leg muscles have been identified physiologically and subsequently injected with dye from a microelectrode. A tract containing the primary neurites of motor neurons innervating the retractor unquis, levator and depressor tarsus, flexor tibiae, and reductor femora is described. All motor neurons studied have regions in which their dendritic branches overlap with those of other leg motor neurons. Identified, serially homologous motor neurons in the three thoracic ganglia were found to have: (1) cell bodies at similar locations and morphologically similar primary neurites (e.g., flexor tibiae motor neurons), (2) cell bodies at different locations in each ganglion and morphologically different primary neurites in each ganglion (e.g., fast retractor unguis motor neurons), or (3) cell bodies at similar locations and morphologically similar primary neurites but with a functional switch in one ganglion relative to the function of the neurons in the other two ganglia. As an example of the latter, the morphology of the metathoracic slow extensor tibiae (SETi) motor neurons was similar to that of pro- and mesothoracic fast extensor tibiae (FETi) motor neurons. Similarly the metathoracic FETi bears a striking resemblance to the pro- and the mesothoracic SETi. It is proposed that in the metathoracic ganglion the two extensor tibiae motor neurons have switched functions while retaining similar morphologies relative to the structure and function of their pro- and mesothoracic serial homologues.

  11. Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination.

    PubMed

    Personius, Kirkwood E; Chang, Qiang; Mentis, George Z; O'Donovan, Michael J; Balice-Gordon, Rita J

    2007-07-10

    During late embryonic and early postnatal life, neuromuscular junctions undergo synapse elimination that is modulated by patterns of motor neuron activity. Here, we test the hypothesis that reduced spinal neuron gap junctional coupling decreases temporally correlated motor neuron activity that, in turn, modulates neuromuscular synapse elimination, by using mutant mice lacking connexin 40 (Cx40), a developmentally regulated gap junction protein expressed in motor and other spinal neurons. In Cx40-/- mice, electrical coupling among lumbar motor neurons, measured by whole-cell recordings, was reduced, and single motor unit recordings in awake, behaving neonates showed that temporally correlated motor neuron activity was also reduced. Immunostaining and intracellular recording showed that the neuromuscular synapse elimination was accelerated in muscles from Cx40-/- mice compared with WT littermates. Our work shows that gap junctional coupling modulates neuronal activity patterns that, in turn, mediate synaptic competition, a process that shapes synaptic circuitry in the developing brain.

  12. Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination

    PubMed Central

    Personius, Kirkwood E.; Chang, Qiang; Mentis, George Z.; O'Donovan, Michael J.; Balice-Gordon, Rita J.

    2007-01-01

    During late embryonic and early postnatal life, neuromuscular junctions undergo synapse elimination that is modulated by patterns of motor neuron activity. Here, we test the hypothesis that reduced spinal neuron gap junctional coupling decreases temporally correlated motor neuron activity that, in turn, modulates neuromuscular synapse elimination, by using mutant mice lacking connexin 40 (Cx40), a developmentally regulated gap junction protein expressed in motor and other spinal neurons. In Cx40−/− mice, electrical coupling among lumbar motor neurons, measured by whole-cell recordings, was reduced, and single motor unit recordings in awake, behaving neonates showed that temporally correlated motor neuron activity was also reduced. Immunostaining and intracellular recording showed that the neuromuscular synapse elimination was accelerated in muscles from Cx40−/− mice compared with WT littermates. Our work shows that gap junctional coupling modulates neuronal activity patterns that, in turn, mediate synaptic competition, a process that shapes synaptic circuitry in the developing brain. PMID:17609378

  13. Hypergravity hinders axonal development of motor neurons in Caenorhabditis elegans

    PubMed Central

    Kalichamy, Saraswathi Subbammal; Yoon, Kyoung-hye

    2016-01-01

    As space flight becomes more accessible in the future, humans will be exposed to gravity conditions other than our 1G environment on Earth. Our bodies and physiology, however, are adapted for life at 1G gravity. Altering gravity can have profound effects on the body, particularly the development of muscles, but the reasons and biology behind gravity’s effect are not fully known. We asked whether increasing gravity had effects on the development of motor neurons that innervate and control muscle, a relatively unexplored area of gravity biology. Using the nematode model organism Caenorhabditis elegans, we examined changes in response to hypergravity in the development of the 19 GABAergic DD/VD motor neurons that innervate body muscle. We found that a high gravity force above 10G significantly increases the number of animals with defects in the development of axonal projections from the DD/VD neurons. We showed that a critical period of hypergravity exposure during the embryonic/early larval stage was sufficient to induce defects. While characterizing the nature of the axonal defects, we found that in normal 1G gravity conditions, DD/VD axonal defects occasionally occurred, with the majority of defects occurring on the dorsal side of the animal and in the mid-body region, and a significantly higher rate of error in the 13 VD axons than the 6 DD axons. Hypergravity exposure increased the rate of DD/VD axonal defects, but did not change the distribution or the characteristics of the defects. Our study demonstrates that altering gravity can impact motor neuron development. PMID:27833821

  14. Targeting Motor End Plates for Delivery of Adenoviruses: An Approach to Maximize Uptake and Transduction of Spinal Cord Motor Neurons

    PubMed Central

    Tosolini, Andrew Paul; Morris, Renée

    2016-01-01

    Gene therapy can take advantage of the skeletal muscles/motor neurons anatomical relationship to restrict gene expression to the spinal cord ventral horn. Furthermore, recombinant adenoviruses are attractive viral-vectors as they permit spatial and temporal modulation of transgene expression. In the literature, however, several inconsistencies exist with regard to the intramuscular delivery parameters of adenoviruses. The present study is an evaluation of the optimal injection sites on skeletal muscle, time course of expression and mice’s age for maximum transgene expression in motor neurons. Targeting motor end plates yielded a 2.5-fold increase in the number of transduced motor neurons compared to injections performed away from this region. Peak adenoviral transgene expression in motor neurons was detected after seven days. Further, greater numbers of transduced motor neurons were found in juvenile (3–7 week old) mice as compared with adults (8+ weeks old). Adenoviral injections produced robust transgene expression in motor neurons and skeletal myofibres. In addition, dendrites of transduced motor neurons were shown to extend well into the white matter where the descending motor pathways are located. These results also provide evidence that intramuscular delivery of adenovirus can be a suitable gene therapy approach to treat spinal cord injury. PMID:27619631

  15. A new method of isolating spinal motor neurons from fetal mouse.

    PubMed

    Wang, Weifang; Qi, Bao; Lv, Hui; Wu, Fei; Liu, Lulu; Wang, Wei; Wang, Quanquan; Hu, Liangchen; Hao, Yanlei; Wang, Yuzhong

    2017-08-15

    Isolating of primary motor neurons from animal embryos is critical for the study of neurological disease including mechanistic discovery and therapeutic development. Density gradient centrifuge taking advantage of the buoyant of motor neuron permits the enrichment of motor neurons. Despite the metrizamide, an OptiPrep medium has been introduced to separate the motor neurons by gradient centrifuge. We hereby used single density gradient of OptiPrep medium to isolate the spinal motor neurons from the fetal mouse. Single density gradient of OptiPrep medium is effective to isolate spinal motor neurons from the fetal mouse. The immunofluorescence staining analysis showed that the purity of cultured motor neurons at 72h was between 90% and 95%. Four gradients of OptiPrep medium have been previously used to isolate the motor neurons from spinal cord of mouse. In this study, the single gradient of OptiPrep medium was demonstrated to effectively isolate spinal motor neurons from the fetal mouse. The single gradient of OptiPrep medium is enough to produce high purity of spinal motor neurons from the fetal mouse. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Neurotrophic Requirements of Human Motor Neurons Defined Using Amplified and Purified Stem Cell-Derived Cultures

    PubMed Central

    Lamas, Nuno Jorge; Johnson-Kerner, Bethany; Roybon, Laurent; Kim, Yoon A.; Garcia-Diaz, Alejandro; Wichterle, Hynek; Henderson, Christopher E.

    2014-01-01

    Human motor neurons derived from embryonic and induced pluripotent stem cells (hESCs and hiPSCs) are a potentially important tool for studying motor neuron survival and pathological cell death. However, their basic survival requirements remain poorly characterized. Here, we sought to optimize a robust survival assay and characterize their response to different neurotrophic factors. First, to increase motor neuron yield, we screened a small-molecule collection and found that the Rho-associated kinase (ROCK) inhibitor Y-27632 enhances motor neuron progenitor proliferation up to 4-fold in hESC and hiPSC cultures. Next, we FACS-purified motor neurons expressing the Hb9::GFP reporter from Y-27632-amplified embryoid bodies and cultured them in the presence of mitotic inhibitors to eliminate dividing progenitors. Survival of these purified motor neurons in the absence of any other cell type was strongly dependent on neurotrophic support. GDNF, BDNF and CNTF all showed potent survival effects (EC50 1–2 pM). The number of surviving motor neurons was further enhanced in the presence of forskolin and IBMX, agents that increase endogenous cAMP levels. As a demonstration of the ability of the assay to detect novel neurotrophic agents, Y-27632 itself was found to support human motor neuron survival. Thus, purified human stem cell-derived motor neurons show survival requirements similar to those of primary rodent motor neurons and can be used for rigorous cell-based screening. PMID:25337699

  17. Localization of Motor Neurons and Central Pattern Generators for Motor Patterns Underlying Feeding Behavior in Drosophila Larvae

    PubMed Central

    Hückesfeld, Sebastian; Schoofs, Andreas; Schlegel, Philipp; Miroschnikow, Anton; Pankratz, Michael J.

    2015-01-01

    Motor systems can be functionally organized into effector organs (muscles and glands), the motor neurons, central pattern generators (CPG) and higher control centers of the brain. Using genetic and electrophysiological methods, we have begun to deconstruct the motor system driving Drosophila larval feeding behavior into its component parts. In this paper, we identify distinct clusters of motor neurons that execute head tilting, mouth hook movements, and pharyngeal pumping during larval feeding. This basic anatomical scaffold enabled the use of calcium-imaging to monitor the neural activity of motor neurons within the central nervous system (CNS) that drive food intake. Simultaneous nerve- and muscle-recordings demonstrate that the motor neurons innervate the cibarial dilator musculature (CDM) ipsi- and contra-laterally. By classical lesion experiments we localize a set of CPGs generating the neuronal pattern underlying feeding movements to the subesophageal zone (SEZ). Lesioning of higher brain centers decelerated all feeding-related motor patterns, whereas lesioning of ventral nerve cord (VNC) only affected the motor rhythm underlying pharyngeal pumping. These findings provide a basis for progressing upstream of the motor neurons to identify higher regulatory components of the feeding motor system. PMID:26252658

  18. Localization of Motor Neurons and Central Pattern Generators for Motor Patterns Underlying Feeding Behavior in Drosophila Larvae.

    PubMed

    Hückesfeld, Sebastian; Schoofs, Andreas; Schlegel, Philipp; Miroschnikow, Anton; Pankratz, Michael J

    2015-01-01

    Motor systems can be functionally organized into effector organs (muscles and glands), the motor neurons, central pattern generators (CPG) and higher control centers of the brain. Using genetic and electrophysiological methods, we have begun to deconstruct the motor system driving Drosophila larval feeding behavior into its component parts. In this paper, we identify distinct clusters of motor neurons that execute head tilting, mouth hook movements, and pharyngeal pumping during larval feeding. This basic anatomical scaffold enabled the use of calcium-imaging to monitor the neural activity of motor neurons within the central nervous system (CNS) that drive food intake. Simultaneous nerve- and muscle-recordings demonstrate that the motor neurons innervate the cibarial dilator musculature (CDM) ipsi- and contra-laterally. By classical lesion experiments we localize a set of CPGs generating the neuronal pattern underlying feeding movements to the subesophageal zone (SEZ). Lesioning of higher brain centers decelerated all feeding-related motor patterns, whereas lesioning of ventral nerve cord (VNC) only affected the motor rhythm underlying pharyngeal pumping. These findings provide a basis for progressing upstream of the motor neurons to identify higher regulatory components of the feeding motor system.

  19. Inverse modulation of motor neuron cellular and synaptic properties can maintain the same motor output.

    PubMed

    McClelland, Thomas James; Parker, David

    2017-09-30

    Although often examined in isolation, a single neuromodulator typically has multiple cellular and synaptic effects. Here, we have examined the interaction of the cellular and synaptic effects of 5-HT in the lamprey spinal cord. 5-HT reduces the amplitude of glutamatergic synaptic inputs and the slow post-spike afterhyperpolarization (sAHP) in motor neurons. We examined the interaction between these effects using ventral root activity evoked by stimulation of the spinal cord. While 5-HT reduced excitatory glutamatergic synaptic inputs in motor neurons to approximately 60% of control, ventral root activity was not significantly affected. The reduction of the sAHP by 5-HT increased motor neuron excitability by reducing spike frequency adaptation, an effect that could in principle have opposed the reduction of the excitatory synaptic input. Support for this was sought by reducing the amplitude of the sAHP by applying the toxin apamin before 5-HT application. In these experiments, 5-HT reduced the ventral root response, presumably because the reduction of the synaptic input now dominated. This was supported by computer simulations that showed that the motor output could be maintained over a wide range of synaptic input values if they were matched by changes in postsynaptic excitability. The effects of 5-HT on ventral root responses were altered by spinal cord lesions: 5-HT significantly increased ventral root responses in animals that recovered good locomotor function, consistent with a lesion-induced reduction in the synaptic effects of 5-HT, which thus biases its effects to the increase in motor neuron excitability. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  20. Motor neuronal activity varies least among individuals when it matters most for behavior

    PubMed Central

    Cullins, Miranda J.; Shaw, Kendrick M.; Gill, Jeffrey P.

    2014-01-01

    How does motor neuronal variability affect behavior? To explore this question, we quantified activity of multiple individual identified motor neurons mediating biting and swallowing in intact, behaving Aplysia californica by recording from the protractor muscle and the three nerves containing the majority of motor neurons controlling the feeding musculature. We measured multiple motor components: duration of the activity of identified motor neurons as well as their relative timing. At the same time, we measured behavioral efficacy: amplitude of grasping movement during biting and amplitude of net inward food movement during swallowing. We observed that the total duration of the behaviors varied: Within animals, biting duration shortened from the first to the second and third bites; between animals, biting and swallowing durations varied. To study other sources of variation, motor components were divided by behavior duration (i.e., normalized). Even after normalization, distributions of motor component durations could distinguish animals as unique individuals. However, the degree to which a motor component varied among individuals depended on the role of that motor component in a behavior. Motor neuronal activity that was essential for the expression of biting or swallowing was similar among animals, whereas motor neuronal activity that was not essential for that behavior varied more from individual to individual. These results suggest that motor neuronal activity that matters most for the expression of a particular behavior may vary least from individual to individual. Shaping individual variability to ensure behavioral efficacy may be a general principle for the operation of motor systems. PMID:25411463

  1. Paraneoplastic subacute lower motor neuron syndrome associated with solid cancer.

    PubMed

    Verschueren, Annie; Gallard, Julien; Boucraut, José; Honnorat, Jerome; Pouget, Jean; Attarian, Shahram

    2015-11-15

    We retrospectively analyzed three patients with pure motor neuronopathy followed for more than four years in our center. The patients presented a rapidly progressive lower motor neuron syndrome (LMNS) over the course of a few weeks leading to a severe functional impairment. The neurological symptoms preceded the diagnosis of a breast adenocarcinoma and a thymoma in the first two patients, one of them with anti-CV2/CRMP5 antibodies. Cancer was not detected in the third patient who had circulating anti-Hu antibodies. A final diagnosis of paraneoplastic syndrome was made after investigations for alternative causes of lower motor neuron syndrome. Early diagnosis, combined treatment of the underlying cancer, and immunomodulatory treatment led to neurological improvement of the disease in two out of the three cases in which the cancer was diagnosed. Cases of subacute LMNS with rapid progression may occur as an expression of a paraneoplastic neurological syndrome. Identification of these syndromes is important, as the treatment of underlying malignancy along with immunomodulatory treatment may result in a favorable long-term outcome of these potentially fatal diseases.

  2. Histone deacetylases and their role in motor neuron degeneration

    PubMed Central

    Lazo-Gómez, Rafael; Ramírez-Jarquín, Uri N.; Tovar-y-Romo, Luis B.; Tapia, Ricardo

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by the progressive loss of motor neurons. The cause of this selective neuronal death is unknown, but transcriptional dysregulation is recently emerging as an important factor. The physical substrate for the regulation of the transcriptional process is chromatin, a complex assembly of histones and DNA. Histones are subject to several post-translational modifications, like acetylation, that are a component of the transcriptional regulation process. Histone acetylation and deacetylation is performed by a group of enzymes (histone acetyltransferases (HATs) and deacetylases, respectively) whose modulation can alter the transcriptional state of many regions of the genome, and thus may be an important target in diseases that share this pathogenic process, as is the case for ALS. This review will discuss the present evidence of transcriptional dysregulation in ALS, the role of histone deacetylases (HDACs) in disease pathogenesis, and the novel pharmacologic strategies that are being comprehensively studied to prevent motor neuron death, with focus on sirtuins (SIRT) and their effectors. PMID:24367290

  3. Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not.

    PubMed

    Hardy, John; Rogaeva, Ekaterina

    2014-12-01

    Over the last 5 years, several new genes have been described for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While it has long been clear that there are many kindreds in which the two diseases co-occur, there are also many in which the diseases segregate alone. In this brief review, we suggest that keeping the loci which lead to both diseases separate from those which lead to just one gives a clearer conclusion about disease mechanisms than lumping them together. The hypothesis that this separation leads to is that loci which cause both ALS and FTD affect the autophagic machinery leading to damaged protein aggregation and those which lead to just ALS are mainly involved in RNA/DNA metabolism. Two of the genes causing FTD alone (CHMP2B and GRN) are associated with damaged autophagy/lysosomal pathway. However, the third FTD gene (MAPT) maps to a different pathway, which perhaps is not surprising, since it is associated with a different (not p62-related) brain pathology characterized by abnormal tau filaments. We conclude that the current state of knowledge points to common mechanisms responsible for susceptibilities specific to neuronal classes. This includes the disruption of RNA metabolism in motor neurons and protein clearance, which is common between cortical and motor neurons. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Dynamics of neurons controlling movements of a locust hind leg. III. Extensor tibiae motor neurons.

    PubMed

    Newland, P L; Kondoh, Y

    1997-06-01

    Imposed movements of the apodeme of the femoral chordotonal organ (FeCO) of the locust hind leg elicit resistance reflexes in extensor and flexor tibiae motor neurons. The synaptic responses of the fast and slow extensor tibiae motor neurons (FETi and SETi, respectively) and the spike responses of SETi were analyzed with the use of the Wiener kernel white noise method to determine their response properties. The first-order Wiener kernels computed from soma recordings were essentially monophasic, or low passed, indicating that the motor neurons were primarily sensitive to the position of the tibia about the femorotibial joint. The responses of both extensor motor neurons had large nonlinear components. The second-order kernels of the synaptic responses of FETi and SETi had large on-diagonal peaks with two small off-diagonal valleys. That of SETi had an additional elongated valley on the diagonal, which was accompanied by two off-diagonal depolarizing peaks at a cutoff frequency of 58 Hz. These second-order components represent a half-wave rectification of the position-sensitive depolarizing response in FETi and SETi, and a delayed inhibitory input to SETi, indicating that both motor neurons were directionally sensitive. Model predictions of the responses of the motor neurons showed that the first-order (linear) characterization poorly predicted the actual responses of FETi and SETi to FeCO stimulation, whereas the addition of the second-order (nonlinear) term markedly improved the performance of the model. Simultaneous recordings from the soma and a neuropilar process of FETi showed that its synaptic responses to FeCO stimulation were phase delayed by about -30 degrees at 20 Hz, and reduced in amplitude by 30-40% when recorded in the soma. Similar configurations of the first and second-order kernels indicated that the primary process of FETi acted as a low-pass filter. Cross-correlation between a white noise stimulus and a unitized spike discharge of SETi again

  5. Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line.

    PubMed

    Genç, Barış; Lagrimas, Amiko Krisa Bunag; Kuru, Pınar; Hess, Robert; Tu, Michael William; Menichella, Daniela Maria; Miller, Richard J; Paller, Amy S; Özdinler, P Hande

    2015-01-01

    Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP) 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1)] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP) expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

  6. Respiratory function after selective respiratory motor neuron death from intrapleural CTB-saporin injections.

    PubMed

    Nichols, Nicole L; Vinit, Stéphane; Bauernschmidt, Lorene; Mitchell, Gordon S

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, paralysis and death by ventilatory failure. In rodent ALS models: 1) breathing capacity is preserved until late in disease progression despite major respiratory motor neuron death, suggesting unknown forms of compensatory respiratory plasticity; and 2) spinal microglia become activated in association with motor neuron cell death. Here, we report a novel experimental model to study the impact of respiratory motor neuron death on compensatory responses without many complications attendant to spontaneous motor neuron disease. In specific, we used intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) to selectively kill motor neurons with access to the pleural space. Motor neuron survival, CD11b labeling (microglia), ventilatory capacity and phrenic motor output were assessed in rats 3-28days after intrapleural injections of: 1) CTB-SAP (25 and 50μg), or 2) unconjugated CTB and SAP (i.e. control; (CTB+SAP). CTB-SAP elicited dose-dependent phrenic and intercostal motor neuron death; 7days post-25μg CTB-SAP, motor neuron survival approximated that in end-stage ALS rats (phrenic: 36±7%; intercostal: 56±10% of controls; n=9; p<0.05). CTB-SAP caused minimal cell death in other brainstem or spinal cord regions. 1) increased CD11b fractional area in the phrenic motor nucleus, indicating microglial activation; 2) decreased breathing during maximal chemoreceptor stimulation; and 3) diminished phrenic motor output in anesthetized rats (7days post-25μg, 0.3±0.07V; CTB+SAP: 1.5±0.3; n=9; p<0.05). Intrapleural CTB-SAP represents a novel, inducible model of respiratory motor neuron death and provides an opportunity to study compensation for respiratory motor neuron loss. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Calbindin-D28K, parvalbumin and calretinin in primate lower motor neurons.

    PubMed

    Fahandejsaadi, Ashkan; Leung, Elaine; Rahaii, Rhoda; Bu, Jing; Geula, Changiz

    2004-03-01

    It has been suggested that lower motor neurons containing calcium-binding proteins (CBP) may be resistant to degeneration in motor neuron disease. The testing of this hypothesis is hampered by lack of comprehensive information regarding the presence of CBPs in motor neurons. To address this shortcoming, we investigated the distribution of the CBPs calbindin-D28K (CB), parvalbumin (PV) and calretinin (CRT) in lower motor neurons in the normal human and two non-human primates (rhesus monkey and common marmoset) using immunohistochemistry. A variable proportion of motor neurons in cranial nerve motor nuclei contained immunoreactivity for one or more CBPs. A subpopulation of spinal cord alpha-motor neurons was also CBP-positive. Comparison of staining for choline acetyltransferase (ChAT) and CBPs in the human spinal cord demonstrated that approximately 63% of ventral horn motor neurons contained PV, 53% contained CRT and 56% contained CB. CBP immunoreactivity within motor neurons was of variable staining intensity. It remains to be established whether the presence of these CBPs confers protection against the pathogenic mechanisms of motor neuron disease.

  8. dnc-1/dynactin 1 knockdown disrupts transport of autophagosomes and induces motor neuron degeneration.

    PubMed

    Ikenaka, Kensuke; Kawai, Kaori; Katsuno, Masahisa; Huang, Zhe; Jiang, Yue-Mei; Iguchi, Yohei; Kobayashi, Kyogo; Kimata, Tsubasa; Waza, Masahiro; Tanaka, Fumiaki; Mori, Ikue; Sobue, Gen

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. We previously showed that the expression of dynactin 1, an axon motor protein regulating retrograde transport, is markedly reduced in spinal motor neurons of sporadic ALS patients, although the mechanisms by which decreased dynactin 1 levels cause neurodegeneration have yet to be elucidated. The accumulation of autophagosomes in degenerated motor neurons is another key pathological feature of sporadic ALS. Since autophagosomes are cargo of dynein/dynactin complexes and play a crucial role in the turnover of several organelles and proteins, we hypothesized that the quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neuron. In the present study, we generated a Caenorhabditis elegans model in which the expression of DNC-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.

  9. MicroRNA-128 governs neuronal excitability and motor behavior in mice.

    PubMed

    Tan, Chan Lek; Plotkin, Joshua L; Venø, Morten T; von Schimmelmann, Melanie; Feinberg, Philip; Mann, Silas; Handler, Annie; Kjems, Jørgen; Surmeier, D James; O'Carroll, Dónal; Greengard, Paul; Schaefer, Anne

    2013-12-06

    The control of motor behavior in animals and humans requires constant adaptation of neuronal networks to signals of various types and strengths. We found that microRNA-128 (miR-128), which is expressed in adult neurons, regulates motor behavior by modulating neuronal signaling networks and excitability. miR-128 governs motor activity by suppressing the expression of various ion channels and signaling components of the extracellular signal-regulated kinase ERK2 network that regulate neuronal excitability. In mice, a reduction of miR-128 expression in postnatal neurons causes increased motor activity and fatal epilepsy. Overexpression of miR-128 attenuates neuronal responsiveness, suppresses motor activity, and alleviates motor abnormalities associated with Parkinson's-like disease and seizures in mice. These data suggest a therapeutic potential for miR-128 in the treatment of epilepsy and movement disorders.

  10. Divergent Hox Coding and Evasion of Retinoid Signaling Specifies Motor Neurons Innervating Digit Muscles.

    PubMed

    Mendelsohn, Alana I; Dasen, Jeremy S; Jessell, Thomas M

    2017-02-22

    The establishment of spinal motor neuron subclass diversity is achieved through developmental programs that are aligned with the organization of muscle targets in the limb. The evolutionary emergence of digits represents a specialized adaptation of limb morphology, yet it remains unclear how the specification of digit-innervating motor neuron subtypes parallels the elaboration of digits. We show that digit-innervating motor neurons can be defined by selective gene markers and distinguished from other LMC neurons by the expression of a variant Hox gene repertoire and by the failure to express a key enzyme involved in retinoic acid synthesis. This divergent developmental program is sufficient to induce the specification of digit-innervating motor neurons, emphasizing the specialized status of digit control in the evolution of skilled motor behaviors. Our findings suggest that the emergence of digits in the limb is matched by distinct mechanisms for specifying motor neurons that innervate digit muscles.

  11. Brain-wide neuronal dynamics during motor adaptation in zebrafish

    PubMed Central

    Ahrens, Misha B; Li, Jennifer M; Orger, Michael B; Robson, Drew N; Schier, Alexander F; Engert, Florian; Portugues, Ruben

    2013-01-01

    A fundamental question in neuroscience is how entire neural circuits generate behavior and adapt it to changes in sensory feedback. Here we use two-photon calcium imaging to record activity of large populations of neurons at the cellular level throughout the brain of larval zebrafish expressing a genetically-encoded calcium sensor, while the paralyzed animals interact fictively with a virtual environment and rapidly adapt their motor output to changes in visual feedback. We decompose the network dynamics involved in adaptive locomotion into four types of neural response properties, and provide anatomical maps of the corresponding sites. A subset of these signals occurred during behavioral adjustments and are candidates for the functional elements that drive motor learning. Lesions to the inferior olive indicate a specific functional role for olivocerebellar circuitry in adaptive locomotion. This study enables the analysis of brain-wide dynamics at single-cell resolution during behavior. PMID:22622571

  12. Four cases of equine motor neuron disease in Japan

    PubMed Central

    SASAKI, Naoki; IMAMURA, Yui; SEKIYA, Akio; ITOH, Megumi; FURUOKA, Hidefumi

    2016-01-01

    ABSTRACT In this study, fasciculation of the limbs and tongue was observed in four horses kept by a riding club. Neurogenic muscle atrophy was also observed in biopsy of pathological tissues. In addition, in two cases that subjected to autopsy, Bunina-like bodies of inclusion in the cell bodies of neurons in the spinal cord ventral horn were confirmed, leading to a diagnosis of equine motor neuron disease (EMND). Serum vitamin E concentrations varied between 0.3 and 0.4µg/ml, which is significantly lower than the levels in normal horses. Although lack of vitamin E is speculated to be a contributory factor for development of EMND, no significant improvement was observed following administration of vitamin E. PMID:27703407

  13. Dysmyelinated lower motor neurons retract and regenerate dysfunctional synaptic terminals.

    PubMed

    Yin, Xinghua; Kidd, Grahame J; Pioro, Erik P; McDonough, Jennifer; Dutta, Ranjan; Feltri, M Laura; Wrabetz, Lawrence; Messing, Albee; Wyatt, Ryan M; Balice-Gordon, Rita J; Trapp, Bruce D

    2004-04-14

    Axonal degeneration is the major cause of permanent neurological disability in individuals with inherited diseases of myelin. Axonal and neuronal changes that precede axonal degeneration, however, are not well characterized. We show here that dysmyelinated lower motor neurons retract and regenerate dysfunctional presynaptic terminals, leading to severe neurological disability before axonal degeneration. In addition, dysmyelination led to a decreased synaptic quantal content, an indicator of synaptic dysfunction. The amplitude and rise time of miniature endplate potentials were also increased, but these changes were primarily consistent with an increase in the passive membrane properties of the transgenic muscle fibers. Maintenance of synaptic connections should be considered as a therapeutic target for slowing progression of neurological disability in primary diseases of myelin.

  14. Nutritional pathway for people with motor neurone disease.

    PubMed

    Marsden, Rachael; Allan, Philip; Blackwell, Victoria; East, James; Lawson, Clare; Nickol, Annabel H; Millard, Emma; Talbot, Kevin; Thompson, Alexander G; Turner, Martin R

    2016-07-01

    This paper provides an overview of the nutritional management and care of people living with motor neurone disease (MND) in a specialist nutrition clinic. A specialist pathway of care has been developed to enable people living with MND to undergo a percutaneous endoscopic gastrostomy (PEG) procedure in a safe way; the pathway incorporates attendance at a dedicated nutrition clinic, a stratification tool to identify patients with a high periprocedural risk and a PEG insertion team with significant experience in the MND population. Since this pathway has been in place, gastrostomies have been successfully placed in patients with a forced vital capacity (FVC) of less than 50%; previously, this would not have been possible.

  15. Postradiation lower motor neuron syndrome presenting as monomelic amyotrophy.

    PubMed Central

    Lamy, C; Mas, J L; Varet, B; Ziegler, M; de Recondo, J

    1991-01-01

    Monomelic amyotrophy developed 16 months, nine and 12 years after irradiation of the lumbosacral spinal cord for seminoma in one patient and for Hodgkin's disease in two others. In two patients, involvement was clinically limited to one leg, with a subacute course followed by plateau in the first case and with progressive worsening in the second one. In the third patient, the course was progressive with involvement of the other lower limb occurring five years later. From clinical and electrophysiological data, it seems probable that the disease process was a result of a selective injury to the lower motor neuron in the lower spinal cord. PMID:1895131

  16. Postradiation lower motor neuron syndrome presenting as monomelic amyotrophy.

    PubMed

    Lamy, C; Mas, J L; Varet, B; Ziegler, M; de Recondo, J

    1991-07-01

    Monomelic amyotrophy developed 16 months, nine and 12 years after irradiation of the lumbosacral spinal cord for seminoma in one patient and for Hodgkin's disease in two others. In two patients, involvement was clinically limited to one leg, with a subacute course followed by plateau in the first case and with progressive worsening in the second one. In the third patient, the course was progressive with involvement of the other lower limb occurring five years later. From clinical and electrophysiological data, it seems probable that the disease process was a result of a selective injury to the lower motor neuron in the lower spinal cord.

  17. Establishing the UK DNA Bank for motor neuron disease (MND).

    PubMed

    Smith, Lucy; Cupid, B C; Dickie, B G M; Al-Chalabi, A; Morrison, K E; Shaw, C E; Shaw, P J

    2015-07-14

    In 2003 the Motor Neurone Disease (MND) Association, together with The Wellcome Trust, funded the creation of a national DNA Bank specific for MND. It was anticipated that the DNA Bank would constitute an important resource to researchers worldwide and significantly increase activity in MND genetic research. The DNA Bank houses over 3000 high quality DNA samples, all of which were donated by people living with MND, family members and non-related controls, accompanied by clinical phenotype data about the patients. Today the primary focus of the UK MND DNA Bank still remains to identify causative and disease modifying factors for this devastating disease.

  18. Alpha-synuclein in motor neuron disease: an immunohistologic study.

    PubMed

    Doherty, M J; Bird, T D; Leverenz, J B

    2004-02-01

    Alpha-synuclein (ASN) has been implicated in neurodegenerative disorders characterized by Lewy body inclusions such as Parkinson's disease and dementia with Lewy bodies. Lewy body-like inclusions have also been observed in spinal neurons of patients with amyotrophic lateral sclerosis (ALS) and reports suggest possible ASN abnormalities in ALS patients. We assessed ASN immunoreactivity in spinal and brain tissues of subjects who had died of progressive motor neuron disorders (MND). Clinical records of subjects with MND and a comparison group were reviewed to determine the diagnosis according to El-Escariol Criteria of ALS. Cervical, thoracic and lumbar cord sections were stained with an antibody to ASN. A blinded, semiquantitative review of sections from both groups included examination for evidence of spheroids, neuronal staining, cytoplasmic inclusions, anterior horn granules, white and gray matter glial staining, corticospinal tract axonal fiber and myelin changes. MND cases, including ALS and progressive muscular atrophy, displayed significantly increased ASN staining of spheroids ( P< or =0.001), and glial staining in gray and white matter ( P< or =0.05). Significant abnormal staining of corticospinal axon tract fibers and myelin was also observed ( P< or =0.05 and 0.01). Detection of possible ASN-positive neuronal inclusions did not differ between groups. Significant ASN abnormalities were observed in MND. These findings suggest a possible role for ASN in MND; however, the precise nature of this association is unclear.

  19. The patient experience of fatigue in motor neurone disease

    PubMed Central

    Gibbons, Chris J.; Thornton, Everard W.; Young, Carolyn A.

    2013-01-01

    Aims: This paper is a qualitative investigation that aims to investigate the lived experience of fatigue in patients with motor neurone disease—a progressive and fatal neurological condition. Background: Fatigue is a disabling symptom in motor neurone disease (MND) that affects a large number of patients. However, the term “fatigue” is in itself imprecise, as it remains a phenomenon without a widely accepted medical definition. This study sought to investigate the phenomenon of fatigue from the perspective of the MND patient. Methods: Ten patients with MND participated in semi-structured recorded interviews at a regional neuroscience center in Liverpool, UK. Transcripts analysis was broadly informed by the principles of interpretative phenomenological analysis (IPA). Findings: Fatigue was unanimously explained to be disabling and progressive phenomenon. Participants described two forms of fatigue: whole-body tiredness or use-dependent reversible muscle weakness related to exertion of limb and bulbar muscles. Both weakness and whole-body tiredness could be experienced simultaneously, and patients used the terms “fatigue” and “tiredness” interchangeably. Alongside descriptions of fatigue themes of Adaptation, Motivation, Avoidance, Frustration and Stress were revealed. Fatigue could be defined as “reversible motor weakness and whole-body tiredness that was predominantly brought on by muscular exertion and was partially relieved by rest.” Conclusion: The results of this study support a multi-dimensional model of fatigue for patients with MND. Fatigue appears to be experienced and explained in two ways, both as an inability to sustain motor function and as a pervasive tiredness. Fatigue was only partially relieved by rest and tended to worsen throughout the day. It is crucial that MND care practitioners and researchers appreciate the semantic dichotomy within fatigue. PMID:24639657

  20. Zebrafish models of human motor neuron diseases: advantages and limitations.

    PubMed

    Babin, Patrick J; Goizet, Cyril; Raldúa, Demetrio

    2014-07-01

    Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs.

  1. Oxidative stress induced by cumene hydroperoxide evokes changes in neuronal excitability of rat motor cortex neurons.

    PubMed

    Pardillo-Díaz, R; Carrascal, L; Ayala, A; Nunez-Abades, P

    2015-03-19

    Oxidative stress and the production of reactive oxygen radicals play a key role in neuronal cell damage. This paper describes an in vitro study that explores the neuronal responses to oxidative stress focusing on changes in neuronal excitability and functional membrane properties. This study was carried out in pyramidal cells of the motor cortex by applying whole-cell patch-clamp techniques on brain slices from young adult rats. Oxygen-derived free radical formation was induced by bath application of 10μM cumene hydroperoxide (CH) for 30min. CH produced marked changes in the electrophysiological properties of neurons (n=30). Resting membrane potential became progressively depolarized, as well as depolarization voltage, with no variations in voltage threshold. Membrane resistance showed a biphasic behavior, increasing after 5min of drug exposure and then it started to decrease, even under control values, after 15 and 30min. At the same time, changes in membrane resistance produced compensatory variations in the rheobase. The amplitude of the action potentials diminished and the duration increased progressively over time. Some of the neurons under study also lost their ability to discharge action potentials in a repetitive way. Most of the neurons, however, kept their repetitive discharge even though their maximum frequency and gain decreased. Furthermore, cancelation of the repetitive firing discharge took place at intensities that decreased with time of exposure to CH, which resulted in a narrower working range. We can conclude that oxidative stress compromises both neuronal excitability and the capability of generating action potentials, and so this type of neuronal functional failure could precede the neuronal death characteristics of many neurodegenerative diseases.

  2. A case of presumptive primary lateral sclerosis with upper and lower motor neurone pathology.

    PubMed

    Short, Cathy L; Scott, Grace; Blumbergs, Peter C; Koblar, Simon A

    2005-08-01

    Motor Neurone Disease (MND) is one of the commonest neurodegenerative disorders of adulthood. MND characteristically presents with a combination of both upper and lower motor neurone features. Primary Lateral Sclerosis (PLS) is thought to be a variant of MND presenting with purely upper motor neurone signs. Debate continues over whether PLS constitutes a distinct pathological entity or whether it is part of the spectrum of motor neurone diseases that present as an upper motor neurone-predominant form of MND. We present a case of MND with purely upper motor neurone features and a prominent pain component. A pre-mortem diagnosis of PLS was made, however autopsy findings demonstrated both upper and lower motor neurone involvement. We believe these findings support the view that PLS is not a discrete pathological entity, but that it is a part of the range of motor neurone diseases that present with predominant but not exclusive upper motor neurone involvement. This case also highlights the feature that pain may be associated with MND even though it is not appreciated to have a sensory pathology.

  3. Novel combinatorial screening identifies neurotrophic factors for selective classes of motor neurons.

    PubMed

    Schaller, Sébastien; Buttigieg, Dorothée; Alory, Alysson; Jacquier, Arnaud; Barad, Marc; Merchant, Mark; Gentien, David; de la Grange, Pierre; Haase, Georg

    2017-03-21

    Numerous neurotrophic factors promote the survival of developing motor neurons but their combinatorial actions remain poorly understood; to address this, we here screened 66 combinations of 12 neurotrophic factors on pure, highly viable, and standardized embryonic mouse motor neurons isolated by a unique FACS technique. We demonstrate potent, strictly additive, survival effects of hepatocyte growth factor (HGF), ciliary neurotrophic factor (CNTF), and Artemin through specific activation of their receptor complexes in distinct subsets of lumbar motor neurons: HGF supports hindlimb motor neurons through c-Met; CNTF supports subsets of axial motor neurons through CNTFRα; and Artemin acts as the first survival factor for parasympathetic preganglionic motor neurons through GFRα3/Syndecan-3 activation. These data show that neurotrophic factors can selectively promote the survival of distinct classes of embryonic motor neurons. Similar studies on postnatal motor neurons may provide a conceptual framework for the combined therapeutic use of neurotrophic factors in degenerative motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and spinobulbar muscular atrophy.

  4. Motor neurons in the escape response circuit of white shrimp (Litopenaeus setiferus)

    PubMed Central

    2015-01-01

    Many decapod crustaceans perform escape tailflips with a neural circuit involving giant interneurons, a specialized fast flexor motor giant (MoG) neuron, populations of larger, less specialized fast flexor motor neurons, and fast extensor motor neurons. These escape-related neurons are well described in crayfish (Reptantia), but not in more basal decapod groups. To clarify the evolution of the escape circuit, I examined the fast flexor and fast extensor motor neurons of white shrimp (Litopenaeus setiferus; Dendrobranchiata) using backfilling. In crayfish, the MoGs in each abdominal ganglion are a bilateral pair of separate neurons. In L. setiferus, the MoGs have massive, possibly syncytial, cell bodies and fused axons. The non-MoG fast flexor motor neurons and fast extensor motor neurons are generally found in similar locations to where they are found in crayfish, but the number of motor neurons in both the flexor and extensor pools is smaller than in crayfish. The loss of fusion in the MoGs and increased number of fast motor neurons in reptantian decapods may be correlated with an increased reliance on non-giant mediated tailflipping. PMID:26244117

  5. One’s motor performance predictably modulates the understanding of others’ actions through adaptation of premotor visuo-motor neurons

    PubMed Central

    Barchiesi, Guido; Tabarelli, Davide; Arfeller, Carola; Sato, Marc; Glenberg, Arthur M.

    2011-01-01

    Neurons firing both during self and other’s motor behavior (mirror neurons) have been described in the brain of vertebrates including humans. The activation of somatic motor programs driven by perceived behavior has been taken as evidence for mirror neurons’ contribution to cognition. The inverse relation, that is the influence of motor behavior on perception, is needed for demonstrating the long-hypothesized causal role of mirror neurons in action understanding. We provide here conclusive behavioral and neurophysiological evidence for that causal role by means of cross-modal adaptation coupled with a novel transcranial magnetic stimulation (TMS)-adaptation paradigm. Blindfolded repeated motor performance of an object-directed action (push or pull) induced in healthy participants a strong visual after-effect when categorizing others’ actions, as a result of motor-to-visual adaptation of visuo-motor neurons. TMS over the ventral premotor cortex, but not over the primary motor cortex, suppressed the after-effect, thus localizing the population of adapted visuo-motor neurons in the premotor cortex. These data are exquisitely consistent in humans with the existence of premotor mirror neurons that have access to the action meaning. We also show that controlled manipulation of the firing properties of this neural population produces strong predictable changes in the way we categorize others’ actions. PMID:21186167

  6. Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis.

    PubMed

    Chen, Liuji; Hambright, William Sealy; Na, Ren; Ran, Qitao

    2015-11-20

    Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show that GPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degeneration of motor neurons in the spinal cord but had no overt neuron degeneration in the cerebral cortex. Consistent with the role of GPX4 as a ferroptosis inhibitor, spinal motor neuron degeneration induced by Gpx4 ablation exhibited features of ferroptosis, including no caspase-3 activation, no TUNEL staining, activation of ERKs, and elevated spinal inflammation. Supplementation with vitamin E, another inhibitor of ferroptosis, delayed the onset of paralysis and death induced by Gpx4 ablation. Also, lipid peroxidation and mitochondrial dysfunction appeared to be involved in ferroptosis of motor neurons induced by Gpx4 ablation. Taken together, the dramatic motor neuron degeneration and paralysis induced by Gpx4 ablation suggest that ferroptosis inhibition by GPX4 is essential for motor neuron health and survival in vivo.

  7. Identification of motor neurons and a mechanosensitive sensory neuron in the defecation circuitry of Drosophila larvae

    PubMed Central

    Zhang, Wei; Yan, Zhiqiang; Li, Bingxue; Jan, Lily Yeh; Jan, Yuh Nung

    2014-01-01

    Defecation allows the body to eliminate waste, an essential step in food processing for animal survival. In contrast to the extensive studies of feeding, its obligate counterpart, defecation, has received much less attention until recently. In this study, we report our characterizations of the defecation behavior of Drosophila larvae and its neural basis. Drosophila larvae display defecation cycles of stereotypic frequency, involving sequential contraction of hindgut and anal sphincter. The defecation behavior requires two groups of motor neurons that innervate hindgut and anal sphincter, respectively, and can excite gut muscles directly. These two groups of motor neurons fire sequentially with the same periodicity as the defecation behavior, as revealed by in vivo Ca2+ imaging. Moreover, we identified a single mechanosensitive sensory neuron that innervates the anal slit and senses the opening of the intestine terminus. This anus sensory neuron relies on the TRP channel NOMPC but not on INACTIVE, NANCHUNG, or PIEZO for mechanotransduction. DOI: http://dx.doi.org/10.7554/eLife.03293.001 PMID:25358089

  8. Segmental distribution of the motor neuron columns that supply the rat hindlimb: A muscle/motor neuron tract-tracing analysis targeting the motor end plates.

    PubMed

    Mohan, R; Tosolini, A P; Morris, R

    2015-10-29

    Spinal cord injury (SCI) that disrupts input from higher brain centers to the lumbar region of the spinal cord results in paraplegia, one of the most debilitating conditions affecting locomotion. Non-human primates have long been considered to be the most appropriate animal to model lower limb dysfunction. More recently, however, there has been a wealth of scientific information gathered in the rat regarding the central control of locomotion. Moreover, rodent models of SCI at lumbar levels have been widely used to validate therapeutic scenarios aimed at the restoration of locomotor activities. Despite the growing use of the rat as a model of locomotor dysfunction, knowledge regarding the anatomical relationship between spinal cord motor neurons and the hindlimb muscles that they innervate is incomplete. Previous studies performed in our laboratory have shown the details of the muscle/motor neuron topographical relationship for the mouse forelimb and hindlimb as well as for the rat forelimb. The present analysis aims to characterize the segmental distribution of the motor neuron pools that innervate the muscles of the rat hindlimb, hence completing this series of studies. The location of the motor end plate (MEP) regions on the main muscles of the rat hindlimb was first revealed with acetylcholinesterase histochemistry. For each muscle under scrutiny, injections of Fluoro-Gold were then performed along the length of the MEP region. Targeting the MEPs gave rise to columns of motor neurons that span more spinal cord segments than previously reported. The importance of this study is discussed in terms of its application to gene therapy for SCI. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  9. Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease.

    PubMed

    Winner, Beate; Marchetto, Maria C; Winkler, Jürgen; Gage, Fred H

    2014-09-15

    While motor neuron diseases are currently incurable, induced pluripotent stem cell research has uncovered some disease-relevant phenotypes. We will discuss strategies to model different aspects of motor neuron disease and the specific neurons involved in the disease. We will then describe recent progress to investigate common forms of motor neuron disease: amyotrophic lateral sclerosis, hereditary spastic paraplegia and spinal muscular atrophy.

  10. Depalmitoylation preferentially downregulates AMPA induced Ca2+ signaling and neurotoxicity in motor neurons.

    PubMed

    Krishnamurthy, Karthik; Mehta, Bhupesh; Singh, Mahendra; Tewari, Bhanu P; Joshi, Preeti G; Joshi, Nanda B

    2013-09-05

    Excessive activation of AMPA receptor has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). However, it is not clear why motor neurons are preferentially sensitive to AMPA receptor mediated excessive [Ca(2+)]i rise and excitotoxicity. In the present study we examined whether palmitoylation regulates Ca(2+) permeability of AMPA receptor and excitotoxicity in cultured spinal cord neurons. We adapted chronic 2-bromopalmitate (2-BrP) treatment to achieve depalmitoylation and examined its effect on the cytotoxicity in spinal cord neurons exposed to AMPA. The change in AMPA induced signaling and cytotoxicity in motor neurons and other spinal neurons under identical conditions of exposure to AMPA was studied. 2-BrP treatment inhibited AMPA induced rise in [Ca(2+)]i and cytotoxicity in both types of neurons but the degree of inhibition was significantly higher in motor neurons as compared to other spinal neurons. The AMPA induced [Na(+)]i rise was moderately affected in both type of neurons on depalmitoylation. Depalmitoylation reduced the expression levels of AMPA receptor subunits (GluR1 and GluR2) and also PSD-95 but stargazin levels remained unaffected. Our results demonstrate that 2-BrP attenuates AMPA receptor activated Ca(2+) signaling and cytotoxicity preferentially in motor neurons and suggest that AMPA receptor modulation by depalmitoylation could play a significant role in preventing motor neuron degeneration. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Dementia and aphasia in motor neuron disease: an underrecognised association?

    PubMed Central

    Rakowicz, W.; Hodges, J.

    1998-01-01

    OBJECTIVES—To determine the prevalence and nature of global cognitive dysfunction and language deficits in an unselected population based cohort of patients with motor neuron disease (MND).
METHODS——A battery of neuropsychological and language tests was administered to patients presenting consecutively over a 3 year period to a regional neurology service with a new diagnosis of sporadic motor neuron disease.
RESULTS—The 18 patients could be divided on the basis of their performance into three groups: Three patients were demented and had impaired language function (group 1); two non-demented patients had an aphasic syndrome characterised by word finding difficulties and anomia (group 2). Major cognitive deficits were therefore found in five of the 18 patients (28%). The remaining 13 performed normally on the test battery apart from decreased verbal fluency (group 3).
CONCLUSIONS—The prevalence of cognitive impairment in MND in this population based study of an unselected cohort was higher than has been previously reported. Language deficits, especially anomia, may be relatively frequent in the MND population. Aphasia in MND may be masked by dysarthria and missed if not specifically examined.

 PMID:9854965

  12. Neuronal correlates of motor performance and motor learning in the primary motor cortex of monkeys adapting to an external force field.

    PubMed

    Li, C S; Padoa-Schioppa, C; Bizzi, E

    2001-05-01

    The primary motor cortex (M1) is known to control motor performance. Recent findings have also implicated M1 in motor learning, as neurons in this area show learning-related plasticity. In the present study, we analyzed the neuronal activity recorded in M1 in a force field adaptation task. Our goal was to investigate the neuronal reorganization across behavioral epochs (before, during, and after adaptation). Here we report two main findings. First, memory cells were present in two classes. With respect to the changes of preferred direction (Pd), these two classes complemented each other after readaptation. Second, for the entire neuronal population, the shift of Pd matched the shift observed for muscles. These results provide a framework whereby the activity of distinct neuronal subpopulations combines to subserve both functions of motor performance and motor learning.

  13. Expression of diverse neuropeptide cotransmitters by identified motor neurons in Aplysia

    SciTech Connect

    Church, P.J.; Lloyd, P.E. )

    1991-03-01

    Neuropeptide synthesis was determined for individual identified ventral-cluster neurons in the buccal ganglia of Aplysia. Each of these cells was shown to be a motor neuron that innervates buccal muscles that generate biting and swallowing movements during feeding. Individual neurons were identified by a battery of physiological criteria and stained with intracellular injection of a vital dye, and the ganglia were incubated in 35S-methionine. Peptide synthesis was determined by measuring labeled peptides in extracts from individually dissected neuronal cell bodies analyzed by HPLC. Previously characterized peptides found to be synthesized included buccalin, FMRFamide, myomodulin, and the 2 small cardioactive peptides (SCPs). Each of these neuropeptides has been shown to modulate buccal muscle responses to motor neuron stimulation. Two other peptides were found to be synthesized in individual motor neurons. One peptide, which was consistently observed in neurons that also synthesized myomodulin, is likely to be the recently sequenced myomodulin B. The other peptide was observed in a subset of the neurons that synthesize FMRFamide. While identified motor neurons consistently synthesized the same peptide(s), neurons that innervate the same muscle often express different peptides. Neurons that synthesized the SCPs also contained SCP-like activity, as determined by snail heart bioassay. Our results indicate that every identified motor neuron synthesizes a subset of these methionine-containing peptides, and that several neurons consistently synthesize peptides that are likely to be processed from multiple precursors.

  14. Neuronal Roles of the Bicaudal D Family of Motor Adaptors.

    PubMed

    Budzinska, M; Wicher, K B; Terenzio, M

    2017-01-01

    All cell types rely on active intracellular cargo transport to shuttle essential cellular components such as proteins, lipids, RNA, and even organelles from the center to the periphery and vice versa. Additionally, several signaling pathways take advantage of intracellular transport to propagate their signals by moving activated receptors and protein effectors to specific locations inside the cell. Neurons particularly, being a very polarized cell type, are highly dependent on molecular motors for the anterograde and retrograde delivery of essential cellular components and signaling molecules. For these reasons, motor adaptor proteins have been extensively investigated in regard to their role in physiology and pathology of the nervous system. In this chapter, we will concentrate on a family of motor adaptor proteins, Bicaudal D (BICD), and their function in the context of the nervous system. BicD was originally described as essential for the correct localization of maternal mRNAs in Drosophila's oocyte and a regulator of the Golgi to ER retrograde transport in mammalian cells. Both mammalian BICD1 and BICD2 are highly expressed in the nervous system during development, and their importance in neuronal homeostasis has been recently under scrutiny. Several mutations in BICD2 have been linked to the development of neuromuscular diseases, and BICD2 knockout (KO) mice display migration defects of the radial cerebellar granule cells. More in line with the overall topic of this book, BICD1 was identified as a novel regulator of neurotrophin (NT) signaling as its deletion leads to defective sorting of ligand-activated NT receptors with dramatic consequences on the NT-mediated signaling pathway.

  15. Optimization of input patterns and neuronal properties to evoke motor neuron synchronization.

    PubMed

    Taylor, Anna M; Enoka, Roger M

    2004-01-01

    The study used a computational approach to identify combinations of synaptic input timing and strength superimposed on a variety of active dendritic conductances that could evoke similar levels of motor unit synchronization in model motor neurons. Two motor neurons with low recruitment thresholds but different passive properties were modeled using GENESIS software. The timing and strength of synaptic inputs and the density of dendritic ion channels were optimized with a genetic algorithm to produce a set of target discharge times. The target times were taken from experimental recordings made in a human subject and had the synchronization characteristics that are commonly observed in hand muscles. The main finding was that the two parameters with the highest association to output synchrony were the ratio of inward-to-outward ionic conductances (r = 0.344; P = 0.003) and the degree of correlation in inhibitory inputs (r = 0.306; P = 0.009). Variation in the amount of correlation in the excitatory input was not positively correlated with variation in output synchrony. Further, the variability in discharge rate of the model neurons was positively correlated with the density of N -type calcium channels in the dendritic compartments (r = 0.727; P < 0.001 and r = 0.533; P < 0.001 for the two cells). This result suggests that the experimentally observed correlation between discharge variability and synchronization is caused by an increase in fast inward ionic conductances in the dendrites. Given the moderate level of correlation between output synchrony and each of the model parameters, especially at moderate levels of synchrony (E < 0.09 and CIS < 1.0), the results suggest caution in ascribing mechanisms to observations of motor unit synchronization.

  16. Use of human intravenous immunoglobulin in lower motor neuron syndromes

    PubMed Central

    Ellis, C; Leary, S; Payan, J; Shaw, C; Hu, M; O'Brien, M; Leigh, P

    1999-01-01

    OBJECTIVE—To determine whether patients with the clinical phenotype of multifocal motor neuropathy but without the electrophysiological criteria for conduction block would respond to intravenous immunoglobulin (IVIg).
METHODS—Ten patients were selected with a slowly progressive, asymmetric, lower motor neuron disorder, and were treated prospectively with IVIg at a dose of 2g/kg over 5 days. All subjects had neurophysiological testing to look for evidence of conduction block before treatment. Muscle strength was assessed by MRC grades and hand held myometry, measuring pinch and grip strength. A 20% increase in both pinch and grip myometry was considered a positive response.
RESULTS—In no patient was conduction block detected. Four of the 10 patients showed a positive response to IVIg, with the best response occurring in two patients who presented with weakness but without severe muscle wasting. Three of the four responders have continued to receive IVIg for a mean period of 17 months (range 15-24 months), with continued effect. The response to IVIg was not related to the presence of anti-GM1 antiganglioside antibodies, but responders had a selective pattern of muscle weakness and normal (>90% predicted) vital capacity.
CONCLUSION—The findings suggest that a course of IVIg should be considered in patients with the clinical phenotype of multifocal motor neuropathy but without neurophysiological evidence of conduction block.

 PMID:10369816

  17. Extensive Fusion of Mitochondria in Spinal Cord Motor Neurons

    PubMed Central

    Owens, Geoffrey C.; Walcott, Elisabeth C.

    2012-01-01

    The relative roles played by trafficking, fission and fusion in the dynamics of mitochondria in neurons have not been fully elucidated. In the present study, a slow widespread redistribution of mitochondria within cultured spinal cord motor neurons was observed as a result of extensive organelle fusion. Mitochondria were labeled with a photoconvertible fluorescent protein (mitoKaede) that is red-shifted following brief irradiation with blue light. The behavior of these selectively labeled mitochondria was followed by live fluorescence imaging. Marking mitochondria within the cell soma revealed a complete mixing, within 18 hours, of these organelles with mitochondria coming from the surrounding neurites. Fusion of juxtaposed mitochondria was directly observed in neuritic processes at least 200 microns from the cell body. Within 24 hours, photoconverted mitoKaede was dispersed to all of the mitochondria in the portion of neurite under observation. When time lapse imaging over minutes was combined with long-term observation of marked mitochondria, moving organelles that traversed the field of view did not initially contain photoconverted protein, but after several hours organelles in motion contained both fluorescent proteins, coincident with widespread fusion of all of the mitochondria within the length of neurite under observation. These observations suggest that there is a widespread exchange of mitochondrial components throughout a neuron as a result of organelle fusion. PMID:22701641

  18. Extensive fusion of mitochondria in spinal cord motor neurons.

    PubMed

    Owens, Geoffrey C; Walcott, Elisabeth C

    2012-01-01

    The relative roles played by trafficking, fission and fusion in the dynamics of mitochondria in neurons have not been fully elucidated. In the present study, a slow widespread redistribution of mitochondria within cultured spinal cord motor neurons was observed as a result of extensive organelle fusion. Mitochondria were labeled with a photoconvertible fluorescent protein (mitoKaede) that is red-shifted following brief irradiation with blue light. The behavior of these selectively labeled mitochondria was followed by live fluorescence imaging. Marking mitochondria within the cell soma revealed a complete mixing, within 18 hours, of these organelles with mitochondria coming from the surrounding neurites. Fusion of juxtaposed mitochondria was directly observed in neuritic processes at least 200 microns from the cell body. Within 24 hours, photoconverted mitoKaede was dispersed to all of the mitochondria in the portion of neurite under observation. When time lapse imaging over minutes was combined with long-term observation of marked mitochondria, moving organelles that traversed the field of view did not initially contain photoconverted protein, but after several hours organelles in motion contained both fluorescent proteins, coincident with widespread fusion of all of the mitochondria within the length of neurite under observation. These observations suggest that there is a widespread exchange of mitochondrial components throughout a neuron as a result of organelle fusion.

  19. Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons

    PubMed Central

    Magrané, Jordi; Sahawneh, Mary Anne; Przedborski, Serge; Estévez, Álvaro G.; Manfredi, Giovanni

    2012-01-01

    Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease. Mutant SOD1 has pleiotropic toxic effects on motor neurons, among which mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise. Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired mitochondrial dynamics in motor neurons may be involved in pathogenesis. We addressed this hypothesis by live imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing mutant or wild type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential. Furthermore, mislocalization of mitochondria at synapses among motor neurons, in vitro, correlates with abnormal synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron mitochondria, since they are absent in wild type SOD1 motor neurons, they do not involve other organelles, and they are not found in cortical neurons. Taken together, these results suggest that impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS. PMID:22219285

  20. Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis.

    PubMed

    Nardelli, Paul; Vincent, Jacob A; Powers, Randall; Cope, Tim C; Rich, Mark M

    2016-08-01

    The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced

  1. Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis

    PubMed Central

    Nardelli, Paul; Vincent, Jacob A.; Powers, Randall; Cope, Tim C.; Rich, Mark M.

    2016-01-01

    The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5 sec) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2 weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to

  2. Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons.

    PubMed

    Boza-Morán, María G; Martínez-Hernández, Rebeca; Bernal, Sara; Wanisch, Klaus; Also-Rallo, Eva; Le Heron, Anita; Alías, Laura; Denis, Cécile; Girard, Mathilde; Yee, Jiing-Kuan; Tizzano, Eduardo F; Yáñez-Muñoz, Rafael J

    2015-06-26

    Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in Survival Motor Neuron 1 (SMN1), leading to degeneration of alpha motor neurons (MNs) but also affecting other cell types. Induced pluripotent stem cell (iPSC)-derived human MN models from severe SMA patients have shown relevant phenotypes. We have produced and fully characterized iPSCs from members of a discordant consanguineous family with chronic SMA. We differentiated the iPSC clones into ISL-1+/ChAT+ MNs and performed a comparative study during the differentiation process, observing significant differences in neurite length and number between family members. Analyses of samples from wild-type, severe SMA type I and the type IIIa/IV family showed a progressive decay in SMN protein levels during iPSC-MN differentiation, recapitulating previous observations in developmental studies. PLS3 underwent parallel reductions at both the transcriptional and translational levels. The underlying, progressive developmental decay in SMN and PLS3 levels may lead to the increased vulnerability of MNs in SMA disease. Measurements of SMN and PLS3 transcript and protein levels in iPSC-derived MNs show limited value as SMA biomarkers.

  3. The development of three identified motor neurons in the larva of an ascidian, Halocynthia roretzi.

    PubMed

    Okada, Toshiaki; Katsuyama, You; Ono, Fumihito; Okamura, Yasushi

    2002-04-15

    The generation of distinct classes of motor neurons underlies the development of complex motile behavior in all animals and is well characterized in chordates. Recent molecular studies indicate that the ascidian larval central nervous system (CNS) exhibits anteroposterior regionalization similar to that seen in the vertebrate CNS. To extend the understanding about the diversity of motor neurons in the ascidian larva, we have identified the number, position, and projection of individual motor neurons in Halocynthia roretzi, using a green fluorescent protein under the control of a neuron-specific promoter. Three pairs of motor neurons, each with a distinct shape and innervation pattern, were identified along the anteroposterior axis of the neural tube: the anterior and posterior pairs extend their axons toward dorsal muscle cells, whereas the middle pair project their axons toward ventral muscle. Overexpression of a dominant-negative form of a potassium channel in these cells resulted in paralysis on the injected side, thus these cells must constitute the major population of motor neurons responsible for swimming behavior. Lim class homeobox genes have been known as candidate genes that determine subtypes of motor neurons. Therefore, the expression pattern of Hrlim, which is a Lim class homeobox gene, was examined in the motor neuron precursors. All three motor neurons expressed Hrlim at the tailbud stage, although each down-regulated Hrlim at a different time. Misexpression of Hrlim in the epidermal lineage led to ectopic expression of TuNa2, a putative voltage-gated channel gene normally expressed predominantly in the three pairs of motor neurons. Hrlim may control membrane excitability of motor neurons by regulating ion channel gene expression.

  4. Embryonic stem cells and prospects for their use in regenerative medicine approaches to motor neurone disease.

    PubMed

    Christou, Y A; Moore, H D; Shaw, P J; Monk, P N

    2007-10-01

    Human embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to valuable insights into the principles of developmental and cell biology and to the proposed use of human embryonic stem cells or their differentiated progeny in regenerative medicine. This review focuses on the prospects for the use of embryonic stem cells in cell-based therapy for motor neurone disease or amyotrophic lateral sclerosis, a progressive neurodegenerative disease that specifically affects upper and lower motor neurones and leads ultimately to death from respiratory failure. Stem cell-derived motor neurones could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurones, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro by embryonic stem cells. Here we discuss the need for new therapeutic strategies in the treatment of motor neurone disease, the developmental processes that result in motor neurone formation in vivo, a number of experimental approaches to motor neurone production in vitro and recent progress in the application of stem cells to the treatment and understanding of motor neurone disease.

  5. The alluring but misleading analogy between mirror neurons and the motor theory of speech.

    PubMed

    Holt, Lori L; Lotto, Andrew J

    2014-04-01

    Speech is commonly claimed to relate to mirror neurons because of the alluring surface analogy of mirror neurons to the Motor Theory of speech perception, which posits that perception and production draw upon common motor-articulatory representations. We argue that the analogy fails and highlight examples of systems-level developmental approaches that have been more fruitful in revealing perception-production associations.

  6. Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons.

    PubMed

    Satriotomo, I; Nichols, N L; Dale, E A; Emery, A T; Dahlberg, J M; Mitchell, G S

    2016-05-13

    Repetitive acute intermittent hypoxia (rAIH) increases growth/trophic factor expression in respiratory motor neurons, thereby eliciting spinal respiratory motor plasticity and/or neuroprotection. Here we demonstrate that rAIH effects are not unique to respiratory motor neurons, but are also expressed in non-respiratory, spinal alpha motor neurons and upper motor neurons of the motor cortex. In specific, we used immunohistochemistry and immunofluorescence to assess growth/trophic factor protein expression in spinal sections from rats exposed to AIH three times per week for 10weeks (3×wAIH). 3×wAIH increased brain-derived neurotrophic factor (BDNF), its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and phosphorylated TrkB (pTrkB) immunoreactivity in putative alpha motor neurons of spinal cervical 7 (C7) and lumbar 3 (L3) segments, as well as in upper motor neurons of the primary motor cortex (M1). 3×wAIH also increased immunoreactivity of vascular endothelial growth factor A (VEGFA), the high-affinity VEGFA receptor (VEGFR-2) and an important VEGF gene regulator, hypoxia-inducible factor-1α (HIF-1α). Thus, rAIH effects on growth/trophic factors are characteristic of non-respiratory as well as respiratory motor neurons. rAIH may be a useful tool in the treatment of disorders causing paralysis, such as spinal injury and motor neuron disease, as a pretreatment to enhance motor neuron survival during disease, or as preconditioning for cell-transplant therapies.

  7. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

    PubMed Central

    Boyd, Penelope J.; Shorrock, Hannah K.; Carter, Roderick N.; Powis, Rachael A.; Thomson, Sophie R.; Thomson, Derek; Graham, Laura C.; Motyl, Anna A. L.; Highley, J. Robin; Becker, Thomas; Becker, Catherina G.; Heath, Paul R.

    2017-01-01

    Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo. PMID:28426667

  8. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy.

    PubMed

    Boyd, Penelope J; Tu, Wen-Yo; Shorrock, Hannah K; Groen, Ewout J N; Carter, Roderick N; Powis, Rachael A; Thomson, Sophie R; Thomson, Derek; Graham, Laura C; Motyl, Anna A L; Wishart, Thomas M; Highley, J Robin; Morton, Nicholas M; Becker, Thomas; Becker, Catherina G; Heath, Paul R; Gillingwater, Thomas H

    2017-04-01

    Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

  9. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

    PubMed

    Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

    2017-03-29

    Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43(Q331K) mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43(Q331K) gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

  10. Modeling ALS with motor neurons derived from human induced pluripotent stem cells.

    PubMed

    Sances, Samuel; Bruijn, Lucie I; Chandran, Siddharthan; Eggan, Kevin; Ho, Ritchie; Klim, Joseph R; Livesey, Matt R; Lowry, Emily; Macklis, Jeffrey D; Rushton, David; Sadegh, Cameron; Sareen, Dhruv; Wichterle, Hynek; Zhang, Su-Chun; Svendsen, Clive N

    2016-04-01

    Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop new models of amyotrophic lateral sclerosis (ALS). However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques. We then suggest how these motor neurons may be matured further either through direct expression or administration of specific factors or coculture approaches with other tissues. Ultimately, through a greater understanding of motor neuron biology, it will be possible to establish more reliable models of ALS. These in turn will have a greater chance of validating new drugs that may be effective for the disease.

  11. Slow motor neuron stimulation of locust skeletal muscle: model and measurement.

    PubMed

    Wilson, Emma; Rustighi, Emiliano; Newland, Philip L; Mace, Brian R

    2013-06-01

    The isometric force response of the locust hind leg extensor tibia muscle to stimulation of a slow extensor tibia motor neuron is experimentally investigated, and a mathematical model describing the response presented. The measured force response was modelled by considering the ability of an existing model, developed to describe the response to the stimulation of a fast extensor tibia motor neuron and to also model the response to slow motor neuron stimulation. It is found that despite large differences in the force response to slow and fast motor neuron stimulation, which could be accounted for by the differing physiology of the fibres they innervate, the model is able to describe the response to both fast and slow motor neuron stimulation. Thus, the presented model provides a potentially generally applicable, robust, simple model to describe the isometric force response of a range of muscles.

  12. Spinal muscular atrophy and the antiapoptotic role of survival of motor neuron (SMN) protein.

    PubMed

    Anderton, Ryan S; Meloni, Bruno P; Mastaglia, Frank L; Boulos, Sherif

    2013-04-01

    Spinal muscular atrophy (SMA) is a devastating and often fatal neurodegenerative disease that affects spinal motor neurons and leads to progressive muscle wasting and paralysis. The survival of motor neuron (SMN) gene is mutated or deleted in most forms of SMA, which results in a critical reduction in SMN protein. Motor neurons appear particularly vulnerable to reduced SMN protein levels. Therefore, understanding the functional role of SMN in protecting motor neurons from degeneration is an essential prerequisite for the design of effective therapies for SMA. To this end, there is increasing evidence indicating a key regulatory antiapoptotic role for the SMN protein that is important in motor neuron survival. The aim of this review is to highlight key findings that support an antiapoptotic role for SMN in modulating cell survival and raise possibilities for new therapeutic approaches.

  13. Modeling ALS using motor neurons derived from human induced pluripotent stem cells

    PubMed Central

    Sances, S; Bruijn, LI; Chandran, S; Eggan, K; Ho, R; Klim, J; Livesey, MR; Lowry, E; Macklis, JD; Rushton, D; Sadegh, C; Sareen, D; Wichterle, H; Zhang, SC; Svendsen, CN

    2016-01-01

    Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop novel models of ALS. However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques. We then suggest how these motor neurons may be matured further either through direct expression or administration of specific factors or co-culture approaches with other tissues. Ultimately, through a greater understanding of motor neuron biology, it will be possible to establish more reliable models of ALS. These in turn will have a greater chance of validating new drugs that may be effective for the disease. PMID:27021939

  14. Mitochondrial DNA variations in Madras motor neuron disease

    PubMed Central

    Govindaraj, Periyasamy; Nalini, Atchayaram; Krishna, Nithin; Sharath, Anugula; Khan, Nahid Akhtar; Tamang, Rakesh; Devi, M. Gourie; Brown, Robert H.; Thangaraj, Kumarasamy

    2013-01-01

    Although the Madras Motor Neuron Disease (MMND) was found three decades ago, its genetic basis has not been elucidated, so far. The symptom at onset was impaired hearing, upper limb weakness and atrophy. Since some clinical features of MMND overlap with mitochondrial disorders, we analyzed the complete mitochondrial genome of 45 MMND patients and found 396 variations, including 13 disease-associated, 2 mt-tRNA and 33 non-synonymous (16 MT-ND, 10 MT-CO, 3 MT-CYB and 4 MT-ATPase). A rare variant (m.8302A>G) in mt-tRNALeu was found in three patients. We predict that these variation(s) may influence the disease pathogenesis along with some unknown factor(s). PMID:23419391

  15. Motor neurone disease: a practical update on diagnosis and management.

    PubMed

    Wood-Allum, Clare; Shaw, Pamela J

    2010-06-01

    Motor neurone disease (MND) is an adult-onset neurodegenerative disease which leads inexorably via weakness of limb, bulbar and respiratory muscles to death from respiratory failure three to five years later. Most MND is sporadic but approximately 10% is inherited. In exciting recent breakthroughs two new MND genes have been identified. Diagnosis is clinical and sometimes difficult--treatable mimics must be excluded before the diagnosis is ascribed. Riluzole prolongs life by only three to four months and is only available for the amyotrophic lateral sclerosis (ALS) form of MND. Management therefore properly focuses on symptom relief and the preservation of independence and quality of life. Malnutrition is a poor prognostic factor. In appropriate patients enteral feeding is recommended although its use has yet to be shown to improve survival. In ALS patients with respiratory failure and good or only moderately impaired bulbar function non-invasive positive pressure ventilation prolongs life and improves quality of life.

  16. Evidence for neuronal localisation of enteroviral sequences in motor neurone disease/amyotrophic lateral sclerosis by in situ hybridization.

    PubMed

    Woodall, C J; Graham, D I

    2004-01-01

    Sequences resembling those of human enterovirus type B sequences have been associated with motor neurone disease/amyotrophic lateral sclerosis. In a previous study we detected enteroviral sequences in spinal cord/brain stem from cases of motor neurone disease/amyotrophic lateral sclerosis, but not controls. Adjacent tissue sections to two of those strongly positive for these sequences by reverse-transcriptase polymerase chain reaction were analyzed by in situ hybridization with digoxigenin-labelled virus-specific antisense riboprobes. In one case, a female aged 83 showing 12 month rapid progressive disease, signal was specifically localized to cells identifiable as motor neurones of the anterior horn. In another case, a male aged 63 with a 60-month history of progressive muscle weakness, dysarthia, dyspnoea and increased tendon reflexes, signal was located to neurones in the gracile/cuneate nuclei of the brain stem tissue block that had been analyzed. This case showed loss of neurones in the anterior horn of the spinal cord by histopathologic examination which would account for clinical signs of motor neurone disease/amyotrophic lateral sclerosis. Dysfunction of the gracile/cuneate nuclei might have been masked by the paralytic disease. These structures are adjacent to the hypoglossal nuclei, and suggest either localised dissemination from hypoglossal nuclei or a possible route of dissemination of infection through the brainstem to the hypoglossal nuclei. These findings provide further evidence for the possible involvement of enteroviruses in motor neurone disease/amyotrophic lateral sclerosis.

  17. Anti-Hu associated paraneoplastic sensory neuronopathy with upper motor neurone involvement.

    PubMed

    Ogawa, M; Nishie, M; Kurahashi, K; Kaimori, M; Wakabayashi, K

    2004-07-01

    Paraneoplastic neurological syndrome is characterised by neuronal degeneration with lymphocytic infiltration in various regions of the central and peripheral nervous systems. Motor neurone symptoms may occur as a remote effect of malignancy, and have been considered because of the involvement of lower motor neurones. A case is reported of an 80 year old woman suffering from paraneoplastic sensory neuronopathy with anti-Hu antibody. Postmortem examination showed adenocarcinoma of the gall bladder and small cell carcinoma of the duodenum. Neuronal loss with lymphocytic infiltration was found in the dorsal root ganglia, brain stem, and cerebellum. Despite the absence of upper motor neurone signs, there was severe loss of Betz cells and degeneration of the bilateral pyramidal tracts. To our knowledge, this is the first demonstration of upper motor neurone involvement in anti-Hu associated paraneoplatic syndrome.

  18. The role of the ETS gene PEA3 in the development of motor and sensory neurons.

    PubMed

    Ladle, David R; Frank, Eric

    2002-12-01

    The ETS family of transcription factors includes two members, ER81 and PEA3, which are expressed in groups of sensory and motor neurons supplying individual muscles. To investigate a possible role of these genes in determining sensory and/or motor neuron phenotype, we studied mice in which each of these genes was deleted. In contrast to the deletion of ER81, which blocks the formation of projections from muscle sensory neurons to motor neurons in the spinal cord, deletion of PEA3 causes no obvious effects on sensory neurons or on their synaptic connections with motor neurons. PEA3 does play a major role in the formation of some brachial motoneurons however. Motoneurons innervating the cutaneous maximus muscle, which are normally PEA3(+), fail to develop normally so that postnatally the muscle is innervated by few motoneurons and is severely atrophic. Other studies suggest that these motoneurons initially appear during development but fail to contact their normal muscle targets.

  19. Pattern of motor neurone disease in eastern India.

    PubMed

    Saha, S P; Das, S K; Gangopadhyay, P K; Roy, T N; Maiti, B

    1997-07-01

    A clinical study about the pattern of motor neurone disease in eastern India was carried out from July 1993 to June 1995 at Bangur Institute of Neurology, Calcutta and SSKM Hospital, Calcutta. A total of 110 cases were studied and they constituted 0.11% of all neurological cases seen in the general OPD. Of 110 cases, amyotropic lateral sclerosis (ALS) constituted 43.6%, progressive muscular atrophy (PMA) 10.9%, post-polio progressive muscular atrophy (PPMA) 1.8%, spinal muscular atrophy (SMA) 20%, atypical form Madras pattern of MND (MMND) 0.9% and monomelic amyotrophy (MMA) 22.7% of cases. Disease is more common in males than females and average duration of symptoms before presentation varied from 1 to 12 months. Most of the patients were either agricultural labourers or manual workers in ALS variety whereas MMA variety was evenly distributed in both hard labourers and sedentary workers. Most of the patients in MMA and SMA groups presented before 30 years of age whereas ALS and PMA group presented after 30 years. Trauma was the commonest antecedent event in ALS and MMA followed by electrocution in the same two groups. Family history was found to be absent in SMA group though the disease is considered as a hereditary one. Weakness of the limbs and wasting of the muscles were common presenting symptoms and signs. Bulbar symptoms and signs were found only in the ALS group. EMG showed neurogenic pattern and mixed pattern in most of the patients in all groups. Only a few patients showed myopathic pattern. Neuroimaging study helped in exclusion of compressive lesion excepting two cases of MMA where facetal hypertrophy was present. Monomelic amyotrophy, a special variety of motor neurone disease, is not rare in this part as compared to other parts of India and Asia.

  20. The Gemin Associates of Survival Motor Neuron Are Required for Motor Function in Drosophila

    PubMed Central

    Borg, Rebecca; Cauchi, Ruben J.

    2013-01-01

    Membership of the survival motor neuron (SMN) complex extends to nine factors, including the SMN protein, the product of the spinal muscular atrophy (SMA) disease gene, Gemins 2–8 and Unrip. The best-characterised function of this macromolecular machine is the assembly of the Sm-class of uridine-rich small nuclear ribonucleoprotein (snRNP) particles and each SMN complex member has a key role during this process. So far, however, only little is known about the function of the individual Gemin components in vivo. Here, we make use of the Drosophila model organism to uncover loss-of-function phenotypes of Gemin2, Gemin3 and Gemin5, which together with SMN form the minimalistic fly SMN complex. We show that ectopic overexpression of the dead helicase Gem3ΔN mutant or knockdown of Gemin3 result in similar motor phenotypes, when restricted to muscle, and in combination cause lethality, hence suggesting that Gem3ΔN overexpression mimics a loss-of-function. Based on the localisation pattern of Gem3ΔN, we predict that the nucleus is the primary site of the antimorphic or dominant-negative mechanism of Gem3ΔN-mediated interference. Interestingly, phenotypes induced by human SMN overexpression in Drosophila exhibit similarities to those induced by overexpression of Gem3ΔN. Through enhanced knockdown we also uncover a requirement of Gemin2, Gemin3 and Gemin5 for viability and motor behaviour, including locomotion as well as flight, in muscle. Notably, in the case of Gemin3 and Gemin5, such function also depends on adequate levels of the respective protein in neurons. Overall, these findings lead us to speculate that absence of any one member is sufficient to arrest the SMN-Gemins complex function in a nucleocentric pathway, which is critical for motor function in vivo. PMID:24391840

  1. Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons.

    PubMed

    Fallini, Claudia; Rouanet, Jeremy P; Donlin-Asp, Paul G; Guo, Peng; Zhang, Honglai; Singer, Robert H; Rossoll, Wilfried; Bassell, Gary J

    2014-03-01

    Spinal muscular atrophy (SMA) is a lethal neurodegenerative disease specifically affecting spinal motor neurons. SMA is caused by the homozygous deletion or mutation of the survival of motor neuron 1 (SMN1) gene. The SMN protein plays an essential role in the assembly of spliceosomal ribonucleoproteins. However, it is still unclear how low levels of the ubiquitously expressed SMN protein lead to the selective degeneration of motor neurons. An additional role for SMN in the regulation of the axonal transport of mRNA-binding proteins (mRBPs) and their target mRNAs has been proposed. Indeed, several mRBPs have been shown to interact with SMN, and the axonal levels of few mRNAs, such as the β-actin mRNA, are reduced in SMA motor neurons. In this study we have identified the β-actin mRNA-binding protein IMP1/ZBP1 as a novel SMN-interacting protein. Using a combination of biochemical assays and quantitative imaging techniques in primary motor neurons, we show that IMP1 associates with SMN in individual granules that are actively transported in motor neuron axons. Furthermore, we demonstrate that IMP1 axonal localization depends on SMN levels, and that SMN deficiency in SMA motor neurons leads to a dramatic reduction of IMP1 protein levels. In contrast, no difference in IMP1 protein levels was detected in whole brain lysates from SMA mice, further suggesting neuron specific roles of SMN in IMP1 expression and localization. Taken together, our data support a role for SMN in the regulation of mRNA localization and axonal transport through its interaction with mRBPs such as IMP1. Copyright © 2013 Wiley Periodicals, Inc.

  2. Non-viral gene therapy that targets motor neurons in vivo

    PubMed Central

    Rogers, Mary-Louise; Smith, Kevin S.; Matusica, Dusan; Fenech, Matthew; Hoffman, Lee; Rush, Robert A.; Voelcker, Nicolas H.

    2014-01-01

    A major challenge in neurological gene therapy is safe delivery of transgenes to sufficient cell numbers from the circulation or periphery. This is particularly difficult for diseases involving spinal cord motor neurons such as amyotrophic lateral sclerosis (ALS). We have examined the feasibility of non-viral gene delivery to spinal motor neurons from intraperitoneal injections of plasmids carried by “immunogene” nanoparticles targeted for axonal retrograde transport using antibodies. PEGylated polyethylenimine (PEI-PEG12) as DNA carrier was conjugated to an antibody (MLR2) to the neurotrophin receptor p75 (p75NTR). We used a plasmid (pVIVO2) designed for in vivo gene delivery that produces minimal immune responses, has improved nuclear entry into post mitotic cells and also expresses green fluorescent protein (GFP). MLR2-PEI-PEG12 carried pVIVO2 and was specific for mouse motor neurons in mixed cultures containing astrocytes. While only 8% of motor neurons expressed GFP 72 h post transfection in vitro, when the immunogene was given intraperitonealy to neonatal C57BL/6J mice, GFP specific motor neuron expression was observed in 25.4% of lumbar, 18.3% of thoracic and 17.0% of cervical motor neurons, 72 h post transfection. PEI-PEG12 carrying pVIVO2 by itself did not transfect motor neurons in vivo, demonstrating the need for specificity via the p75NTR antibody MLR2. This is the first time that specific transfection of spinal motor neurons has been achieved from peripheral delivery of plasmid DNA as part of a non-viral gene delivery agent. These results stress the specificity and feasibility of immunogene delivery targeted for p75NTR expressing motor neurons, but suggests that further improvements are required to increase the transfection efficiency of motor neurons in vivo. PMID:25352776

  3. Functional Diversification of Motor Neuron-specific Isl1 Enhancers during Evolution

    PubMed Central

    Kim, Namhee; Park, Chungoo; Jeong, Yongsu; Song, Mi-Ryoung

    2015-01-01

    Functional diversification of motor neurons has occurred in order to selectively control the movements of different body parts including head, trunk and limbs. Here we report that transcription of Isl1, a major gene necessary for motor neuron identity, is controlled by two enhancers, CREST1 (E1) and CREST2 (E2) that allow selective gene expression of Isl1 in motor neurons. Introduction of GFP reporters into the chick neural tube revealed that E1 is active in hindbrain motor neurons and spinal cord motor neurons, whereas E2 is active in the lateral motor column (LMC) of the spinal cord, which controls the limb muscles. Genome-wide ChIP-Seq analysis combined with reporter assays showed that Phox2 and the Isl1-Lhx3 complex bind to E1 and drive hindbrain and spinal cord-specific expression of Isl1, respectively. Interestingly, Lhx3 alone was sufficient to activate E1, and this may contribute to the initiation of Isl1 expression when progenitors have just developed into motor neurons. E2 was induced by onecut 1 (OC-1) factor that permits Isl1 expression in LMCm neurons. Interestingly, the core region of E1 has been conserved in evolution, even in the lamprey, a jawless vertebrate with primitive motor neurons. All E1 sequences from lamprey to mouse responded equally well to Phox2a and the Isl1-Lhx3 complex. Conversely, E2, the enhancer for limb-innervating motor neurons, was only found in tetrapod animals. This suggests that evolutionarily-conserved enhancers permit the diversification of motor neurons. PMID:26447474

  4. Enhancing survival motor neuron expression extends lifespan and attenuates neurodegeneration in mutant TDP-43 mice.

    PubMed

    Perera, Nirma D; Sheean, Rebecca K; Crouch, Peter J; White, Anthony R; Horne, Malcolm K; Turner, Bradley J

    2016-09-15

    Defects in the RNA-binding proteins survival motor neuron (SMN) and TAR DNA-binding protein 43 (TDP-43) cause progressive motor neuron degeneration in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), respectively. While low levels of SMN protein in motor neurons result in SMA, recent studies implicate abnormal SMN levels and function in ALS pathogenesis. Here, we determine that SMN protein is upregulated early and progressively in spinal and cortical motor neurons of male transgenic mutant TDP-43(A315T) mice. Cytoplasmic SMN aggregates that contain TDP-43 and HuR were identified in motor neurons of TDP-43(A315T) mice, consistent with the incorporation of SMN into stress granules. To test the impact of augmenting SMN levels in TDP-43 proteinopathy, we demonstrate that neuronal overexpression of human SMN in TDP-43(A315T) mice delayed symptom onset and prolonged survival. SMN upregulation also countered motor neuron degeneration, attenuated activation of astrocytes and microglia and restored AMP kinase activation in spinal cords of TDP-43(A315T) mice. We also reveal that expression of another factor conferring motor neuron vulnerability, androgen receptor (AR), is reduced in spinal cords of male TDP-43(A315T) mice. These results establish that SMN overexpression in motor neurons slows disease onset and outcome by ameliorating pathological signs in this model of mutant TDP-43-mediated ALS. Further approaches to augment SMN levels using pharmacological or gene therapy agents may therefore be warranted in ALS. Our data also reinforce a novel potential link between ALS and spinal bulbar muscular atrophy (SBMA), another motor neurodegenerative disease mediated by reduced AR function in motor neurons. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. The effective neural drive to muscles is the common synaptic input to motor neurons

    PubMed Central

    Farina, Dario; Negro, Francesco; Dideriksen, Jakob Lund

    2014-01-01

    We analysed the transformation of synaptic input to the pool of motor neurons into the neural drive to the muscle. The aim was to explain the relations between common oscillatory signals sent to motor neurons and the effective component of the neural signal sent to muscles as output of the spinal cord circuitries. The approach is based on theoretical derivations, computer simulations, and experiments. It is shown theoretically that for frequencies smaller than the average discharge rates of the motor neurons, the pool of motor neurons determines a pure amplification of the frequency components common to all motor neurons, so that the common input is transmitted almost undistorted and the non-common components are strongly attenuated. The effective neural drive to the muscle thus mirrors the common synaptic input to motor neurons. The simulations with three models of motor neuron confirmed the theoretical results by showing that the coherence function between common input components and the neural drive to the muscle tends to 1 when increasing the number of active motor neurons. This result, which was relatively insensitive to the type of model used, was also supported experimentally by observing that, in the low-pass signal bandwidth, the peak in coherence between groups of motor units of the abductor digiti minimi muscle of five healthy subjects tended to 1 when increasing the number of motor units. These results have implications for our understanding of the neural control of muscles as well as for methods used for estimating the strength of common input to populations of motor neurons. PMID:24860172

  6. Stress exacerbates neuron loss and microglia proliferation in a rat model of excitotoxic lower motor neuron injury

    PubMed Central

    Puga, Denise A.; Tovar, C. Amy; Guan, Zhen; C.Gensel, John; Lyman, Matthew S.; McTigue, Dana M.; Popovich, Phillip G.

    2015-01-01

    All individuals experience stress and hormones (e.g., glucocorticoids/GCs) released during stressful events can affect the structure and function of neurons. These effects of stress are best characterized for brain neurons; however, the mechanisms controlling the expression and binding affinity of glucocorticoid receptors in the spinal cord are different than those in the brain. Accordingly, whether stress exerts unique effects on spinal cord neurons, especially in the context of pathology, is unknown. Using a controlled model of focal excitotoxic lower motor neuron injury in rats, we examined the effects of acute or chronic variable stress on spinal cord motor neuron survival and glial activation. New data indicate that stress exacerbates excitotoxic spinal cord motor neuron loss and associated activation of microglia. In contrast, hypertrophy and hyperplasia of astrocytes and NG2+ glia were unaffected or were modestly suppressed by stress. Although excitotoxic lesions cause significant motor neuron loss and stress exacerbates this pathology, overt functional impairment did not develop in the relevant forelimb up to one week post-lesion. These data indicate that stress is a disease-modifying factor capable of altering neuron and glial responses to pathological challenges in the spinal cord. PMID:26100488

  7. Stress exacerbates neuron loss and microglia proliferation in a rat model of excitotoxic lower motor neuron injury.

    PubMed

    Puga, Denise A; Tovar, C Amy; Guan, Zhen; Gensel, John C; Lyman, Matthew S; McTigue, Dana M; Popovich, Phillip G

    2015-10-01

    All individuals experience stress and hormones (e.g., glucocorticoids/GCs) released during stressful events can affect the structure and function of neurons. These effects of stress are best characterized for brain neurons; however, the mechanisms controlling the expression and binding affinity of glucocorticoid receptors in the spinal cord are different than those in the brain. Accordingly, whether stress exerts unique effects on spinal cord neurons, especially in the context of pathology, is unknown. Using a controlled model of focal excitotoxic lower motor neuron injury in rats, we examined the effects of acute or chronic variable stress on spinal cord motor neuron survival and glial activation. New data indicate that stress exacerbates excitotoxic spinal cord motor neuron loss and associated activation of microglia. In contrast, hypertrophy and hyperplasia of astrocytes and NG2+ glia were unaffected or were modestly suppressed by stress. Although excitotoxic lesions cause significant motor neuron loss and stress exacerbates this pathology, overt functional impairment did not develop in the relevant forelimb up to one week post-lesion. These data indicate that stress is a disease-modifying factor capable of altering neuron and glial responses to pathological challenges in the spinal cord. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Motor Neurons Tune Premotor Activity in a Vertebrate Central Pattern Generator.

    PubMed

    Lawton, Kristy J; Perry, Wick M; Yamaguchi, Ayako; Zornik, Erik

    2017-03-22

    Central patterns generators (CPGs) are neural circuits that drive rhythmic motor output without sensory feedback. Vertebrate CPGs are generally believed to operate in a top-down manner in which premotor interneurons activate motor neurons that in turn drive muscles. In contrast, the frog (Xenopus laevis) vocal CPG contains a functionally unexplored neuronal projection from the motor nucleus to the premotor nucleus, indicating a recurrent pathway that may contribute to rhythm generation. In this study, we characterized the function of this bottom-up connection. The X. laevis vocal CPG produces a 50-60 Hz "fast trill" song used by males during courtship. We recorded "fictive vocalizations" in the in vitro CPG from the laryngeal nerve while simultaneously recording premotor activity at the population and single-cell level. We show that transecting the motor-to-premotor projection eliminated the characteristic firing rate of premotor neurons. Silencing motor neurons with the intracellular sodium channel blocker QX-314 also disrupted premotor rhythms, as did blockade of nicotinic synapses in the motor nucleus (the putative location of motor neuron-to-interneuron connections). Electrically stimulating the laryngeal nerve elicited primarily IPSPs in premotor neurons that could be blocked by a nicotinic receptor antagonist. Our results indicate that an inhibitory signal, activated by motor neurons, is required for proper CPG function. To our knowledge, these findings represent the first example of a CPG in which precise premotor rhythms are tuned by motor neuron activity.SIGNIFICANCE STATEMENT Central pattern generators (CPGs) are neural circuits that produce rhythmic behaviors. In vertebrates, motor neurons are not commonly known to contribute to CPG function, with the exception of a few spinal circuits where the functional significance of motor neuron feedback is still poorly understood. The frog hindbrain vocal circuit contains a previously unexplored connection from

  9. Respiratory complications related to bulbar dysfunction in motor neuron disease.

    PubMed

    Hadjikoutis, S; Wiles, C M

    2001-04-01

    Bulbar dysfunction resulting from corticobulbar pathway or brainstem neuron degeneration is one of the most important clinical problems encountered in motor neuron disease (MND) and contributes to various respiratory complications which are major causes of morbidity and mortality. Chronic malnutrition as a consequence of bulbar muscle weakness may have a considerable bearing on respiratory muscle function and survival. Abnormalities of the control and strength of the laryngeal and pharyngeal muscles may cause upper airway obstruction increasing resistance to airflow. Bulbar muscle weakness prevents adequate peak cough flows to clear airway debris. Dysphagia can lead to aspiration of microorganisms, food and liquids and hence pneumonia. MND patients with bulbar involvement commonly display an abnormal respiratory pattern during swallow characterized by inspiration after swallow, prolonged swallow apnoea and multiple swallows per bolus. Volitional respiratory function tests such as forced vital capacity can be inaccurate in patients with bulbofacial weakness and/or impaired volitional respiratory control. Bulbar muscle weakness with abundant secretions may increase the risk of aspiration and make successful non-invasive assisted ventilation more difficult. We conclude that an evaluation of bulbar dysfunction is an essential element in the assessment of respiratory dysfunction in MND.

  10. Accelerated high-yield generation of limb-innervating motor neurons from human stem cells

    PubMed Central

    Amoroso, Mackenzie W.; Croft, Gist F.; Williams, Damian J.; O’Keeffe, Sean; Carrasco, Monica A.; Davis, Anne R.; Roybon, Laurent; Oakley, Derek H.; Maniatis, Tom; Henderson, Christopher E.; Wichterle, Hynek

    2013-01-01

    Human pluripotent stem cells are a promising source of differentiated cells for developmental studies, cell transplantation, disease modeling, and drug testing. However, their widespread use even for intensely studied cell types like spinal motor neurons is hindered by the long duration and low yields of existing protocols for in vitro differentiation and by the molecular heterogeneity of the populations generated. We report a combination of small molecules that within 3 weeks induce motor neurons at up to 50% abundance and with defined subtype identities of relevance to neurodegenerative disease. Despite their accelerated differentiation, motor neurons expressed combinations of HB9, ISL1 and column-specific markers that mirror those observed in vivo in human fetal spinal cord. They also exhibited spontaneous and induced activity, and projected axons towards muscles when grafted into developing chick spinal cord. Strikingly, this novel protocol preferentially generates motor neurons expressing markers of limb-innervating lateral motor column motor neurons (FOXP1+/LHX3−). Access to high-yield cultures of human limb-innervating motor neuron subtypes will facilitate in-depth study of motor neuron subtype-specific properties, disease modeling, and development of large-scale cell-based screening assays. PMID:23303937

  11. Induction of mice adult bone marrow mesenchymal stem cells into functional motor neuron-like cells.

    PubMed

    Abdullah, Rafal H; Yaseen, Nahi Y; Salih, Shahlaa M; Al-Juboory, Ahmad Adnan; Hassan, Ayman; Al-Shammari, Ahmed Majeed

    2016-11-01

    The differentiation of mesenchymal stem cells (MSC) into acetylcholine secreted motor neuron-like cells, followed by elongation of the cell axon, is a promising treatment for spinal cord injury and motor neuron cell dysfunction in mammals. Differentiation is induced through a pre-induction step using Beta- mercaptoethanol (BME) followed by four days of induction with retinoic acid and sonic hedgehog. This process results in a very efficient differentiation of BM-MSCs into motor neuron-like cells. Immunocytochemistry showed that these treated cells had specific motor neural markers: microtubule associated protein-2 and acetylcholine transferase. The ability of these cells to function as motor neuron cells was assessed by measuring acetylcholine levels in a culture media during differentiation. High-performance liquid chromatography (HPLC) showed that the differentiated cells were functional. Motor neuron axon elongation was then induced by adding different concentrations of a nerve growth factor (NGF) to the differentiation media. Using a collagen matrix to mimic the natural condition of neural cells in a three-dimensional model showed that the MSCs were successfully differentiated into motor neuron-like cells. This process can efficiently differentiate MSCs into functional motor neurons that can be used for autologous nervous system therapy and especially for treating spinal cord injuries. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Motor neuronal activity varies least among individuals when it matters most for behavior.

    PubMed

    Cullins, Miranda J; Shaw, Kendrick M; Gill, Jeffrey P; Chiel, Hillel J

    2015-02-01

    How does motor neuronal variability affect behavior? To explore this question, we quantified activity of multiple individual identified motor neurons mediating biting and swallowing in intact, behaving Aplysia californica by recording from the protractor muscle and the three nerves containing the majority of motor neurons controlling the feeding musculature. We measured multiple motor components: duration of the activity of identified motor neurons as well as their relative timing. At the same time, we measured behavioral efficacy: amplitude of grasping movement during biting and amplitude of net inward food movement during swallowing. We observed that the total duration of the behaviors varied: Within animals, biting duration shortened from the first to the second and third bites; between animals, biting and swallowing durations varied. To study other sources of variation, motor components were divided by behavior duration (i.e., normalized). Even after normalization, distributions of motor component durations could distinguish animals as unique individuals. However, the degree to which a motor component varied among individuals depended on the role of that motor component in a behavior. Motor neuronal activity that was essential for the expression of biting or swallowing was similar among animals, whereas motor neuronal activity that was not essential for that behavior varied more from individual to individual. These results suggest that motor neuronal activity that matters most for the expression of a particular behavior may vary least from individual to individual. Shaping individual variability to ensure behavioral efficacy may be a general principle for the operation of motor systems. Copyright © 2015 the American Physiological Society.

  13. Dopamine-Dependent Compensation Maintains Motor Behavior in Mice with Developmental Ablation of Dopaminergic Neurons

    PubMed Central

    DeMaro, Joseph A.; Knoten, Amanda; Hoshi, Masato; Pehek, Elizabeth; Johnson, Eugene M.; Gereau, Robert W.

    2013-01-01

    The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and consequent depletion of striatal dopamine are known to underlie the motor deficits observed in Parkinson's disease (PD). Adaptive changes in dopaminergic terminals and in postsynaptic striatal neurons can compensate for significant losses of striatal dopamine, resulting in preservation of motor behavior. In addition, compensatory changes independent of striatal dopamine have been proposed based on PD therapies that modulate nondopaminergic circuits within the basal ganglia. We used a genetic strategy to selectively destroy dopaminergic neurons in mice during development to determine the necessity of these neurons for the maintenance of normal motor behavior in adult and aged mice. We find that loss of 90% of SNc dopaminergic neurons and consequent depletion of >95% of striatal dopamine does not result in changes in motor behavior in young-adult or aged mice as evaluated by an extensive array of motor behavior tests. Treatment of aged mutant mice with the dopamine receptor antagonist haloperidol precipitated motor behavior deficits in aged mutant mice, indicating that <5% of striatal dopamine is sufficient to maintain motor function in these mice. We also found that mutant mice exhibit an exaggerated response to l-DOPA compared with control mice, suggesting that preservation of motor function involves sensitization of striatal dopamine receptors. Our results indicate that congenital loss of dopaminergic neurons induces remarkable adaptions in the nigrostriatal system where limited amounts of dopamine in the dorsal striatum can maintain normal motor function. PMID:24155314

  14. BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB

    NASA Technical Reports Server (NTRS)

    Hu, Peter; Kalb, Robert G.; Walton, K. D. (Principal Investigator)

    2003-01-01

    The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

  15. Growth of primary motor neurons on horizontally aligned carbon nanotube thin films and striped patterns

    NASA Astrophysics Data System (ADS)

    Roberts, Megan J.; Leach, Michelle K.; Bedewy, Mostafa; Meshot, Eric R.; Copic, Davor; Corey, Joseph M.; Hart, A. John

    2014-06-01

    Objective. Carbon nanotubes (CNTs) are attractive for use in peripheral nerve interfaces because of their unique combination of strength, flexibility, electrical conductivity and nanoscale surface texture. Here we investigated the growth of motor neurons on thin films of horizontally aligned CNTs (HACNTs). Approach. We cultured primary embryonic rat motor neurons on HACNTs and performed statistical analysis of the length and orientation of neurites. We next presented motor neurons with substrates of alternating stripes of HACNTs and SiO2. Main results. The neurons survived on HACNT substrates for up to eight days, which was the full duration of our experiments. Statistical analysis of the length and orientation of neurites indicated that the longest neurites on HACNTs tended to align with the CNT direction, although the average neurite length was similar between HACNTs and glass control substrates. We observed that when motor neurons were presented with alternating stripes of HACNTs and SiO2, the proportion of neurons on HACNTs increases over time, suggesting that neurons selectively migrate toward and adhere to the HACNT surface. Significance. The behavior of motor neurons on CNTs has not been previously investigated, and we show that aligned CNTs could provide a viable interface material to motor neurons. Combined with emerging techniques to build complex hierarchical structures of CNTs, our results suggest that organised CNTs could be incorporated into nerve grafts that use physical and electrical cues to guide regenerating axons.

  16. BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB

    NASA Technical Reports Server (NTRS)

    Hu, Peter; Kalb, Robert G.; Walton, K. D. (Principal Investigator)

    2003-01-01

    The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

  17. Rapid, efficient, and simple motor neuron differentiation from human pluripotent stem cells.

    PubMed

    Shimojo, Daisuke; Onodera, Kazunari; Doi-Torii, Yukiko; Ishihara, Yasuharu; Hattori, Chinatsu; Miwa, Yukino; Tanaka, Satoshi; Okada, Rina; Ohyama, Manabu; Shoji, Masanobu; Nakanishi, Atsushi; Doyu, Manabu; Okano, Hideyuki; Okada, Yohei

    2015-12-01

    Human pluripotent stem cells (hPSCs) are being applied in regenerative medicine and for the in vitro modeling of human intractable disorders. In particular, neural cells derived from disease-specific human induced pluripotent stem cells (hiPSCs) established from patients with neurological disorders have been used as in vitro disease models to recapitulate in vivo pathogenesis because neural cells cannot be usually obtained from patients themselves. In this study, we established a rapid, efficient, and simple method for efficiently deriving motor neurons from hPSCs that is useful for pathophysiological analysis and the development of drugs to treat motor neuron diseases. Treatment with GSK3β inhibitors during the initial phase of differentiation in combination with dual SMAD inhibition was sufficient to induce PAX6 (+) and SOX1 (+) neural progenitors within 1 week, and subsequent treatment with retinoic acid (RA) and purmorphamine, which activates sonic hedgehog (SHH) signaling, resulted in the highly efficient induction of HB9(+) and ISL-1(+) motor neurons within 2 weeks. After 4 weeks of monolayer differentiation in motor neuron maturation medium, hPSC-derived motor neurons were shown to mature, displaying larger somas and clearer staining for the mature motor neuron marker choline acetyltransferase (ChAT). Moreover, hPSC-derived motor neurons were able to form neuromuscular junctions with human myotubes in vitro and induced acetylcholine receptor (AChR) clustering, as detected by Alexa 555-conjugated α-Bungarotoxin (α-BTX), suggesting that these hPSC-derived motor neurons formed functional contacts with skeletal muscles. This differentiation system is simple and is reproducible in several hiPSC clones, thereby minimizing clonal variation among hPSC clones. We also established a system for visualizing motor neurons with a lentiviral reporter for HB9 (HB9 (e438) ::Venus). The specificity of this reporter was confirmed through immunocytochemistry and

  18. Wnt7A identifies embryonic γ-motor neurons and reveals early postnatal dependence of γ-motor neurons on a muscle spindle-derived signal.

    PubMed

    Ashrafi, Soha; Lalancette-Hébert, Melanie; Friese, Andreas; Sigrist, Markus; Arber, Silvia; Shneider, Neil A; Kaltschmidt, Julia A

    2012-06-20

    Motor pools comprise a heterogeneous population of motor neurons that innervate distinct intramuscular targets. While the organization of motor neurons into motor pools has been well described, the time course and mechanism of motor pool diversification into functionally distinct classes remains unclear. γ-Motor neurons (γ-MNs) and α-motor neurons (α-MNs) differ in size, molecular identity, synaptic input and peripheral target. While α-MNs innervate extrafusal skeletal muscle fibers to mediate muscle contraction, γ-MNs innervate intrafusal fibers of the muscle spindle, and regulate sensitivity of the muscle spindle in response to stretch. In this study, we find that the secreted signaling molecule Wnt7a is selectively expressed in γ-MNs in the mouse spinal cord by embryonic day 17.5 and continues to molecularly distinguish γ-from α-MNs into the third postnatal week. Our data demonstrate that Wnt7a is the earliest known γ-MN marker, supporting a model of developmental divergence between α- and γ-MNs at embryonic stages. Furthermore, using Wnt7a expression as an early marker of γ-MN identity, we demonstrate a previously unknown dependence of γ-MNs on a muscle spindle-derived, GDNF-independent signal during the first postnatal week.

  19. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration.

    PubMed

    Iguchi, Yohei; Katsuno, Masahisa; Niwa, Jun-ichi; Takagi, Shinnosuke; Ishigaki, Shinsuke; Ikenaka, Kensuke; Kawai, Kaori; Watanabe, Hirohisa; Yamanaka, Koji; Takahashi, Ryosuke; Misawa, Hidemi; Sasaki, Shoichi; Tanaka, Fumiaki; Sobue, Gen

    2013-05-01

    Amyotrophic lateral sclerosis is a devastating, progressive neurodegenerative disease that affects upper and lower motor neurons. Although several genes are identified as the cause of familial cases, the pathogeneses of sporadic forms, which account for 90% of amyotrophic lateral sclerosis, have not been elucidated. Transactive response DNA-binding protein 43 a nuclear protein regulating RNA processing, redistributes to the cytoplasm and forms aggregates, which are the histopathological hallmark of sporadic amyotrophic lateral sclerosis, in affected motor neurons, suggesting that loss-of-function of transactive response DNA-binding protein 43 is one of the causes of the neurodegeneration. To test this hypothesis, we assessed the effects of knockout of transactive response DNA-binding protein 43 in mouse postnatal motor neurons using Cre/loxp system. These mice developed progressive weight loss and motor impairment around the age of 60 weeks, and exhibited degeneration of large motor axon, grouped atrophy of the skeletal muscle, and denervation in the neuromuscular junction. The spinal motor neurons lacking transactive response DNA-binding protein 43 were not affected for 1 year, but exhibited atrophy at the age of 100 weeks; whereas, extraocular motor neurons, that are essentially resistant in amyotrophic lateral sclerosis, remained preserved even at the age of 100 weeks. Additionally, ultra structural analysis revealed autolysosomes and autophagosomes in the cell bodies and axons of motor neurons of the 100-week-old knockout mice. In summary, the mice in which transactive response DNA-binding protein 43 was knocked-out specifically in postnatal motor neurons exhibited an age-dependent progressive motor dysfunction accompanied by neuropathological alterations, which are common to sporadic amyotrophic lateral sclerosis. These findings suggest that transactive response DNA-binding protein 43 plays an essential role in the long term maintenance of motor neurons and

  20. Somatosensory response properties of excitatory and inhibitory neurons in rat motor cortex

    PubMed Central

    Murray, Peter D.

    2011-01-01

    In sensory cortical networks, peripheral inputs differentially activate excitatory and inhibitory neurons. Inhibitory neurons typically have larger responses and broader receptive field tuning compared with excitatory neurons. These differences are thought to underlie the powerful feedforward inhibition that occurs in response to sensory input. In the motor cortex, as in the somatosensory cortex, cutaneous and proprioceptive somatosensory inputs, generated before and during movement, strongly and dynamically modulate the activity of motor neurons involved in a movement and ultimately shape cortical command. Human studies suggest that somatosensory inputs modulate motor cortical activity in a center excitation, surround inhibition manner such that input from the activated muscle excites motor cortical neurons that project to it, whereas somatosensory input from nearby, nonactivated muscles inhibit these neurons. A key prediction of this hypothesis is that inhibitory and excitatory motor cortical neurons respond differently to somatosensory inputs. We tested this prediction with the use of multisite extracellular recordings in anesthetized rats. We found that fast-spiking (presumably inhibitory) neurons respond to tactile and proprioceptive inputs at shorter latencies and larger response magnitudes compared with regular-spiking (presumably excitatory) neurons. In contrast, we found no differences in the receptive field size of these neuronal populations. Strikingly, all fast-spiking neuron pairs analyzed with cross-correlation analysis displayed common excitation, which was significantly more prevalent than common excitation for regular-spiking neuron pairs. These findings suggest that somatosensory inputs preferentially evoke feedforward inhibition in the motor cortex. We suggest that this provides a mechanism for dynamic selection of motor cortical modules during voluntary movements. PMID:21653707

  1. Somatosensory response properties of excitatory and inhibitory neurons in rat motor cortex.

    PubMed

    Murray, Peter D; Keller, Asaf

    2011-09-01

    In sensory cortical networks, peripheral inputs differentially activate excitatory and inhibitory neurons. Inhibitory neurons typically have larger responses and broader receptive field tuning compared with excitatory neurons. These differences are thought to underlie the powerful feedforward inhibition that occurs in response to sensory input. In the motor cortex, as in the somatosensory cortex, cutaneous and proprioceptive somatosensory inputs, generated before and during movement, strongly and dynamically modulate the activity of motor neurons involved in a movement and ultimately shape cortical command. Human studies suggest that somatosensory inputs modulate motor cortical activity in a center excitation, surround inhibition manner such that input from the activated muscle excites motor cortical neurons that project to it, whereas somatosensory input from nearby, nonactivated muscles inhibit these neurons. A key prediction of this hypothesis is that inhibitory and excitatory motor cortical neurons respond differently to somatosensory inputs. We tested this prediction with the use of multisite extracellular recordings in anesthetized rats. We found that fast-spiking (presumably inhibitory) neurons respond to tactile and proprioceptive inputs at shorter latencies and larger response magnitudes compared with regular-spiking (presumably excitatory) neurons. In contrast, we found no differences in the receptive field size of these neuronal populations. Strikingly, all fast-spiking neuron pairs analyzed with cross-correlation analysis displayed common excitation, which was significantly more prevalent than common excitation for regular-spiking neuron pairs. These findings suggest that somatosensory inputs preferentially evoke feedforward inhibition in the motor cortex. We suggest that this provides a mechanism for dynamic selection of motor cortical modules during voluntary movements.

  2. Neurogenic differentiation of dental pulp stem cells to neuron-like cells in dopaminergic and motor neuronal inductive media.

    PubMed

    Chang, Chia-Chieh; Chang, Kai-Chun; Tsai, Shang-Jye; Chang, Hao-Hueng; Lin, Chun-Pin

    2014-12-01

    Dental pulp stem cells (DPSCs) have been proposed as a promising source of stem cells in nerve regeneration due to their close embryonic origin and ease of harvest. The aim of this study was to evaluate the efficacy of dopaminergic and motor neuronal inductive media on transdifferentiation of human DPSCs (hDPSCs) into neuron-like cells. Isolation, cultivation, and identification of hDPSCs were performed with morphological analyses and flow cytometry. The proliferation potential of DPSCs was evaluated with an XTT [(2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide)] assay. Media for the induction of dopaminergic and spinal motor neuronal differentiation were prepared. The efficacy of neural induction was evaluated by detecting the expression of neuron cell-specific cell markers in DPSCs by immunocytochemistry and quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). In the XTT assay, there was a 2.6- or 2-fold decrease in DPSCs cultured in dopaminergic or motor neuronal inductive media, respectively. The proportions of βIII-tubulin (βIII-tub), glial fibrillary acidic protein (GFAP), and oligodendrocyte (O1)-positive cells were significantly higher in DPSCs cultured in both neuronal inductive media compared with those cultured in control media. Furthermore, hDPSC-derived dopaminergic and spinal motor neuron cells after induction expressed a higher density of neuron cell markers than those before induction. These findings suggest that in response to the neuronal inductive stimuli, a greater proportion of DPSCs stop proliferation and acquire a phenotype resembling mature neurons. Such neural crest-derived adult DPSCs may provide an alternative stem cell source for therapy-based treatments of neuronal disorders and injury. Copyright © 2014. Published by Elsevier B.V.

  3. Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex

    PubMed Central

    Jara, J H; Stanford, M J; Zhu, Y; Tu, M; Hauswirth, W W; Bohn, M C; DeVries, S H; Özdinler, P H

    2016-01-01

    Direct gene delivery to the neurons of interest, without affecting other neuron populations in the cerebral cortex, represent a challenge owing to the heterogeneity and cellular complexity of the brain. Genetic modulation of corticospinal motor neurons (CSMN) is required for developing effective and long-term treatment strategies for motor neuron diseases, in which voluntary movement is impaired. Adeno-associated viruses (AAV) have been widely used for neuronal transduction studies owing to long-term and stable gene expression as well as low immunoreactivity in humans. Here we report that AAV2-2 transduces CSMN with high efficiency upon direct cortex injection and that transduction efficiencies are similar during presymptomatic and symptomatic stages in hSOD1G93A transgenic amyotrophic lateral sclerosis (ALS) mice. Our findings reveal that choice of promoter improves selectivity as AAV2-2 chicken β-actin promoter injection results in about 70% CSMN transduction, the highest percentage reported to date. CSMN transduction in both wild-type and transgenic ALS mice allows detailed analysis of single axon fibers within the corticospinal tract in both cervical and lumbar spinal cord and reveals circuitry defects, which mainly occur between CSMN and spinal motor neurons in hSOD1G93A transgenic ALS mice. Our findings set the stage for CSMN gene therapy in ALS and related motor neuron diseases. PMID:26704722

  4. Modulation of motor cortex neuronal activity and motor behavior during subthalamic nucleus stimulation in the normal primate.

    PubMed

    Johnson, Luke A; Xu, Weidong; Baker, Kenneth B; Zhang, Jianyu; Vitek, Jerrold L

    2015-04-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established surgical therapy for advanced Parkinson's disease (PD). An emerging hypothesis is that the therapeutic benefit of DBS is derived from direct modulation of primary motor cortex (M1), yet little is known about the influence of STN DBS on individual neurons in M1. We investigated the effect of STN DBS, delivered at discrete interval intensities (20, 40, 60, 80, and 100%) of corticospinal tract threshold (CSTT), on motor performance and M1 neuronal activity in a naive nonhuman primate. Motor performance during a food reach and retrieval task improved during low-intensity stimulation (20% CSTT) but worsened as intensity approached the threshold for activation of corticospinal fibers (80% and 100% CSTT). To assess cortical effects of STN DBS, spontaneous, extracellular neuronal activity was collected from M1 neurons before, during, and after DBS at the same CSTT stimulus intensities. STN DBS significantly modulated the firing of a majority of M1 neurons; however, the direction of effect varied with stimulus intensity such that, at 20% CSTT, most neurons were suppressed, whereas at the highest stimulus intensities the majority of neurons were activated. At a population level, firing rates increased as stimulus intensity increased. These results show that STN DBS influences both motor performance and M1 neuronal activity systematically according to stimulus intensity. In addition, the unanticipated reduction in reach times suggests that STN DBS, at stimulus intensities lower than typically used for treatment of PD motor signs, can enhance normal motor performance.

  5. Demonstration of motor imagery movement and phantom movement-related neuronal activity in human thalamus.

    PubMed

    Anderson, William S; Weiss, Nirit; Lawson, Herman Christopher; Ohara, Shinji; Rowland, Lance; Lenz, Frederick A

    2011-01-26

    Functional imaging studies show that motor imagery activates multiple structures in the human forebrain. We now show that phantom movements in an amputee and imagined movements in intact individuals elicit responses from neurons in several human thalamic nuclei. These include the somatic sensory nucleus receiving input from the periphery (ventral caudal), and the motor nuclei receiving input from the cerebellum [ventral intermediate (Vim)] and the basal ganglia [ventral oral posterior (Vop)]. Seven neurons in the amputee showed phantom movement-related activity (three Vim, two Vop, and two ventral caudal). In addition, seven neurons in a group of three controls showed motor imagery-related activity (four Vim and three Vop). These studies were performed during single neuron recording sessions in patients undergoing therapeutic treatment of phantom pain, tremor, and chronic pain conditions by thalamic stimulation. The activity of neurons in these sensory and motor nuclei, respectively, may encode the expected sensory consequences and the dynamics of planned movements.

  6. Demonstration of Motor Imagery- and Phantom-Movement Related Neuronal Activity in Human Thalamus

    PubMed Central

    Weiss, Nirit; Lawson, Herman Christopher; Ohara, Shinji; Rowland, Lance; Lenz, Frederick A.

    2010-01-01

    Functional imaging studies demonstrate that motor imagery activates multiple structures in the human forebrain. We now show that phantom movements in an amputee and imagined movements in intact subjects elicit responses from neurons in several human thalamic nuclei. These include the somatic sensory nucleus receiving input from the periphery (ventral caudal – Vc), and the motor nuclei receiving input from the cerebellum (ventral intermediate -Vim) and the basal ganglia (ventral oral posterior - Vop). Seven neurons in the amputee demonstrated phantom movement-related activity (3 Vim, 2 Vop, and 2 Vc). Additionally, seven neurons in a group of three controls demonstrated motor imagery-related activity (4 Vim, and 3 Vop). These studies were performed during single neuron recording sessions in patients undergoing therapeutic treatment of phantom pain, tremor, and chronic pain conditions by thalamic stimulation. The activity of neurons in these sensory and motor nuclei respectively may encode the expected sensory consequences and the dynamics of planned movements. PMID:21150804

  7. The primary locus of motor neuron death in an ALS–PDC mouse model

    PubMed Central

    Lee, Grace; Chu, Tony; Shaw, Christopher A.

    2010-01-01

    A mouse model of amyotrophic lateral sclerosis–parkinsonism–dementia complex based on the consumption of cycad seed flour was used to determine whether the observed pathology of motor neuron loss begins in the distal axons or the spinal cord. Assessments of neuromuscular junction integrity and motor neurons were performed at multiple time points. Mice fed cycad pellets performed worse on the wire hang than controls. Microglial activation in cycad-fed mice was observed with motor neuron degeneration at 12 weeks, but reactive astrocyte proliferation was not observed. After 33 weeks of cycad feeding, motor neuron loss had stabilized, with no evidence of neuromuscular junction endplate denervation. These data suggest that neuronal pathology begins at the soma and proceeds distally in a ‘dying forward’ pattern. PMID:19633581

  8. The critical role of membralin in postnatal motor neuron survival and disease.

    PubMed

    Yang, Bo; Qu, Mingliang; Wang, Rengang; Chatterton, Jon E; Liu, Xiao-Bo; Zhu, Bing; Narisawa, Sonoko; Millan, Jose Luis; Nakanishi, Nobuki; Swoboda, Kathryn; Lipton, Stuart A; Zhang, Dongxian

    2015-05-15

    Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5-6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.

  9. Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice

    PubMed Central

    de Waard, Monique C.; Zuiderveen Borgesius, Nils; Comley, Laura H.; Haasdijk, Elize D.; Rijksen, Yvonne; Ridwan, Yanto; Zondag, Gerben; Hoeijmakers, Jan H. J.; Elgersma, Ype; Gillingwater, Thomas H.

    2010-01-01

    Degeneration of motor neurons contributes to senescence-associated loss of muscle function and underlies human neurodegenerative conditions such as amyotrophic lateral sclerosis and spinal muscular atrophy. The identification of genetic factors contributing to motor neuron vulnerability and degenerative phenotypes in vivo are therefore important for our understanding of the neuromuscular system in health and disease. Here, we analyzed neurodegenerative abnormalities in the spinal cord of progeroid Ercc1Δ/− mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair, and double strand break repair. Ercc1Δ/− mice develop age-dependent motor abnormalities, and have a shortened life span of 6–7 months. Pathologically, Ercc1Δ/− mice develop widespread astrocytosis and microgliosis, and motor neuron loss and denervation of skeletal muscle fibers. Degenerating motor neurons in many occasions expressed genotoxic-responsive transcription factors p53 or ATF3, and in addition, displayed a range of Golgi apparatus abnormalities. Furthermore, Ercc1Δ/− motor neurons developed perikaryal and axonal intermediate filament abnormalities reminiscent of cytoskeletal pathology observed in aging spinal cord. Our findings support the notion that accumulation of DNA damage and genotoxic stress may contribute to neuronal aging and motor neuron vulnerability in human neuromuscular disorders. Electronic supplementary material The online version of this article (doi:10.1007/s00401-010-0715-9) contains supplementary material, which is available to authorized users. PMID:20602234

  10. More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases

    PubMed Central

    Boyer, Justin G.; Ferrier, Andrew; Kothary, Rashmi

    2013-01-01

    Spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and spinal-bulbar muscular atrophy (SBMA) are devastating diseases characterized by the degeneration of motor neurons. Although the molecular causes underlying these diseases differ, recent findings have highlighted the contribution of intrinsic skeletal muscle defects in motor neuron diseases. The use of cell culture and animal models has led to the important finding that muscle defects occur prior to and independently of motor neuron degeneration in motor neuron diseases. In SMA for instance, the muscle specific requirements of the SMA disease-causing gene have been demonstrated by a series of genetic rescue experiments in SMA models. Conditional ALS mouse models expressing a muscle specific mutant SOD1 gene develop atrophy and muscle degeneration in the absence of motor neuron pathology. Treating SBMA mice by over-expressing IGF-1 in a skeletal muscle-specific manner attenuates disease severity and improves motor neuron pathology. In the present review, we provide an in depth description of muscle intrinsic defects, and discuss how they impact muscle function in these diseases. Furthermore, we discuss muscle-specific therapeutic strategies used to treat animal models of SMA, ALS, and SBMA. The study of intrinsic skeletal muscle defects is crucial for the understanding of the pathophysiology of these diseases and will open new therapeutic options for the treatment of motor neuron diseases. PMID:24391590

  11. Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy

    PubMed Central

    Tovar-y-Romo, Luis B.; Ramírez-Jarquín, Uri Nimrod; Lazo-Gómez, Rafael; Tapia, Ricardo

    2014-01-01

    Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF), glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and insulin-like growth factor 1 (IGF-1). Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this minireview we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use. PMID:24616665

  12. Motor neuron derivation from human embryonic and induced pluripotent stem cells: experimental approaches and clinical perspectives.

    PubMed

    Faravelli, Irene; Bucchia, Monica; Rinchetti, Paola; Nizzardo, Monica; Simone, Chiara; Frattini, Emanuele; Corti, Stefania

    2014-07-14

    Motor neurons are cells located in specific areas of the central nervous system, such as brain cortex (upper motor neurons), brain stem, and spinal cord (lower motor neurons), which maintain control over voluntary actions. Motor neurons are affected primarily by a wide spectrum of neurological disorders, generally indicated as motor neuron diseases (MNDs): these disorders share symptoms related to muscular atrophy and paralysis leading to death. No effective treatments are currently available. Stem cell-derived motor neurons represent a promising research tool in disease modeling, drug screening, and development of therapeutic approaches for MNDs and spinal cord injuries. Directed differentiation of human pluripotent stem cells - human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) - toward specific lineages is the first crucial step in order to extensively employ these cells in early human development investigation and potential clinical applications. Induced pluripotent stem cells (iPSCs) can be generated from patients' own somatic cells (for example, fibroblasts) by reprogramming them with specific factors. They can be considered embryonic stem cell-like cells, which express stem cell markers and have the ability to give rise to all three germ layers, bypassing the ethical concerns. Thus, hiPSCs constitute an appealing alternative source of motor neurons. These motor neurons might be a great research tool, creating a model for investigating the cellular and molecular interactions underlying early human brain development and pathologies during neurodegeneration. Patient-specific iPSCs may also provide the premises for autologous cell replacement therapies without related risks of immune rejection. Here, we review the most recent reported methods by which hESCs or iPSCs can be differentiated toward functional motor neurons with an overview on the potential clinical applications.

  13. Morphological features and responses to AMPA receptor-mediated excitotoxicity of mouse motor neurons: comparison in purified, mixed anterior horn or motor neuron/glia cocultures.

    PubMed

    De Paola, Massimiliano; Diana, Valentina; Bigini, Paolo; Mennini, Tiziana

    2008-05-15

    Primary motor neuron cultures are widely used as in vitro model to study the early mechanisms involved in the aetiology of amyotrophic lateral sclerosis. In this study, we directly compared the morphological features and the responses to AMPA receptor (AMPAR) activation of mouse spinal cord motor neurons under different culture conditions (OptiPrep-purified, mixed anterior horn or motor neuron/glia cocultures). Motor neurons cocultured with a confluent glial layer had significant improvements in axonal length and in somata perimeter and area, compared both to mixed anterior horn cultures and to purified cultures, suggesting that the presence of more "mature" glial cells was determinant to obtain healthier motor neurons. By immuno-cytochemical assays we found that both in mixed anterior horn cultures and in cocultures, lower AMPA (0.3 microM) or kainate (5 microM) concentrations, but not the higher (1 or 15 microM, respectively), induced classical apoptotic events such as the nuclear fragmentation, the membrane externalization of phosphatidylserine residues and the activation of caspases-9 and -3. The morphological features and the different degenerative pathways induced by AMPAR agonist concentrations suggest that the experimental conditions used for in vitro studies are key factors that should be deeply considered to obtain more valid and reproducible results.

  14. Economic Studies in Motor Neurone Disease: A Systematic Methodological Review.

    PubMed

    Moore, Alan; Young, Carolyn A; Hughes, Dyfrig A

    2017-04-01

    Motor neurone disease (MND) is a devastating condition which greatly diminishes patients' quality of life and limits life expectancy. Health technology appraisals of future interventions in MND need robust data on costs and utilities. Existing economic evaluations have been noted to be limited and fraught with challenges. The aim of this study was to identify and critique methodological aspects of all published economic evaluations, cost studies, and utility studies in MND. We systematically reviewed all relevant published studies in English from 1946 until January 2016, searching the databases of Medline, EMBASE, Econlit, NHS Economic Evaluation Database (NHS EED) and the Health Economics Evaluation Database (HEED). Key data were extracted and synthesised narratively. A total of 1830 articles were identified, of which 15 economic evaluations, 23 cost and 3 utility studies were included. Most economic studies focused on riluzole (n = 9). Six studies modelled the progressive decline in motor function using a Markov design but did not include mutually exclusive health states. Cost estimates for a number of evaluations were based on expert opinion and were hampered by high variability and location-specific characteristics. Few cost studies reported disease-stage-specific costs (n = 3) or fully captured indirect costs. Utilities in three studies of MND patients used the EuroQol EQ-5D questionnaire or standard gamble, but included potentially unrepresentative cohorts and did not consider any health impacts on caregivers. Economic evaluations in MND suffer from significant methodological issues such as a lack of data, uncertainty with the disease course and use of inappropriate modelling framework. Limitations may be addressed through the collection of detailed and representative data from large cohorts of patients.

  15. Suppression of proprioceptor--motor neuron interactions by proprioceptors in crayfish claw.

    PubMed

    Lindsey, B G

    1982-11-04

    Crayfish claw proprioceptors and slow closer exciter and opener inhibitor motor neurons were monitored simultaneously during imposed claw displacements. With increasing displacement velocity and decreasing joint angle, the activity of closing sensitive receptors increased, while dynamic-static opening sensitive receptor activity decreased during claw closing. Motor neuron activity evoked by claw opening varied inversely as a function of preceding closing velocity, and directly with preceding pause duration at the closed position. This dependence on closing history cannot be accounted for by changes in opening sensitive receptor activity. Data demonstrate that closing sensitive receptors can suppress excitatory interactions between claw proprioceptors and motor neurons.

  16. Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase.

    PubMed

    Estévez, A G; Crow, J P; Sampson, J B; Reiter, C; Zhuang, Y; Richardson, G J; Tarpey, M M; Barbeito, L; Beckman, J S

    1999-12-24

    Mutations in copper, zinc superoxide dismutase (SOD) have been implicated in the selective death of motor neurons in 2 percent of amyotrophic lateral sclerosis (ALS) patients. The loss of zinc from either wild-type or ALS-mutant SODs was sufficient to induce apoptosis in cultured motor neurons. Toxicity required that copper be bound to SOD and depended on endogenous production of nitric oxide. When replete with zinc, neither ALS-mutant nor wild-type copper, zinc SODs were toxic, and both protected motor neurons from trophic factor withdrawal. Thus, zinc-deficient SOD may participate in both sporadic and familial ALS by an oxidative mechanism involving nitric oxide.

  17. Edited GluR2, a gatekeeper for motor neurone survival?

    PubMed

    Buckingham, S D; Kwak, S; Jones, A K; Blackshaw, S E; Sattelle, D B

    2008-11-01

    Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of motor neurones. Although the genetic basis of familial forms of ALS has been well explored, the molecular basis of sporadic ALS is less well understood. Recent evidence has linked sporadic ALS with the failure to edit key residues in ionotropic glutamate receptors, resulting in excessive influx of calcium ions into motor neurones which in turn triggers cell death. Here we suggest that edited AMPA glutamate (GluR2) receptor subunits serve as gatekeepers for motor neurone survival.

  18. Non-motor function of the midbrain dopaminergic neurons.

    PubMed

    Da Cunha, Claudio; Wietzikoski, Evellyn Claudia; Bortolanza, Mariza; Dombrowski, Patricia Andréia; dos Santos, Lucélia Mendes; Boschen, Suelen Lúcio; Miyoshi, Edmar; Vital, Maria Aparecida Barbato Frazão; Boerngen-Lacerda, Roseli; Andreatini, Roberto

    2009-01-01

    The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subject's world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinson's disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinson's disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinson's disease patients.

  19. Slow saccades in bulbar-onset motor neurone disease.

    PubMed

    Donaghy, Colette; Pinnock, Ralph; Abrahams, Sharon; Cardwell, Chris; Hardiman, Orla; Patterson, Victor; McGivern, R Canice; Gibson, J Mark

    2010-07-01

    Historical studies of eye movements in motor neurone disease (MND) have been conflicting although current findings suggest that eye movement abnormalities relate to frontal lobe impairment. Numerous case reports, however, describe slow saccades and supranuclear gaze palsies in patients with MND often associated with bulbar-onset disease. We performed a study of saccades and smooth pursuit in a large group of patients with MND to examine for any differences between bulbar-onset and spinal-onset patients. Forty-four patients (14 bulbar-onset and 30 spinal-onset patients) and 45 controls were recruited. Reflexive saccades, antisaccades and smooth pursuit were examined using infra-red oculography and all subjects then underwent neuropsychological evaluation. Reflexive saccades were found to be slower in bulbar-onset compared to spinal-onset patients and controls (p = 0.03, p = 0.05). Antisaccade latency (p = 0.01) and antisaccade type 1 errors (p = 0.03, p = 0.04) were increased in patients compared to controls. 'Proportion of time spent in smooth pursuit' and smooth pursuit 'velocity gain' were reduced in patients compared to controls (p = 0.000, p = 0.001). Antisaccade errors and velocity gain correlated with neuropsychological measures sensitive to lesions of the frontal lobes. This is the first study to highlight the presence of slow saccades in bulbar-onset MND. These findings suggest that slow saccades may be due to increased brainstem pathology in bulbar-onset disease that involves burst cell neurons. Furthermore these observations highlight the potential for overlap between bulbar-onset MND and progressive supranuclear palsy (PSP) as both can have a bulbar palsy and slowed saccades.

  20. Birth of projection neurons in adult avian brain may be related to perceptual or motor learning

    SciTech Connect

    Alvarez-Buylla, A.; Kirn, J.R.; Nottebohm, F. )

    1990-09-21

    Projection neurons that form part of the motor pathway for song control continue to be produced and to replace older projection neurons in adult canaries and zebra finches. This is shown by combining (3H)thymidine, a cell birth marker, and fluorogold, a retrogradely transported tracer of neuronal connectivity. Species and seasonal comparisons suggest that this process is related to the acquisition of perceptual or motor memories. The ability of an adult brain to produce and replace projection neurons should influence our thinking on brain repair.

  1. Deficiency of the Survival of Motor Neuron Protein Impairs mRNA Localization and Local Translation in the Growth Cone of Motor Neurons.

    PubMed

    Fallini, Claudia; Donlin-Asp, Paul G; Rouanet, Jeremy P; Bassell, Gary J; Rossoll, Wilfried

    2016-03-30

    Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily affecting spinal motor neurons. It is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays an essential role in the biogenesis of spliceosomal small nuclear ribonucleoproteins in all tissues. The etiology of the specific defects in the motor circuitry in SMA is still unclear, but SMN has also been implicated in mediating the axonal localization of mRNA-protein complexes, which may contribute to the axonal degeneration observed in SMA. Here, we report that SMN deficiency severely disrupts local protein synthesis within neuronal growth cones. We also identify the cytoskeleton-associated growth-associated protein 43 (GAP43) mRNA as a new target of SMN and show that motor neurons from SMA mouse models have reduced levels ofGAP43mRNA and protein in axons and growth cones. Importantly, overexpression of two mRNA-binding proteins, HuD and IMP1, restoresGAP43mRNA and protein levels in growth cones and rescues axon outgrowth defects in SMA neurons. These findings demonstrate that SMN plays an important role in the localization and local translation of mRNAs with important axonal functions and suggest that disruption of this function may contribute to the axonal defects observed in SMA. The motor neuron disease spinal muscular atrophy (SMA) is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays a key role in assembling RNA/protein complexes that are essential for mRNA splicing. It remains unclear whether defects in this well characterized housekeeping function cause the specific degeneration of spinal motor neurons observed in SMA. Here, we describe an additional role of SMN in regulating the axonal localization and local translation of the mRNA encoding growth-associated protein 43 (GAP43). This study supports a model whereby SMN deficiency impedes transport and local translation of mRNAs important for neurite outgrowth and stabilization

  2. Deficiency of the Survival of Motor Neuron Protein Impairs mRNA Localization and Local Translation in the Growth Cone of Motor Neurons

    PubMed Central

    Fallini, Claudia; Donlin-Asp, Paul G.; Rouanet, Jeremy P.

    2016-01-01

    Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily affecting spinal motor neurons. It is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays an essential role in the biogenesis of spliceosomal small nuclear ribonucleoproteins in all tissues. The etiology of the specific defects in the motor circuitry in SMA is still unclear, but SMN has also been implicated in mediating the axonal localization of mRNA-protein complexes, which may contribute to the axonal degeneration observed in SMA. Here, we report that SMN deficiency severely disrupts local protein synthesis within neuronal growth cones. We also identify the cytoskeleton-associated growth-associated protein 43 (GAP43) mRNA as a new target of SMN and show that motor neurons from SMA mouse models have reduced levels of GAP43 mRNA and protein in axons and growth cones. Importantly, overexpression of two mRNA-binding proteins, HuD and IMP1, restores GAP43 mRNA and protein levels in growth cones and rescues axon outgrowth defects in SMA neurons. These findings demonstrate that SMN plays an important role in the localization and local translation of mRNAs with important axonal functions and suggest that disruption of this function may contribute to the axonal defects observed in SMA. SIGNIFICANCE STATEMENT The motor neuron disease spinal muscular atrophy (SMA) is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays a key role in assembling RNA/protein complexes that are essential for mRNA splicing. It remains unclear whether defects in this well characterized housekeeping function cause the specific degeneration of spinal motor neurons observed in SMA. Here, we describe an additional role of SMN in regulating the axonal localization and local translation of the mRNA encoding growth-associated protein 43 (GAP43). This study supports a model whereby SMN deficiency impedes transport and local translation of mRNAs important for neurite

  3. Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control

    PubMed Central

    Kuo, Sheng-Han; Tai, Chun-Hwei; Liou, Jyun-You; Pei, Ju-Chun; Chang, Chia-Yuan; Wang, Yi-Mei; Liu, Wen-Chuan; Wang, Tien-Rei

    2016-01-01

    Neuronal oscillations at beta frequencies (20–50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson’s disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy. PMID:27797341

  4. Integrated health care for patients with motor neurone disease.

    PubMed

    Brewah, Helen

    This article presents the findings from a study trip to Kaiser Permanente (KP), a private healthcare provider in the USA. The aim of the trip was to understand how healthcare integration is managed in KP and how this might help patients in the UK with motor neurone disease (MND). This article makes reference to the American and British healthcare systems, identifying the simple differences between health economies, and their impact on health care, with specific reference to MND. The trip was undertaken as part of the author's ongoing work on how patients with MND rate services delivered by the multidisciplinary team (MDT) in the UK. The author's community matron role involves caring for patients with long-term conditions (LTCs) including long-term neurological conditions (LTNCs). In executing this role and in service delivery to patients with LTNCs, specifically MND, the author noticed a lack of robust integration, highlighting the need to consider and address the various contributory factors. This article presents a literature review and analyses the role of the MDT including specialist neurological professionals in executing duties and in delivering healthcare services to patients diagnosed with MND. The implications for practice are also presented along with areas for practice development.

  5. Inferring thought and action in motor neurone disease.

    PubMed

    Gibbons, Z C; Snowden, J S; Thompson, J C; Happé, F; Richardson, A; Neary, D

    2007-03-25

    The traditional assumption that classical motor neurone disease (MND) invariably spares cognitive function is now recognised to be incorrect. Deficits have most commonly been demonstrated on executive tasks suggesting impaired function of frontal systems. Yet, crucial aspects of frontal lobe function have not hitherto been explored. The study used tests of theory of mind (ToM) (interpretation of cartoons and stories) to examine the ability of 16 patients with MND to interpret social situations and ascribe mental states to others. Only minor differences were elicited in the MND group as a whole compared to controls, and performance was not differentially affected for cartoons and stories requiring inference of another's mental state (mental) compared to control (physical) cartoons and stories. However, abnormalities were elicited on both mental and physical tasks in a subgroup of patients with bulbar signs. Moreover, examination of individual patient scores revealed a spectrum of performance ranging from normal to severely impaired. Errors were qualitatively similar to those seen in frontotemporal dementia (FTD). Performance on the ToM tasks was significantly correlated with conventional, untimed measures of executive function, suggesting that ToM deficits in MND are likely to be linked to a more general executive failure. The findings contribute to the understanding of ToM performance in neurodegenerative disease and provide further evidence of the association between MND and FTD.

  6. Genetic overlap between apparently sporadic motor neuron diseases.

    PubMed

    van Blitterswijk, Marka; Vlam, Lotte; van Es, Michael A; van der Pol, W-Ludo; Hennekam, Eric A M; Dooijes, Dennis; Schelhaas, Helenius J; van der Kooi, Anneke J; de Visser, Marianne; Veldink, Jan H; van den Berg, Leonard H

    2012-01-01

    Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS.

  7. Genetic Overlap between Apparently Sporadic Motor Neuron Diseases

    PubMed Central

    van Blitterswijk, Marka; Vlam, Lotte; van Es, Michael A.; van der Pol, W-Ludo; Hennekam, Eric A. M.; Dooijes, Dennis; Schelhaas, Helenius J.; van der Kooi, Anneke J.; de Visser, Marianne

    2012-01-01

    Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS. PMID:23155438

  8. RPM-1 is localized to distinct subcellular compartments and regulates axon length in GABAergic motor neurons.

    PubMed

    Opperman, Karla J; Grill, Brock

    2014-05-10

    The PAM/Highwire/RPM-1 (PHR) proteins are conserved signaling proteins that regulate axon length and synapse formation during development. Loss of function in Caenorhabditis elegans rpm-1 results in axon termination and synapse formation defects in the mechanosensory neurons. An explanation for why these two phenotypes are observed in a single neuronal cell has remained absent. Further, it is uncertain whether the axon termination phenotypes observed in the mechanosensory neurons of rpm-1 mutants are unique to this specific type of neuron, or more widespread defects that occur with loss of function in rpm-1. Here, we show that RPM-1 is localized to both the mature axon tip and the presynaptic terminals of individual motor neurons and individual mechanosensory neurons. Genetic analysis indicated that GABAergic motor neurons, like the mechanosensory neurons, have both synapse formation and axon termination defects in rpm-1 mutants. RPM-1 functions in parallel with the active zone component SYD-2 (Liprin) to regulate not only synapse formation, but also axon termination in motor neurons. Our analysis of rpm-1-/-; syd-2-/- double mutants also revealed a role for RPM-1 in axon extension. The MAP3K DLK-1 partly mediated RPM-1 function in both axon termination and axon extension, and the relative role of DLK-1 was dictated by the anatomical location of the neuron in question. Our findings show that axon termination defects are a core phenotype caused by loss of function in rpm-1, and not unique to the mechanosensory neurons. We show in motor neurons and in mechanosensory neurons that RPM-1 is localized to multiple, distinct subcellular compartments in a single cell. Thus, RPM-1 might be differentially regulated or RPM-1 might differentially control signals in distinct subcellular compartments to regulate multiple developmental outcomes in a single neuron. Our findings provide further support for the previously proposed model that PHR proteins function to coordinate axon

  9. Joining forces: Motor control meets mirror neurons. Comment on "Grasping synergies: A motor-control approach to the mirror neuron mechanism" by D'Ausilio, Bartoli, and Maffongelli

    NASA Astrophysics Data System (ADS)

    Casile, Antonino

    2015-03-01

    Several consistent and compelling experimental findings suggest that in primates the observation of actions or movements activates the observer's motor cortex (for a recent and very thorough review see [1]). One important piece of evidence was the discovery of mirror neurons, that are neurons in the macaque ventral pre-motor (area F5), motor and parietal cortices (area PFG) that respond both when the monkey executes a goal-directed motor act (e.g. breaking a peanut) or when it sees a similar action executed by others [2-5]. A similar system has been later reported also in humans ([6-8] but see also [9,10] for negative results).

  10. Mst-1 deficiency promotes post-traumatic spinal motor neuron survival via enhancement of autophagy flux.

    PubMed

    Zhang, Mengting; Tao, Wufan; Yuan, Zengqiang; Liu, Yaobo

    2017-08-21

    The mammalian Ste20-like kinase 1 (Mst-1) is a serine-threonine kinase and a component of the Hippo tumor suppressor pathway, which reacts to pathologically relevant stress and regulates cell death. However, little is known about its role in spinal cord injury (SCI). Here, we found that p-Mst-1, the activated form of Mst-1, was induced in the post-traumatic spinal motor neurons. In vivo evidence demonstrated that Mst-1 deficiency promoted post-traumatic spinal motor neuron survival, BMS scores, and synapse survival. Moreover, we found autophagosome formation and autolysosome degradation enhanced by Mst-1 deficiency were crucial to attenuate the death of injured spinal motor neurons. Taken together, our findings demonstrate that Mst-1 deficiency promotes post-traumatic spinal motor neuron survival via enhancement of autophagy flux. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  11. Dopamine from the brain promotes spinal motor neuron generation during development and adult regeneration.

    PubMed

    Reimer, Michell M; Norris, Anneliese; Ohnmacht, Jochen; Patani, Rickie; Zhong, Zhen; Dias, Tatyana B; Kuscha, Veronika; Scott, Angela L; Chen, Yu-Chia; Rozov, Stanislav; Frazer, Sarah L; Wyatt, Cameron; Higashijima, Shin-ichi; Patton, E Elizabeth; Panula, Pertti; Chandran, Siddharthan; Becker, Thomas; Becker, Catherina G

    2013-06-10

    Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway. Inhibiting this essential signal during early neurogenesis leads to a long-lasting reduction of motor neuron numbers and impaired motor responses of free-swimming larvae. Importantly, during successful spinal cord regeneration in adult zebrafish, endogenous dopamine promotes generation of spinal motor neurons, and dopamine agonists augment this process. Hence, we describe a supraspinal control mechanism for the development and regeneration of specific spinal cell types that uses dopamine as a signal.

  12. Respiratory management of motor neurone disease: a review of current practice and new developments.

    PubMed

    Rafiq, Muhammad Khizar; Proctor, Alison Ruth; McDermott, Christopher J; Shaw, Pamela J

    2012-06-01

    Motor neurone disease is a neurodegenerative condition with a significant morbidity and shortened life expectancy. Hypoventilatory respiratory failure is the most common cause of death and respiratory function significantly predicts both survival and quality of life in patients with motor neurone disease. Accordingly, supporting and maintaining respiratory function is important in caring for these patients. The most significant advance in motor neurone disease care of recent years has been the domiciliary provision of non-invasive ventilation for treating respiratory failure. Neuromuscular respiratory weakness also leads to ineffective cough and retained airways secretions, predisposing to recurrent chest infections. In this review, we discuss current practice and recent developments in the respiratory management of motor neurone disease, in terms of ventilatory support and cough augmentation.

  13. MotomiRs: miRNAs in Motor Neuron Function and Disease

    PubMed Central

    Hawley, Zachary C. E.; Campos-Melo, Danae; Droppelmann, Cristian A.; Strong, Michael J.

    2017-01-01

    MiRNAs are key regulators of the mammalian transcriptome that have been increasingly linked to degenerative diseases of the motor neurons. Although many of the miRNAs currently incriminated as participants in the pathogenesis of these diseases are also important to the normal development and function of motor neurons, at present there is no knowledge of the complete miRNA profile of motor neurons. In this review, we examine the current understanding with respect to miRNAs that are specifically required for motor neuron development, function and viability, and provide evidence that these should be considered as a functional network of miRNAs which we have collectively termed MotomiRs. We will also summarize those MotomiRs currently known to be associated with both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), and discuss their potential use as biomarkers. PMID:28522960

  14. MotomiRs: miRNAs in Motor Neuron Function and Disease.

    PubMed

    Hawley, Zachary C E; Campos-Melo, Danae; Droppelmann, Cristian A; Strong, Michael J

    2017-01-01

    MiRNAs are key regulators of the mammalian transcriptome that have been increasingly linked to degenerative diseases of the motor neurons. Although many of the miRNAs currently incriminated as participants in the pathogenesis of these diseases are also important to the normal development and function of motor neurons, at present there is no knowledge of the complete miRNA profile of motor neurons. In this review, we examine the current understanding with respect to miRNAs that are specifically required for motor neuron development, function and viability, and provide evidence that these should be considered as a functional network of miRNAs which we have collectively termed MotomiRs. We will also summarize those MotomiRs currently known to be associated with both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), and discuss their potential use as biomarkers.

  15. Induction of motor neuron differentiation by transduction of Olig2 protein.

    PubMed

    Mie, Masayasu; Kaneko, Mami; Henmi, Fumiaki; Kobatake, Eiry

    2012-10-26

    Olig2 protein, a member of the basic helix-loop-helix transcription factor family, was introduced into the mouse embryonic carcinoma cell line P19 for induction of motor neuron differentiation. We show that Olig2 protein has the ability to permeate the cell membrane without the addition of a protein transduction domain (PTD), similar to other basic helix-loop-helix transcription factors such as MyoD and NeuroD2. Motor neuron differentiation was evaluated for the elongation of neurites and the expression of choline acetyltransferase (ChAT) mRNA, a differentiation marker of motor neurons. By addition of Olig2 protein, motor neuron differentiation was induced in P19 cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Subcortical neuronal ensembles: an analysis of motor task association, tremor, oscillations, and synchrony in human patients.

    PubMed

    Hanson, Timothy L; Fuller, Andrew M; Lebedev, Mikhail A; Turner, Dennis A; Nicolelis, Miguel A L

    2012-06-20

    Deep brain stimulation (DBS) has expanded as an effective treatment for motor disorders, providing a valuable opportunity for intraoperative recording of the spiking activity of subcortical neurons. The properties of these neurons and their potential utility in neuroprosthetic applications are not completely understood. During DBS surgeries in 25 human patients with either essential tremor or Parkinson's disease, we acutely recorded the single-unit activity of 274 ventral intermediate/ventral oralis posterior motor thalamus (Vim/Vop) neurons and 123 subthalamic nucleus (STN) neurons. These subcortical neuronal ensembles (up to 23 neurons sampled simultaneously) were recorded while the patients performed a target-tracking motor task using a cursor controlled by a haptic glove. We observed that modulations in firing rate of a substantial number of neurons in both Vim/Vop and STN represented target onset, movement onset/direction, and hand tremor. Neurons in both areas exhibited rhythmic oscillations and pairwise synchrony. Notably, all tremor-associated neurons exhibited synchrony within the ensemble. The data further indicate that oscillatory (likely pathological) neurons and behaviorally tuned neurons are not distinct but rather form overlapping sets. Whereas previous studies have reported a linear relationship between power spectra of neuronal oscillations and hand tremor, we report a nonlinear relationship suggestive of complex encoding schemes. Even in the presence of this pathological activity, linear models were able to extract motor parameters from ensemble discharges. Based on these findings, we propose that chronic multielectrode recordings from Vim/Vop and STN could prove useful for further studying, monitoring, and even treating motor disorders.

  17. Direct lineage reprogramming reveals disease-specific phonotypes of motor neurons from human ALS patients

    PubMed Central

    Liu, Meng-Lu; Zang, Tong; Zhang, Chun-Li

    2015-01-01

    SUMMARY Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS-patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS-hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification. PMID:26725112

  18. Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients.

    PubMed

    Liu, Meng-Lu; Zang, Tong; Zhang, Chun-Li

    2016-01-05

    Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification.

  19. Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death.

    PubMed

    Nichols, Nicole L; Craig, Taylor A; Tanner, Miles A

    2017-08-16

    Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and death by ventilatory failure. In a rat model of ALS (SOD1(G93A)), phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is enhanced greater than expected at disease end-stage but the mechanism is unknown. We suggest that one trigger for this enhancement is motor neuron death itself. Intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) selectively kill respiratory motor neurons and mimic motor neuron death observed in SOD1(G93A) rats. This CTB-SAP model allows us to study the impact of respiratory motor neuron death on breathing without many complications attendant to ALS. Here, we tested the hypothesis that phrenic motor neuron death is sufficient to enhance pLTF. pLTF was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 7 and 28days following bilateral intrapleural injections of: 1) CTB-SAP (25μg), or 2) un-conjugated CTB and SAP (control). CTB-SAP enhanced pLTF at 7 (CTB-SAP: 162±18%, n=8 vs. 63±3%; n=8; p<0.05), but not 28days post-injection (CTB-SAP: 64±10%, n=10 vs. 60±13; n=8; p>0.05). Thus, pLTF at 7 (not 28) days post-CTB-SAP closely resembles pLTF in end-stage ALS rats, suggesting that processes unique to the early period of motor neuron death enhance pLTF. This project increases our understanding of respiratory plasticity and its implications for breathing in motor neuron disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration.

    PubMed

    Sopher, Bryce L; Thomas, Patrick S; LaFevre-Bernt, Michelle A; Holm, Ida E; Wilke, Scott A; Ware, Carol B; Jin, Lee-Way; Libby, Randell T; Ellerby, Lisa M; La Spada, Albert R

    2004-03-04

    X-linked spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration. SBMA is caused by polyglutamine repeat expansions in the androgen receptor (AR). To determine the basis of AR polyglutamine neurotoxicity, we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells. The AR100 transgenic mice developed a late-onset, gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration, indicating striking recapitulation of the human disease. We then tested the hypothesis that polyglutamine-expanded AR interferes with CREB binding protein (CBP)-mediated transcription of vascular endothelial growth factor (VEGF) and observed altered CBP-AR binding and VEGF reduction in AR100 mice. We found that mutant AR-induced death of motor neuron-like cells could be rescued by VEGF. Our results suggest that SBMA motor neuronopathy involves altered expression of VEGF, consistent with a role for VEGF as a neurotrophic/survival factor in motor neuron disease.

  1. Patterns of Weakness, Classification of Motor Neuron Disease & Clinical Diagnosis of Sporadic ALS

    PubMed Central

    Statland, Jeffrey M.; Barohn, Richard J.; McVey, April L.; Katz, Jonathan; Dimachkie, Mazen M.

    2015-01-01

    Synopsis When approaching the patient with suspected motor neuron disease (MND) the pattern of weakness on exam helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing, in the absence of other abnormalities on neuroimaging or serological testing. MNDs exist on a spectrum: from a pure lower motor neuron; to mixed upper and lower motor neuron; to a pure upper motor neuron variant in addition to regional variants restricted to the arms, legs or bulbar region. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic (~85%), which is invariably fatal. The only FDA approved treatments for ALS are riluzole, which prolongs life by about 3 months, and dextromethorphan/quinidine which provides symptomatic relief for pseudobulbar affect (inappropriate bouts of laughter or crying). Here we describe a pattern approach to identifying motor neuron disease, and clinical features of sporadic ALS. PMID:26515618

  2. Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population

    PubMed Central

    Loci, Lorena; Mitsumoto, Hiroshi; Lomen-Hoerth, Catherine; Kisanuki, Yasushi; Simmons, Zachary; Maragakis, Nicholas J; McVey, April L; Al-Lahham, Tawfiq; Heiman-Patterson, Terry D; Andrews, Jinsy; McDonnell, Erin; Cudkowicz, Merit; Atassi, Nazem

    2015-01-01

    Objectives The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Methods Twenty northeast ALS consortium (NEALS) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia (HSP) or meeting revised El Escorial electrodiagnostic criteria for ALS were excluded. Patients were classified into two groups according to the presence or absence of minor electromyography (EMG) abnormalities. Results 233 subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the two groups. No difference was seen in clinical symptoms, disability, or outcome measures between the two groups after correcting for multiple comparisons. Conclusions Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the NEALS network and suggests feasibility for conducting clinical trials in this population. PMID:26905909

  3. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B; Corti, Stefania

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches.

  4. Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

    PubMed

    Fournier, Christina N; Murphy, Alyssa; Loci, Lorena; Mitsumoto, Hiroshi; Lomen-Hoerth, Catherine; Kisanuki, Yasushi; Simmons, Zachary; Maragakis, Nicholas J; McVey, April L; Al-Lahham, Tawfiq; Heiman-Patterson, Terry D; Andrews, Jinsy; McDonnell, Erin; Cudkowicz, Merit; Atassi, Nazem

    2016-03-01

    The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

  5. Is Spinal Muscular Atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed Central

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B.; Corti, Stefania

    2016-01-01

    Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development. PMID:26681261

  6. Different motor neuron spike patterns produce contractions with very similar rises in graded slow muscles.

    PubMed

    Hooper, Scott L; Guschlbauer, Christoph; von Uckermann, Géraldine; Büschges, Ansgar

    2007-02-01

    Graded muscles produce small twitches in response to individual motor neuron spikes. During the early part of their contractions, contraction amplitude in many such muscles depends primarily on the number of spikes the muscle has received, not the frequency or pattern with which they were delivered. Stick insect (Carausius morosus) extensor muscles are graded and thus would likely show spike-number dependency early in their contractions. Tonic stimulations of the extensor motor nerve showed that the response of the muscles differed from the simplest form of spike-number dependency. However, these differences actually increased the spike-number range over which spike-number dependency was present. When the motor nerve was stimulated with patterns mimicking the motor neuron activity present during walking, amplitude during contraction rises also depended much more on spike number than on spike frequency. A consequence of spike-number dependency is that brief changes in spike frequency do not alter contraction slope and we show here that extensor motor neuron bursts with different spike patterns give rise to contractions with very similar contraction rises. We also examined in detail the early portions of a large number of extensor motor neuron bursts recorded during single-leg walking and show that these portions of the bursts do not appear to have any common spike pattern. Although alternative explanations are possible, the simplest interpretation of these data is that extensor motor neuron firing during leg swing is not tightly controlled.

  7. Fezf2 expression in layer 5 projection neurons of mature mouse motor cortex.

    PubMed

    Tantirigama, Malinda L S; Oswald, Manfred J; Clare, Alison J; Wicky, Hollie E; Day, Robert C; Hughes, Stephanie M; Empson, Ruth M

    2016-03-01

    The mature cerebral cortex contains a wide diversity of neuron phenotypes. This diversity is specified during development by neuron-specific expression of key transcription factors, some of which are retained for the life of the animal. One of these key developmental transcription factors that is also retained in the adult is Fezf2, but the neuron types expressing it in the mature cortex are unknown. With a validated Fezf2-Gfp reporter mouse, whole-cell electrophysiology with morphology reconstruction, cluster analysis, in vivo retrograde labeling, and immunohistochemistry, we identify a heterogeneous population of Fezf2(+) neurons in both layer 5A and layer 5B of the mature motor cortex. Functional electrophysiology identified two distinct subtypes of Fezf2(+) neurons that resembled pyramidal tract projection neurons (PT-PNs) and intratelencephalic projection neurons (IT-PNs). Retrograde labeling confirmed the former type to include corticospinal projection neurons (CSpPNs) and corticothalamic projection neurons (CThPNs), whereas the latter type included crossed corticostriatal projection neurons (cCStrPNs) and crossed-corticocortical projection neurons (cCCPNs). The two Fezf2(+) subtypes expressed either CTIP2 or SATB2 to distinguish their physiological identity and confirmed that specific expression combinations of key transcription factors persist in the mature motor cortex. Our findings indicate a wider role for Fezf2 within gene expression networks that underpin the diversity of layer 5 cortical projection neurons. © 2015 Wiley Periodicals, Inc.

  8. Radiological evidence of subclinical dysphagia in motor neuron disease.

    PubMed

    Briani, C; Marcon, M; Ermani, M; Costantini, M; Bottin, R; Iurilli, V; Zaninotto, G; Primon, D; Feltrin, G; Angelini, C

    1998-04-01

    Dysphagia in motor neuron disease (MND) may lead to dangerous complications such as cachexia and aspiration pneumonia. Functional evaluation of the oropharyngeal tract is crucial for identifying specific swallowing dysfunctions and planning appropriate rehabilitation. As part of a multidisciplinary study on the treatment of dysphagia in patients with neuromuscular diseases, 23 MND patients with different degrees of dysphagia underwent videofluoroscopy, videopharyngolaryngoscopy and pharyngo-oesophageal manometry. The results of the three instrumental investigations were analysed in order (1) to define the pattern of swallowing in MND patients complaining of dysphagia; (2) to evaluate whether subclinical abnormalities may be detected; and (3) to assess the role of videofluoroscopy, videopharyngolaryngoscopy and manometry in the evaluation of MND patients with deglutition problems. Correlations between the instrumental findings and clinical features (age of the patients, duration and severity of the disease, presence and degree of dysphagia) were also assessed. The results of our study showed that: (1) The oral phase of deglutition was compromised most often, followed by the pharyngeal phase. (2) In all patients without clinical evidence of dysphagia, subclinical videofluoroscopic alterations were present in a pattern similar to that found in the dysphagic group. (3) Videofluoroscopy was the most sensitive technique in identifying oropharyngeal alterations of swallowing. Impairment of the oral phase, abnormal pharyngo-oesophageal motility and incomplete relaxation of the upper oesophageal sphincter were the changes most sensitive in detecting dysphagia. Videofluoroscopy was also capable of detecting preclinical abnormalities in non-dysphagic patients who later developed dysphagia. Practical guidelines for the use of instrumental investigations in the assessment and management of dysphagia in MND patients are proposed.

  9. TDP-43 Toxicity Proceeds via Calcium Dysregulation and Necrosis in Aging Caenorhabditis elegans Motor Neurons

    PubMed Central

    Aggad, Dina; Vérièpe, Julie; Tauffenberger, Arnaud

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with either sporadic or genetic origins characterized by the progressive degeneration of motor neurons. At the cellular level, ALS neurons show protein misfolding and aggregation phenotypes. Transactive response DNA-binding protein 43 (TDP-43) has recently been shown to be associated with ALS, but the early pathophysiological deficits causing impairment in motor function are unknown. Here we used Caenorhabditis elegans expressing mutant TDP-43A315T in motor neurons and explored the potential influences of calcium (Ca2+). Using chemical and genetic approaches to manipulate the release of endoplasmic reticulum (ER) Ca2+stores, we observed that the reduction of intracellular Ca2+ ([Ca2+]i) rescued age-dependent paralysis and prevented the neurodegeneration of GABAergic motor neurons. Our data implicate elevated [Ca2+]i as a driver of TDP-43-mediated neuronal toxicity. Furthermore, we discovered that neuronal degeneration is independent of the executioner caspase CED-3, but instead requires the activity of the Ca2+-regulated calpain protease TRA-3, and the aspartyl protease ASP-4. Finally, chemically blocking protease activity protected against mutant TDP-43A315T-associated neuronal toxicity. This work both underscores the potential of the C. elegans system to identify key targets for therapeutic intervention and suggests that a focused effort to regulate ER Ca2+ release and necrosis-like degeneration consequent to neuronal injury may be of clinical importance. PMID:25186754

  10. LGR5/GPR49 is implicated in motor neuron specification in nervous system.

    PubMed

    Song, Shao-jun; Mao, Xing-gang; Wang, Chao; Han, An-guo; Yan, Ming; Xue, Xiao-yan

    2015-01-01

    The biological roles of stem cell marker LGR5, the receptor for the Wnt-agonistic R-spondins, for nervous system are poorly known. Bioinformatics analysis in normal human brain tissues revealed that LGR5 is closely related with neuron development and functions. Interestingly, LGR5 and its ligands R-spondins (RSPO2 and RSPO3) are specifically highly expressed in projection motor neurons in the spinal cord, brain stem and cerebral. Inhibition of Notch activity in neural stem cells (NSCs) increased the percentage of neuronal cells and promoted LGR5 expression, while activation of Notch signal decreased neuronal cells and inhibited the LGR5 expression. Furthermore, knockdown of LGR5 inhibited the expression of neuronal markers MAP2, NeuN, GAP43, SYP and CHRM3, and also reduced the expression of genes that program the identity of motor neurons, including Isl1, Lhx3, PHOX2A, TBX20 and NEUROG2. Our data demonstrated that LGR5 is highly expressed in motor neurons in nervous system and is involved in their development by regulating transcription factors that program motor neuron identity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Orientation-dependent changes in single motor neuron activity during adaptive soft-bodied locomotion.

    PubMed

    Metallo, Cinzia; Trimmer, Barry A

    2015-01-01

    Recent major advances in understanding the organizational principles underlying motor control have focused on a small number of animal species with stiff articulated skeletons. These model systems have the advantage of easily quantifiable mechanics, but the neural codes underlying different movements are difficult to characterize because they typically involve a large population of neurons controlling each muscle. As a result, studying how neural codes drive adaptive changes in behavior is extremely challenging. This problem is highly simplified in the tobacco hawkmoth Manduca sexta, which, in its larval stage (caterpillar), is predominantly soft-bodied. Since each M. sexta muscle is innervated by one, occasionally two, excitatory motor neurons, the electrical activity generated by each muscle can be mapped to individual motor neurons. In the present study, muscle activation patterns were converted into motor neuron frequency patterns by identifying single excitatory junction potentials within recorded electromyographic traces. This conversion was carried out with single motor neuron resolution thanks to the high signal selectivity of newly developed flexible microelectrode arrays, which were specifically designed to record from M. sexta muscles. It was discovered that the timing of motor neuron activity and gait kinematics depend on the orientation of the plane of motion during locomotion. We report that, during climbing, the motor neurons monitored in the present study shift their activity to correlate with movements in the animal's more anterior segments. This orientation-dependent shift in motor activity is in agreement with the expected shift in the propulsive forces required for climbing. Our results suggest that, contrary to what has been previously hypothesized, M.sexta uses central command timing for adaptive load compensation.

  12. Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.

    PubMed

    Bernard-Marissal, Nathalie; Médard, Jean-Jacques; Azzedine, Hamid; Chrast, Roman

    2015-04-01

    Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.

  13. Motor neuron cell bodies are actively positioned by Slit/Robo repulsion and Netrin/DCC attraction.

    PubMed

    Kim, Minkyung; Fontelonga, Tatiana; Roesener, Andrew P; Lee, Haeram; Gurung, Suman; Mendonca, Philipe R F; Mastick, Grant S

    2015-03-01

    Motor neurons differentiate from a ventral column of progenitors and settle in static clusters, the motor nuclei, next to the floor plate. Within these cell clusters, motor neurons receive afferent input and project their axons out to muscle targets. The molecular mechanisms that position motor neurons in the neural tube remain poorly understood. The floor plate produces several types of guidance cues with well-known roles in attracting and repelling axons, including the Slit family of chemorepellents via their Robo receptors, and Netrin1 via its DCC attractive receptor. In the present study we found that Islet1(+) motor neuron cell bodies invaded the floor plate of Robo1/2 double mutant mouse embryos or Slit1/2/3 triple mutants. Misplaced neurons were born in their normal progenitor column, but then migrated tangentially into the ventral midline. Robo1 and 2 receptor expression in motor neurons was confirmed by reporter gene staining and anti-Robo antibody labeling. Mis-positioned motor neurons projected their axons longitudinally within the floor plate, and failed to reach their normal exit points. To test for potential counteracting ventral attractive signals, we examined Netrin-1 and DCC mutants, and found that motor neurons shifted dorsally in the hindbrain and spinal cord, suggesting that Netrin-1/DCC signaling normally attracts motor neurons closer to the floor plate. Our results show that motor neurons are actively migrating cells, and are normally trapped in a static position by Slit/Robo repulsion and Netrin-1/DCC attraction.

  14. Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease.

    PubMed

    Jaiswal, Manoj Kumar

    2017-05-01

    Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3-5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro "disease in dish" and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

  15. Diversification of C. elegans Motor Neuron Identity via Selective Effector Gene Repression.

    PubMed

    Kerk, Sze Yen; Kratsios, Paschalis; Hart, Michael; Mourao, Romulo; Hobert, Oliver

    2017-01-04

    A common organizational feature of nervous systems is the existence of groups of neurons that share common traits but can be divided into individual subtypes based on anatomical or molecular features. We elucidate the mechanistic basis of neuronal diversification processes in the context of C.elegans ventral cord motor neurons that share common traits that are directly activated by the terminal selector UNC-3. Diversification of motor neurons into different classes, each characterized by unique patterns of effector gene expression, is controlled by distinct combinations of phylogenetically conserved, class-specific transcriptional repressors. These repressors are continuously required in postmitotic neurons to prevent UNC-3, which is active in all neuron classes, from activating class-specific effector genes in specific motor neuron subsets via discrete cis-regulatory elements. The strategy of antagonizing the activity of broadly acting terminal selectors of neuron identity in a subtype-specific fashion may constitute a general principle of neuron subtype diversification.

  16. ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neurons

    PubMed Central

    Kim, Kyung-Tai; Kim, Namhee; Kim, Hwan-Ki; Lee, Hojae; Gruner, Hannah N.; Gergics, Peter; Park, Chungoo; Mastick, Grant S.; Park, Hae-Chul; Song, Mi-Ryoung

    2016-01-01

    LIM-homeodomain (HD) transcription factors form a multimeric complex and assign neuronal subtype identities, as demonstrated by the hexameric ISL1-LHX3 complex which gives rise to somatic motor (SM) neurons. However, the roles of combinatorial LIM code in motor neuron diversification and their subsequent differentiation is much less well understood. In the present study, we demonstrate that the ISL1 controls postmitotic cranial branchiomotor (BM) neurons including the positioning of the cell bodies and peripheral axon pathfinding. Unlike SM neurons, which transform into interneurons, BM neurons are normal in number and in marker expression in Isl1 mutant mice. Nevertheless, the movement of trigeminal and facial BM somata is stalled, and their peripheral axons are fewer or misrouted, with ectopic branches. Among genes whose expression level changes in previous ChIP-seq and microarray analyses in Isl1-deficient cell lines, we found that Slit2 transcript was almost absent from BM neurons of Isl1 mutants. Both ISL1-LHX3 and ISL1-LHX4 bound to the Slit2 enhancer and drove endogenous Slit2 expression in SM and BM neurons. Our findings suggest that combinations of ISL1 and LHX factors establish cell-type specificity and functional diversity in terms of motor neuron identities and/or axon development. PMID:27819291

  17. Motor Neuron-specific Disruption of Proteasomes, but Not Autophagy, Replicates Amyotrophic Lateral Sclerosis*

    PubMed Central

    Tashiro, Yoshitaka; Urushitani, Makoto; Inoue, Haruhisa; Koike, Masato; Uchiyama, Yasuo; Komatsu, Masaaki; Tanaka, Keiji; Yamazaki, Maya; Abe, Manabu; Misawa, Hidemi; Sakimura, Kenji; Ito, Hidefumi; Takahashi, Ryosuke

    2012-01-01

    Evidence suggests that protein misfolding is crucially involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, controversy still exists regarding the involvement of proteasomes or autophagy in ALS due to previous conflicting results. Here, we show that impairment of the ubiquitin-proteasome system, but not the autophagy-lysosome system in motor neurons replicates ALS in mice. Conditional knock-out mice of the proteasome subunit Rpt3 in a motor neuron-specific manner (Rpt3-CKO) showed locomotor dysfunction accompanied by progressive motor neuron loss and gliosis. Moreover, diverse ALS-linked proteins, including TAR DNA-binding protein 43 kDa (TDP-43), fused in sarcoma (FUS), ubiquilin 2, and optineurin were mislocalized or accumulated in motor neurons, together with other typical ALS hallmarks such as basophilic inclusion bodies. On the other hand, motor neuron-specific knock-out of Atg7, a crucial component for the induction of autophagy (Atg7-CKO), only resulted in cytosolic accumulation of ubiquitin and p62, and no TDP-43 or FUS pathologies or motor dysfunction was observed. These results strongly suggest that proteasomes, but not autophagy, fundamentally govern the development of ALS in which TDP-43 and FUS proteinopathy may play a crucial role. Enhancement of proteasome activity may be a promising strategy for the treatment of ALS. PMID:23095749

  18. Motor neurons control blood vessel patterning in the developing spinal cord

    PubMed Central

    Himmels, Patricia; Paredes, Isidora; Adler, Heike; Karakatsani, Andromachi; Luck, Robert; Marti, Hugo H.; Ermakova, Olga; Rempel, Eugen; Stoeckli, Esther T.; Ruiz de Almodóvar, Carmen

    2017-01-01

    Formation of a precise vascular network within the central nervous system is of critical importance to assure delivery of oxygen and nutrients and for accurate functionality of neuronal networks. Vascularization of the spinal cord is a highly stereotypical process. However, the guidance cues controlling blood vessel patterning in this organ remain largely unknown. Here we describe a new neuro-vascular communication mechanism that controls vessel guidance in the developing spinal cord. We show that motor neuron columns remain avascular during a developmental time window, despite expressing high levels of the pro-angiogenic vascular endothelial growth factor (VEGF). We describe that motor neurons express the VEGF trapping receptor sFlt1 via a Neuropilin-1-dependent mechanism. Using a VEGF gain-of-function approach in mice and a motor neuron-specific sFlt1 loss-of-function approach in chicken, we show that motor neurons control blood vessel patterning by an autocrine mechanism that titrates motor neuron-derived VEGF via their own expression of sFlt1. PMID:28262664

  19. Specific Retrograde Transduction of Spinal Motor Neurons Using Lentiviral Vectors Targeted to Presynaptic NMJ Receptors

    PubMed Central

    Eleftheriadou, I; Trabalza, A; Ellison, SM; Gharun, K; Mazarakis, ND

    2014-01-01

    To understand how receptors are involved in neuronal trafficking and to be able to utilize them for specific targeting via the peripheral route would be of great benefit. Here, we describe the generation of novel lentiviral vectors with tropism to motor neurons that were made by coexpressing onto the lentiviral surface a fusogenic glycoprotein (mutated sindbis G) and an antibody against a cell-surface receptor (Thy1.1, p75NTR, or coxsackievirus and adenovirus receptor) on the presynaptic terminal of the neuromuscular junction. These vectors exhibit binding specificity and efficient transduction of receptor positive cell lines and primary motor neurons in vitro. Targeting of each of these receptors conferred to these vectors the capability of being transported retrogradely from the axonal tip, leading to transduction of motor neurons in vitro in compartmented microfluidic cultures. In vivo delivery of coxsackievirus and adenovirus receptor-targeted vectors in leg muscles of mice resulted in predicted patterns of motor neuron labeling in lumbar spinal cord. This opens up the clinical potential of these vectors for minimally invasive administration of central nervous system-targeted therapeutics in motor neuron diseases. PMID:24670531

  20. Systemic administration of antisense p75(NTR) oligodeoxynucleotides rescues axotomised spinal motor neurons.

    PubMed

    Lowry, K S; Murray, S S; Coulson, E J; Epa, R; Bartlett, P F; Barrett, G; Cheema, S S

    2001-04-01

    The 75 kD low-affinity neurotrophin receptor (p75(NTR)) is expressed in developing and axotomised spinal motor neurons. There is now convincing evidence that p75(NTR) can, under some circumstances, become cytotoxic and promote neuronal cell death. We report here that a single application of antisense p75(NTR) oligodeoxynucleotides to the proximal nerve stumps of neonatal rats significantly reduces the loss of axotomised motor neurons compared to controls treated with nonsense oligodeoxynucleotides or phosphate-buffered saline. Our investigations also show that daily systemic intraperitoneal injections of antisense p75(NTR) oligodeoxynucleotides for 14 days significantly reduce the loss of axotomised motor neurons compared to controls. Furthermore, we found that systemic delivery over a similar period continues to be effective following axotomy when intraperitoneal injections were 1) administered after a delay of 24 hr, 2) limited to the first 7 days, or 3) administered every third day. In addition, p75(NTR) protein levels were reduced in spinal motor neurons following treatment with antisense p75(NTR) oligodeoxynucleotides. There were also no obvious side effects associated with antisense p75(NTR) oligodeoxynucleotide treatments as determined by behavioural observations and postnatal weight gain. Our findings indicate that antisense-based strategies could be a novel approach for the prevention of motor neuron degeneration associated with injuries or disease.

  1. Gap Junction-Mediated Signaling from Motor Neurons Regulates Motor Generation in the Central Circuits of Larval Drosophila.

    PubMed

    Matsunaga, Teruyuki; Kohsaka, Hiroshi; Nose, Akinao

    2017-02-22

    In this study, we used the peristaltic crawling of Drosophila larvae as a model to study how motor patterns are regulated by central circuits. We built an experimental system that allows simultaneous application of optogenetics and calcium imaging to the isolated ventral nerve cord (VNC). We then investigated the effects of manipulating local activity of motor neurons (MNs) on fictive locomotion observed as waves of MN activity propagating along neuromeres. Optical inhibition of MNs with halorhodopsin3 in a middle segment (A4, A5, or A6), but not other segments, dramatically decreased the frequency of the motor waves. Conversely, local activation of MNs with channelrhodopsin2 in a posterior segment (A6 or A7) increased the frequency of the motor waves. Since peripheral nerves mediating sensory feedback were severed in the VNC preparation, these results indicate that MNs send signals to the central circuits to regulate motor pattern generation. Our results also indicate segmental specificity in the roles of MNs in motor control. The effects of the local MN activity manipulation were lost in shaking-B(2) (shakB(2) ) or ogre(2) , gap-junction mutations in Drosophila, or upon acute application of the gap junction blocker carbenoxolone, implicating electrical synapses in the signaling from MNs. Cell-type-specific RNAi suggested shakB and ogre function in MNs and interneurons, respectively, during the signaling. Our results not only reveal an unexpected role for MNs in motor pattern regulation, but also introduce a powerful experimental system that enables examination of the input-output relationship among the component neurons in this system.SIGNIFICANCE STATEMENT Motor neurons are generally considered passive players in motor pattern generation, simply relaying information from upstream interneuronal circuits to the target muscles. This study shows instead that MNs play active roles in the control of motor generation by conveying information via gap junctions to the

  2. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.

    PubMed

    Sharma, Aarti; Lyashchenko, Alexander K; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z; Shneider, Neil A

    2016-02-04

    Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.

  3. Thalamocortical Projections onto Behaviorally Relevant Neurons Exhibit Plasticity during Adult Motor Learning.

    PubMed

    Biane, Jeremy S; Takashima, Yoshio; Scanziani, Massimo; Conner, James M; Tuszynski, Mark H

    2016-03-16

    Layer 5 neurons of the neocortex receive direct and relatively strong input from the thalamus. However, the intralaminar distribution of these inputs and their capacity for plasticity in adult animals are largely unknown. In slices of the primary motor cortex (M1), we simultaneously recorded from pairs of corticospinal neurons associated with control of distinct motor outputs: distal forelimb versus proximal forelimb. Activation of ChR2-expressing thalamocortical afferents in M1 before motor learning produced equivalent responses in monosynaptic excitation of neurons controlling the distal and proximal forelimb, suggesting balanced thalamic input at baseline. Following skilled grasp training, however, thalamocortical input shifted to bias activation of corticospinal neurons associated with control of the distal forelimb. This increase was associated with a cell-specific increase in mEPSC amplitude but not presynaptic release probability. These findings demonstrate distinct and highly segregated plasticity of thalamocortical projections during adult learning.

  4. Lack of Motor Neuron Differentiation is an Intrinsic Property of the Mouse Secondary Neural Tube

    PubMed Central

    Shum, Alisa S.W.; Tang, Louisa S.C.; Copp, Andrew J.; Roelink, Henk

    2016-01-01

    The cranial part of the amniote neural tube is formed by folding and fusion of the ectoderm-derived neural plate (primary neurulation). After posterior neuropore closure, however, the caudal neural tube is formed by cavitation of tail bud mesenchyme (secondary neurulation). In mouse embryos, the secondary neural tube expresses several genes important in early patterning and induction, in restricted domains similar to the primary neural tube, yet it does not undergo neuronal differentiation, but subsequently degenerates. Although the secondary neural tube, isolated from surrounding tissues, is responsive to exogenous Sonic Hedgehog proteins in vitro, motor neuron differentiation is never observed. This cannot be attributed to the properties of the secondary notochord, since it is able to induce motor neuron differentiation in naïve chick neural plate explants. Taken together, these results support that the lack of motor neuron differentiation is an intrinsic property of the mouse secondary neural tube. PMID:20960561

  5. Ultramicroscopy Reveals Axonal Transport Impairments in Cortical Motor Neurons at Prion Disease

    PubMed Central

    Ermolayev, Vladimir; Friedrich, Mike; Nozadze, Revaz; Cathomen, Toni; Klein, Michael A.; Harms, Gregory S.; Flechsig, Eckhard

    2009-01-01

    Abstract The functional imaging of neuronal circuits of the central nervous system is crucial for phenotype screenings or investigations of defects in neurodegenerative disorders. Current techniques yield either low penetration depth, yield poor resolution, or are restricted by the age of the animals. Here, we present a novel ultramicroscopy protocol for fluorescence imaging and three-dimensional reconstruction in the central nervous system of adult mice. In combination with tracing as a functional assay for axonal transport, retrogradely labeled descending motor neurons were visualized with >4 mm penetration depth. The analysis of the motor cortex shortly before the onset of clinical prion disease revealed that >80% neurons have functional impairments in axonal transport. Our study provides evidence that prion disease is associated with severe axonal transport defects in the cortical motor neurons and suggests a novel mechanism for prion-mediated neurodegeneration. PMID:19383482

  6. Motor cortical control of cardiovascular bulbar neurones projecting to spinal autonomic areas.

    PubMed

    Viltart, Odile; Mullier, Olivia; Bernet, François; Poulain, Pierre; Ba-M'Hamed, Saadia; Sequeira, Henrique

    2003-07-01

    There is evidence that the motor cortex is involved in cardiovascular adjustments associated with somatic motor activity, as it has functional connections with the ventrolateral medulla, a brainstem region critically involved in the control of blood pressure and the regulation of plasma catecholamine levels. The ventrolateral medulla sends projections to the spinal intermediolateral nucleus, where preganglionic neurones controlling heart and blood vessels (T2 segment) and adrenal medulla (T8 segment) are found. The aim of the present study was to determine whether electrical stimulation of the rat motor cortex induces cardiovascular responses and Fos expression in ventrolateral medulla neurones projecting to the T2 and T8 segments. After a set of experiments designed to record cardiovascular parameters (blood pressure and plasma catecholamine levels), injections of retrograde tracer (Fluorogold) were performed in the intermediolateral nucleus of two groups of rats, at the T2 or at the T8 segmental levels. Five days later, the motor cortex was stimulated in order to induce Fos expression in the ventrolateral medulla. Stimulation of the motor cortex induced: (1). hypotension and a significant decrease in plasma noradrenaline levels, and (2). a significant increase in the number of the double-labelled neurones in the rostral ventrolateral medulla projecting to T2. These data demonstrate that cardiovascular adjustments, preparatory to, or concomitant with, motor activity may be initiated in the motor cortex and transmitted to cardiac and vasomotor spinal preganglionic neurones, via the ventrolateral medulla. Copyright 2003 Wiley-Liss, Inc.

  7. Motor neuron disease in a defined English population: estimates of incidence and mortality.

    PubMed Central

    Dean, G; Quigley, M; Goldacre, M

    1994-01-01

    Linked statistics from hospital records and death certificates were used to study the incidence of and mortality from motor neuron disease in a defined English population. The incidence of motor neuron disease, measured as first-admission rates for the disease, was studied from 1963 to 1985 and death certificates for the patients admitted to hospital were obtained to the end of 1990. The average annual first-admission rate for motor neuron disease was 2.1/100,000 men (95% confidence interval (CI) 1.9 to 2.4) and 1.7/100,000 women (95% CI 1.5 to 1.9). First-admission rates increased with age and peaked in the age range 65-84 years. Motor neuron disease was recorded on the death certificate for 86% of patients who died while they had the disease and there was no appreciable change over time in the recording of motor neuron disease as the underlying cause of death. The admission and mortality data derive from different sources, hospital statistical abstracts and death certificates respectively, but trends over time in the two data sets were similar. There was an increase in mortality during the period covered by the study, as there has been in mortality from motor neuron disease nationally, and the increase in mortality in the Oxford region was accompanied by an increase in first-admission rates. It is concluded that the increase in mortality from motor neuron disease probably occurred as a result of an increase in the diagnosed incidence of the disease rather than changes in death certification practice. PMID:8163993

  8. Paired patch clamp recordings from motor-neuron and target skeletal muscle in zebrafish.

    PubMed

    Wen, Hua; Brehm, Paul

    2010-11-20

    Larval zebrafish represent the first vertebrate model system to allow simultaneous patch clamp recording from a spinal motor-neuron and target muscle. This is a direct consequence of the accessibility to both cell types and ability to visually distinguish the single segmental CaP motor-neuron on the basis of morphology and location. This video demonstrates the microscopic methods used to identify a CaP motor-neuron and target muscle cells as well as the methodologies for recording from each cell type. Identification of the CaP motor-neuron type is confirmed by either dye filling or by the biophysical features such as action potential waveform and cell input resistance. Motor-neuron recordings routinely last for one hour permitting long-term recordings from multiple different target muscle cells. Control over the motor-neuron firing pattern enables measurements of the frequency-dependence of synaptic transmission at the neuromuscular junction. Owing to a large quantal size and the low noise provided by whole cell voltage clamp, all of the unitary events can be resolved in muscle. This feature permits study of basic synaptic properties such as release properties, vesicle recycling, as well as synaptic depression and facilitation. The advantages offered by this in vivo preparation eclipse previous neuromuscular model systems studied wherein the motor-neurons are usually stimulated by extracellular electrodes and the muscles are too large for whole cell patch clamp. The zebrafish preparation is amenable to combining electrophysiological analysis with a wide range of approaches including transgenic lines, morpholino knockdown, pharmacological intervention and in vivo imaging. These approaches, coupled with the growing number of neuromuscular disease models provided by mutant lines of zebrafish, open the door for new understanding of human neuromuscular disorders.

  9. Differentiation of Human Neural Stem Cells into Motor Neurons Stimulates Mitochondrial Biogenesis and Decreases Glycolytic Flux

    PubMed Central

    Keeney, Paula M.

    2015-01-01

    Differentiation of human pluripotent stem cells (hPSCs) in vitro offers a way to study cell types that are not accessible in living patients. Previous research suggests that hPSCs generate ATP through anaerobic glycolysis, in contrast to mitochondrial oxidative phosphorylation (OXPHOS) in somatic cells; however, specialized cell types have not been assessed. To test if mitobiogenesis is increased during motor neuron differentiation, we differentiated human embryonic stem cell (hESC)- and induced pluripotent stem cell-derived human neural stem cells (hNSCs) into motor neurons. After 21 days of motor neuron differentiation, cells increased mRNA and protein levels of genes expressed by postmitotic spinal motor neurons. Electrophysiological analysis revealed voltage-gated currents characteristic of excitable cells and action potential formation. Quantitative PCR revealed an increase in peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), an upstream regulator of transcription factors involved in mitobiogenesis, and several of its downstream targets in hESC-derived cultures. This correlated with an increase in protein expression of respiratory subunits, but no increase in protein reflecting mitochondrial mass in either cell type. Respiration analysis revealed a decrease in glycolytic flux in both cell types on day 21 (D21), suggesting a switch from glycolysis to OXPHOS. Collectively, our findings suggest that mitochondrial biogenesis, but not mitochondrial mass, is increased during differentiation of hNSCs into motor neurons. These findings help us to understand human motor neuron mitobiogenesis, a process impaired in amyotrophic lateral sclerosis, a neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. PMID:25892363

  10. Motor Neurons Exhibit Sustained Loss of Atrophy Reversal in Immunodeficent Mice.

    PubMed

    Huang, Zhi; Petitto, John M

    2013-01-01

    Our lab showed previously that whereas a substantial portion of chronically resected facial motor neurons reside in an atrophied state that can be reversed at 14 days following reinjury in wild-type (WT) mice, atrophy reversal was altered in immunodeficient mice. It was unclear, however, if the abnormal response at day 14 post-reinjury in immunodeficient mice might be due to differences in the kinetics of the reversal response or impaired regeneration. We sought to address this question, and test our working hypothesis that the normal regeneration of atrophied motor neurons is dependent on normal adaptive immunity, by comparing WT and immunodeficient recombination activating gene-2 knockout (RAG2-KO) mice that lack a mature T and B lymphocytes, at 3 and 28 days following reinjury. In WT mice, facial motor neurons that were resected for 10 weeks and subsequently reinjured for 3 days were able to regain fully an apparent 40% loss of countable neurons, and nearly 45% of that robust increase in neurons was sustained at 28 days post-reinjury in the WT mice. By contrast, at both 3 and 28 days post-reinjury RAG2-KO mice failed to show any increase in neuronal number. Size measurements showed that the surviving neurons of WT and RAG2-KO mice exhibited substantial motor neuron hypertrophy at 3 days post-reinjury, and similar levels of normal size motor neurons by 28 days post-reinjury. Among the WT mice, small numbers of T lymphocytes where found in the reinjured facial motor nucleus (FMN), and were significantly higher at 3 days, but not 28 days, in the reinjury compared to sham-reinjury groups. No differences were seen between the WT and RAG2-KO mice in overall microglial cell activity using CD11b expression following reinjury. These data suggest that many resected motor neurons did not survive the initial resection in RAG2-KO mice, whereas in WT mice they atrophied and could be restimulated by reinjury to regenerate their phenotype. Moreover, they indicate that normal T

  11. Gamma synchrony predicts neuron-neuron correlations and correlations with motor behavior in extrastriate visual area MT.

    PubMed

    Lee, Joonyeol; Lisberger, Stephen G

    2013-12-11

    Correlated variability of neuronal responses is an important factor in estimating sensory parameters from a population response. Large correlations among neurons reduce the effective size of a neural population and increase the variation of the estimates. They also allow the activity of one neuron to be informative about impending perceptual decisions or motor actions on single trials. In extrastriate visual area MT of the rhesus macaque, for example, some but not all neurons show nonzero "choice probabilities" for perceptual decisions or non-zero "MT-pursuit" correlations between the trial-by-trial variations in neural activity and smooth pursuit eye movements. To understand the functional implications of zero versus nonzero correlations between neural responses and impending perceptions or actions, we took advantage of prior observations that specific frequencies of local field potentials reflect the correlated activity of neurons. We found that the strength of the spike-field coherence of a neuron in the gamma-band frequency range is related to the size of its MT-pursuit correlations for eye direction, as well as to the size of the neuron-neuron correlations. Spike-field coherence predicts MT-pursuit correlations better for direction than for speed, perhaps because the topographic organization of direction preference in MT is more amenable to creating meaningful local field potentials. We suggest that the relationship between spiking and local-field potentials is stronger for neurons that have larger correlations with their neighbors; larger neuron-neuron correlations create stronger MT-pursuit correlations. Neurons that lack strong correlations with their neighbors also have weaker correlations with pursuit behavior, but still could drive pursuit strongly.

  12. eGFP expression under the Uchl1 promoter labels corticospinal motor neurons and a subpopulation of degeneration resistant spinal motor neurons in ALS mouse models

    NASA Astrophysics Data System (ADS)

    Yasvoina, Marina V.

    Current understanding of basic cellular and molecular mechanisms for motor neuron vulnerability during motor neuron disease initiation and progression is incomplete. The complex cytoarchitecture and cellular heterogeneity of the cortex and spinal cord greatly impedes our ability to visualize, isolate, and study specific neuron populations in both healthy and diseased states. We generated a novel reporter line, the Uchl1-eGFP mouse, in which cortical and spinal components of motor neuron circuitry are genetically labeled with eGFP under the Uchl1 promoter. A series of cellular and anatomical analyses combined with retrograde labeling, molecular marker expression, and electrophysiology were employed to determine identity of eGFP expressing cells in the motor cortex and the spinal cord of novel Uchl1-eGFP reporter mice. We conclude that eGFP is expressed in corticospinal motor neurons (CSMN) in the motor cortex and a subset of S-type alpha and gamma spinal motor neurons (SMN) in the spinal cord. hSOD1G93A and Alsin-/- mice, mouse models for amyotrophic lateral sclerosis (ALS), were bred to Uchl1-eGFP reporter mouse line to investigate the pathophysiology and underlying mechanisms of CSMN degeneration in vivo. Evidence suggests early and progressive degeneration of CSMN and SMN in the hSOD1G93A transgenic mice. We show an early increase of autophagosome formation in the apical dendrites of vulnerable CSMN in hSOD1G93A-UeGFP mice, which is localized to the apical dendrites. In addition, labeling S-type alpha and gamma SMN in the hSOD1G93A-UeGFP mice provide a unique opportunity to study basis of their resistance to degeneration. Mice lacking alsin show moderate clinical phenotype and mild CSMN axon degeneration in the spinal cord, which suggests vulnerability of CSMN. Therefore, we investigated the CSMN cellular and axon defects in aged Alsin-/- mice bred to Uchl1-eGFP reporter mouse line. We show that while CSMN are preserved and lack signs of degeneration, CSMN axons

  13. Time and dose dependent effects of oxidative stress induced by cumene hydroperoxide in neuronal excitability of rat motor cortex neurons.

    PubMed

    Pardillo-Díaz, R; Carrascal, L; Muñoz, M F; Ayala, A; Nunez-Abades, P

    2016-03-01

    It has been claimed that oxidative stress and the production of reactive oxygen radicals can contribute to neuron degeneration and might be one factor in the development of different neurological diseases. In our study, we have attempted to clarify how oxidative damage induces dose dependent changes in functional membrane properties of neurons by means of whole cell patch clamp techniques in brain slices from young adult rats. Our research demonstrates physiological changes in membrane properties of pyramidal motor cortex neurons exposed to 3 concentrations of cumene hydroperoxide (CH; 1, 10 and 100μM) during 30min. Results show that oxidative stress induced by CH evokes important changes, in a concentration and time dependent manner, in the neuronal excitability of motor cortex neurons of the rat: (i) Low concentration of the drug (1μM) already blocks inward rectifications (sag) and decreases action potential amplitude and gain, a drug concentration which has no effects on other neuronal populations, (ii) 10μM of CH depresses the excitability of pyramidal motor cortex neurons by decreasing input resistance, amplitude of the action potential, and gain and maximum frequency of the repetitive firing discharge, and (iii) 100μM completely blocks the capability to produce repetitive discharge of action potentials in all cells. Both larger drug concentrations and/or longer times of exposure to CH narrow the current working range. This happens because of the increase in the rheobase, and the reduction of the cancelation current. The effects caused by oxidative stress, including those produced by the level of lipid peroxidation, are practically irreversible and, this, therefore, indicates that neuroprotective agents should be administered at the first symptoms of alterations to membrane properties. In fact, the pre-treatment with melatonin, acting as an antioxidant, prevented the lipid peroxidation and the physiological changes induced by CH. Larger cells (as estimated

  14. Functional clustering of neurons in motor cortex determined by cellular resolution imaging in awake behaving mice

    PubMed Central

    Dombeck, Daniel A.; Graziano, Michael S.; Tank, David W.

    2010-01-01

    Macroscopic (millimeter scale) functional clustering is a hallmark characteristic of motor cortex spatial organization in awake behaving mammals; however, almost no information is known about the functional micro-organization (~100 microns scale). Here, we optically recorded intracellular calcium transients of layer 2/3 neurons with cellular resolution over ~200 micron diameter fields in the forelimb motor cortex of mobile, head-restrained mice during two distinct movements (running and grooming). We showed that the temporal correlation between neurons was statistically larger the closer the neurons were to each other. We further explored this correlation by using two separate methods to spatially segment the neurons within each imaging field: K-means clustering and correlations between single neuron activity and mouse movements. The two methods segmented the neurons similarly and led to the conclusion that the origin of the inverse relationship between correlation and distance seen statistically was two-fold: clusters of highly temporally correlated neurons were often spatially distinct from one another and (even when the clusters were spatially intermingled) within the clusters, the more correlated the neurons were to each other, the shorter the distance between them. Our results represent a direct observation of functional clustering within the micro-circuitry of the awake mouse motor cortex. PMID:19889987

  15. Dementia of frontal lobe type and motor neuron disease. A Golgi study of the frontal cortex.

    PubMed Central

    Ferrer, I; Roig, C; Espino, A; Peiro, G; Matias Guiu, X

    1991-01-01

    Neuropathological findings in a 38 year old patient with dementia of frontal lobe type and motor neuron disease included pyramidal tracts, myelin pallor and neuron loss, gliosis and chromatolysis in the hypoglossal nucleus, together with frontal atrophy, neuron loss, gliosis and spongiosis in the upper cortical layers of the frontal (and temporal) lobes. Most remaining pyramidal and non-pyramidal neurons (multipolar, bitufted and bipolar cells) in the upper layers (layers II and III) of the frontal cortex (area B) had reduced dendritic arbors, proximal dendritic varicosities and amputation of dendrites as revealed in optimally stained rapid Golgi sections. Pyramidal cells in these layers also showed depletion of dendritic spines. Neurons in the inner layers were preserved. Loss of receptive surfaces in neurons of the upper cortical layers in the frontal cortex are indicative of neuronal disconnection, and are "hidden" contributory morphological substrates for the development of dementia. Images PMID:1744652

  16. The utility of cerebral blood flow imaging in patients with the unique syndrome of progressive dementia with motor neuron disease

    SciTech Connect

    Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y. )

    1990-05-01

    Two patients presenting with progressive dementia coupled with motor neuron disease underwent brain SPECT using N-isopropyl-p iodine-123-iodoamphetamine (({sup 123}I)IMP). The characteristic clinical features of progressive dementia and motor neuron disease were noted. IMP SPECT also revealed reduced uptake in the bilateral frontal and temporal regions, with no reduction of uptake in the parietal, parietal-occipital regions. We conclude that IMP SPECT has potential for the evaluation of progressive dementia with motor neuron disease.

  17. Muscle Mitochondrial Uncoupling Dismantles Neuromuscular Junction and Triggers Distal Degeneration of Motor Neurons

    PubMed Central

    Dupuis, Luc; Gonzalez de Aguilar, Jose-Luis; Echaniz-Laguna, Andoni; Eschbach, Judith; Rene, Frédérique; Oudart, Hugues; Halter, Benoit; Huze, Caroline; Schaeffer, Laurent; Bouillaud, Frédéric; Loeffler, Jean-Philippe

    2009-01-01

    Background Amyotrophic lateral sclerosis (ALS), the most frequent adult onset motor neuron disease, is associated with hypermetabolism linked to defects in muscle mitochondrial energy metabolism such as ATP depletion and increased oxygen consumption. It remains unknown whether muscle abnormalities in energy metabolism are causally involved in the destruction of neuromuscular junction (NMJ) and subsequent motor neuron degeneration during ALS. Methodology/Principal Findings We studied transgenic mice with muscular overexpression of uncoupling protein 1 (UCP1), a potent mitochondrial uncoupler, as a model of muscle restricted hypermetabolism. These animals displayed age-dependent deterioration of the NMJ that correlated with progressive signs of denervation and a mild late-onset motor neuron pathology. NMJ regeneration and functional recovery were profoundly delayed following injury of the sciatic nerve and muscle mitochondrial uncoupling exacerbated the pathology of an ALS animal model. Conclusions/Significance These findings provide the proof of principle that a muscle restricted mitochondrial defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases. PMID:19404401

  18. Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders

    PubMed Central

    Jokela, Manu; Huovinen, Sanna; Raheem, Olayinka; Lindfors, Mikaela; Palmio, Johanna; Penttilä, Sini; Udd, Bjarne

    2016-01-01

    The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary “myopathic” changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions. PMID:26999347

  19. Serotonin Promotes Development and Regeneration of Spinal Motor Neurons in Zebrafish.

    PubMed

    Barreiro-Iglesias, Antón; Mysiak, Karolina S; Scott, Angela L; Reimer, Michell M; Yang, Yujie; Becker, Catherina G; Becker, Thomas

    2015-11-03

    In contrast to mammals, zebrafish regenerate spinal motor neurons. During regeneration, developmental signals are re-deployed. Here, we show that, during development, diffuse serotonin promotes spinal motor neuron generation from pMN progenitor cells, leaving interneuron numbers unchanged. Pharmacological manipulations and receptor knockdown indicate that serotonin acts at least in part via 5-HT1A receptors. In adults, serotonin is supplied to the spinal cord mainly (90%) by descending axons from the brain. After a spinal lesion, serotonergic axons degenerate caudal to the lesion but sprout rostral to it. Toxin-mediated ablation of serotonergic axons also rostral to the lesion impaired regeneration of motor neurons only there. Conversely, intraperitoneal serotonin injections doubled numbers of new motor neurons and proliferating pMN-like progenitors caudal to the lesion. Regeneration of spinal-intrinsic serotonergic interneurons was unaltered by these manipulations. Hence, serotonin selectively promotes the development and adult regeneration of motor neurons in zebrafish. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders.

    PubMed

    Jokela, Manu; Huovinen, Sanna; Raheem, Olayinka; Lindfors, Mikaela; Palmio, Johanna; Penttilä, Sini; Udd, Bjarne

    2016-01-01

    The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary "myopathic" changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions.

  1. Lower motor neuron disease with respiratory failure caused by a novel MAPT mutation.

    PubMed

    Di Fonzo, Alessio; Ronchi, Dario; Gallia, Francesca; Cribiù, Fulvia Milena; Trezzi, Ilaria; Vetro, Annalisa; Della Mina, Erika; Limongelli, Ivan; Bellazzi, Riccardo; Ricca, Ivana; Micieli, Giuseppe; Fassone, Elisa; Rizzuti, Mafalda; Bordoni, Andreina; Fortunato, Francesco; Salani, Sabrina; Mora, Gabriele; Corti, Stefania; Ceroni, Mauro; Bosari, Silvano; Zuffardi, Orsetta; Bresolin, Nereo; Nobile-Orazio, Eduardo; Comi, Giacomo Pietro

    2014-06-03

    To investigate the molecular defect underlying a large Italian kindred with progressive adult-onset respiratory failure, proximal weakness of the upper limbs, and evidence of lower motor neuron degeneration. We describe the clinical features of 5 patients presenting with prominent respiratory insufficiency, proximal weakness of the upper limbs, and no signs of frontotemporal lobar degeneration or semantic dementia. Molecular analysis was performed combining linkage and exome sequencing analyses. Further investigations included transcript analysis and immunocytochemical and protein studies on established cell models. Genome-wide linkage analysis showed an association with chromosome 17q21. Exome analysis disclosed a missense change in MAPT segregating dominantly with the disease and resulting in D348G-mutated tau protein. Motor neuron cell lines overexpressing mutated D348G tau isoforms displayed a consistent reduction in neurite length and arborization. The mutation does not seem to modify tau interactions with microtubules. Neuropathologic studies were performed in one affected subject, which exhibited α-motoneuron loss and atrophy of the spinal anterior horns with accumulation of phosphorylated tau within the surviving motor neurons. Staining for 3R- and 4R-tau revealed pathology similar to that observed in familial cases harboring MAPT mutations. Our study broadens the phenotype of tauopathies to include lower motor neuron disease and implicate tau degradation pathway defects in motor neuron degeneration. © 2014 American Academy of Neurology.

  2. Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

    PubMed Central

    Tsuiji, Hitomi; Iguchi, Yohei; Furuya, Asako; Kataoka, Ayane; Hatsuta, Hiroyuki; Atsuta, Naoki; Tanaka, Fumiaki; Hashizume, Yoshio; Akatsu, Hiroyasu; Murayama, Shigeo; Sobue, Gen; Yamanaka, Koji

    2013-01-01

    Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons. PMID:23255347

  3. Muscles innervated by a single motor neuron exhibit divergent synaptic properties on multiple time scales.

    PubMed

    Blitz, Dawn M; Pritchard, Amy E; Latimer, John K; Wakefield, Andrew T

    2017-01-19

    Adaptive changes in the output of neural circuits underlying rhythmic behaviors are relayed to muscles via motor neuron activity. Pre- and postsynaptic properties of neuromuscular junctions can impact the transformation from motor neuron activity to muscle response. Further, synaptic plasticity occurring on the time scale of inter-spike intervals can differ between multiple muscles innervated by the same motor neuron. In rhythmic behaviors, motor neuron bursts can elicit additional synaptic plasticity. However, it is unknown if plasticity regulated by the longer time scale of inter-burst intervals also differs between synapses from the same neuron, and whether any such distinctions occur across a physiological activity range. To address these issues, we measured electrical responses in muscles innervated by a chewing circuit neuron, the lateral gastric (LG) motor neuron, in a well-characterized small motor system, the stomatogastric nervous system (STNS) of the Jonah crab, Cancer borealis In vitro and in vivo, sensory, hormonal and modulatory inputs elicit LG bursting consisting of inter-spike intervals of 50-250 ms and inter-burst intervals of 2-24 s. Muscles expressed similar facilitation measured with paired stimuli except at the shortest inter-spike interval. However distinct decay time constants resulted in differences in temporal summation. In response to bursting activity, augmentation occurred to different extents and saturated at different inter-burst intervals in the three muscles. Further, augmentation interacted with facilitation, resulting in distinct intra-burst facilitation between muscles. Thus, responses of multiple target muscles diverge across a physiological activity range due to distinct synaptic properties sensitive to multiple time scales.

  4. Drosophila Motor Neuron Retraction during Metamorphosis Is Mediated by Inputs from TGF-β/BMP Signaling and Orphan Nuclear Receptors

    PubMed Central

    Boulanger, Ana; Farge, Morgane; Ramanoudjame, Christophe; Wharton, Kristi; Dura, Jean-Maurice

    2012-01-01

    Larval motor neurons remodel during Drosophila neuro-muscular junction dismantling at metamorphosis. In this study, we describe the motor neuron retraction as opposed to degeneration based on the early disappearance of β-Spectrin and the continuing presence of Tubulin. By blocking cell dynamics with a dominant-negative form of Dynamin, we show that phagocytes have a key role in this process. Importantly, we show the presence of peripheral glial cells close to the neuro-muscular junction that retracts before the motor neuron. We show also that in muscle, expression of EcR-B1 encoding the steroid hormone receptor required for postsynaptic dismantling, is under the control of the ftz-f1/Hr39 orphan nuclear receptor pathway but not the TGF-β signaling pathway. In the motor neuron, activation of EcR-B1 expression by the two parallel pathways (TGF-β signaling and nuclear receptor) triggers axon retraction. We propose that a signal from a TGF-β family ligand is produced by the dismantling muscle (postsynapse compartment) and received by the motor neuron (presynaptic compartment) resulting in motor neuron retraction. The requirement of the two pathways in the motor neuron provides a molecular explanation for the instructive role of the postsynapse degradation on motor neuron retraction. This mechanism insures the temporality of the two processes and prevents motor neuron pruning before postsynaptic degradation. PMID:22792255

  5. Down-regulation of apurinic/apyrimidinic endonuclease 1 (APE1) in spinal motor neurones under oxidative stress.

    PubMed

    Chu, Tak-Ho; Guo, Anchen; Wu, Wutian

    2014-06-01

    Apurinic/apyrimidinic endonuclease 1 (APE1) is an intermediate enzyme in base excision repair which is important for removing damaged nucleotides under normal and pathological conditions. Accumulation of damaged bases causes genome instability and jeopardizes cell survival. Our study is to examine APE1 regulation under oxidative stress in spinal motor neurones which are vulnerable to oxidative insult. We challenged the motor neurone-like cell line NSC-34 with hydrogen peroxide and delineated APE1 function by applying various inhibitors. We also examined the expression of APE1 in spinal motor neurones after spinal root avulsion in adult rats. We showed that hydrogen peroxide induced APE1 down-regulation and cell death in a differentiated motor neurone-like cell line. Inhibiting the two functional domains of APE1, namely, DNA repair and redox domains potentiated hydrogen peroxide induced cell death. We further showed that p53 phosphorylation early after hydrogen peroxide treatment might contribute to the down-regulation of APE1. Our in vivo results similarly showed that APE1 was down-regulated after root avulsion injury in spinal motor neurones. Delay of motor neurone death suggested that APE1 might not cause immediate cell death but render motor neurones vulnerable to further oxidative insults. We conclude that spinal motor neurones down-regulate APE1 upon oxidative stress. This property renders motor neurones susceptible to continuous challenge of oxidative stress in pathological conditions. © 2013 British Neuropathological Society.

  6. A Role for SMN Exon 7 Splicing in the Selective Vulnerability of Motor Neurons in Spinal Muscular Atrophy

    PubMed Central

    Ruggiu, Matteo; McGovern, Vicki L.; Lotti, Francesco; Saieva, Luciano; Li, Darrick K.; Kariya, Shingo; Monani, Umrao R.; Burghes, Arthur H. M.

    2012-01-01

    Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by homozygous loss of the Survival Motor Neuron 1 (SMN1) gene. In the absence of SMN1, inefficient inclusion of exon 7 in transcripts from the nearly identical SMN2 gene results in ubiquitous SMN decrease but selective motor neuron degeneration. Here we investigated whether cell type-specific differences in the efficiency of exon 7 splicing contribute to the vulnerability of SMA motor neurons. We show that normal motor neurons express markedly lower levels of full-length SMN mRNA from SMN2 than do other cells in the spinal cord. This is due to inefficient exon 7 splicing that is intrinsic to motor neurons under normal conditions. We also find that SMN depletion in mammalian cells decreases exon 7 inclusion through a negative feedback loop affecting the splicing of its own mRNA. This mechanism is active in vivo and further decreases the efficiency of exon 7 inclusion specifically in motor neurons of severe-SMA mice. Consistent with expression of lower levels of full-length SMN, we find that SMN-dependent downstream molecular defects are exacerbated in SMA motor neurons. These findings suggest a mechanism to explain the selective vulnerability of motor neurons to loss of SMN1. PMID:22037760

  7. Peripherin-mediated death of motor neurons rescued by overexpression of neurofilament NF-H proteins.

    PubMed

    Beaulieu, Jean-Martin; Julien, Jean-Pierre

    2003-04-01

    In previous studies, we showed that overexpression of peripherin, a neuronal intermediate filament (IF) protein, in mice deficient for neurofilament light (NF-L) subunits induced a progressive adult-onset degeneration of spinal motor neurons characterized by the presence of IF inclusion bodies reminiscent of axonal spheroids found in amyotrophic lateral sclerosis (ALS). In contrast, the overexpression of human neurofilament heavy (NF-H) proteins provoked the formation of massive perikaryal IF protein accumulations with no loss of motor neurons. To further investigate the toxic properties of IF protein inclusions, we generated NF-L null mice that co-express both peripherin and NF-H transgenes. The axonal count in L5 ventral roots from 6 and 8-month-old transgenic mice showed that NF-H overexpression rescued the peripherin-mediated degeneration of motor neurons. Our analysis suggests that the protective effect of extra NF-H proteins is related to the sequestration of peripherin into the perikaryon of motor neurons, thereby abolishing the development of axonal IF inclusions that might block transport. These findings illustrate the importance of IF protein stoichiometry in formation, localization and toxicity of neuronal inclusion bodies.

  8. Local connections of excitatory neurons in motor-associated cortical areas of the rat

    PubMed Central

    Kaneko, Takeshi

    2013-01-01

    In spite of recent progress in brain sciences, the local circuit of the cerebral neocortex, including motor areas, still remains elusive. Morphological works on excitatory cortical circuitry from thalamocortical (TC) afferents to corticospinal neurons (CSNs) in motor-associated areas are reviewed here. First, TC axons of motor thalamic nuclei have been re-examined by the single-neuron labeling method. There are middle layer (ML)-targeting and layer (L) 1-preferring TC axon types in motor-associated areas, being analogous to core and matrix types, respectively, of Jones (1998) in sensory areas. However, the arborization of core-like motor TC axons spreads widely and disregards the columnar structure that is the basis of information processing in sensory areas, suggesting that motor areas adopt a different information-processing framework such as area-wide laminar organization. Second, L5 CSNs receive local excitatory inputs not only from L2/3 pyramidal neurons but also from ML spiny neurons, the latter directly processing cerebellar information of core-like TC neurons (TCNs). In contrast, basal ganglia information is targeted to apical dendrites of L2/3 and L5 pyramidal neurons through matrix TCNs. Third, L6 corticothalamic neurons (CTNs) are most densely innervated by ML spiny neurons located just above CTNs. Since CTNs receive only weak connections from L2/3 and L5 pyramidal neurons, the TC recurrent circuit composed of TCNs, ML spiny neurons and CTNs appears relatively independent of the results of processing in L2/3 and L5. It is proposed that two circuits sharing the same TC projection and ML neurons are embedded in the neocortex: one includes L2/3 and L5 neurons, processes afferent information in a feedforward way and sends the processed information to other cortical areas and subcortical regions; and the other circuit participates in a dynamical system of the TC recurrent circuit and may serve as the basis of autonomous activity of the neocortex. PMID

  9. Calcium/calmodulin-dependent protein kinase II expression in motor neurons: effect of axotomy.

    PubMed

    Lund, L M; McQuarrie, I G

    1997-11-20

    Although Ca2+/calmodulin-dependent (CaM) protein kinase II isoforms are present in the nervous system in high amounts, many aspects of in vivo expression, localization, and function remain unexplored. During development, CaM kinase IIalpha and IIbeta are differentially expressed. Here, we examined CaM kinase II isoforms in Sprague-Dawley rat sciatic motor neurons before and after axotomy. We cut the L4-5 spinal nerves unilaterally and exposed the proximal nerve stumps to a fluoroprobe, to retrogradely label the neurons of origin. Anti-CaM kinase IIbeta antibody showed immunoreactivity in motor neurons, which decreased to low levels by 4 days after axotomy. We found a similar response by in situ hybridization with riboprobes. The decrease in expression of mRNA and protein was confined to fluorescent motor neurons. For CaM kinase IIalpha, in situ hybridization showed that the mRNA was in sciatic motor neurons, with a density unaffected by axotomy. However, these neurons were also enlarged, suggesting an up-regulation of expression. Northern blots confirmed an mRNA increase. We were unable to find CaM kinase IIalpha immunoreactivity before or after axotomy in sciatic motor neuron cell bodies, suggesting that CaM kinase IIalpha is in the axons or dendrites, or otherwise unavailable to the antibody. Using rats with crush lesions, we radiolabeled axonal proteins being synthesized in the cell body and used two-dimensional polyacrylamide gel electrophoresis with Western blots to identify CaM kinase IIalpha as a component of slow axonal transport. This differential regulation and expression of kinase isoforms suggests separate and unique intracellular roles. Because we find CaM kinase IIbeta down-regulates during axonal regrowth, its role in these neurons may be related to synaptic transmission. CaM kinase IIalpha appears to support axonal regrowth.

  10. Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy.

    PubMed

    Tapia, Olga; Bengoechea, Rocío; Palanca, Ana; Arteaga, Rosa; Val-Bernal, J Fernando; Tizzano, Eduardo F; Berciano, María T; Lafarga, Miguel

    2012-05-01

    Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by loss or mutations of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to degeneration and death of motor neurons. In this study, we have analyzed the nuclear reorganization of Cajal bodies, PML bodies and nucleoli in type I SMA motor neurons with homozygous deletion of exons 7 and 8 of the SMN1 gene. Western blot analysis is is revealed a marked reduction of SMN levels compared to the control sample. Using a neuronal dissociation procedure to perform a careful immunocytochemical and quantitative analysis of nuclear bodies, we demonstrated a severe decrease in the mean number of Cajal bodies per neuron and in the proportion of motor neurons containing these structures in type I SMA. Moreover, most Cajal bodies fail to recruit SMN and spliceosomal snRNPs, but contain the proteasome activator PA28, a molecular marker associated with the cellular stress response. Neuronal stress in SMA motor neurons also increases PML body number. The existence of chromatolysis and eccentric nuclei in SMA motor neurons correlates with Cajal body disruption and nucleolar relocalization of coil in, a Cajal body marker. Our results indicate that the Cajal body is a pathophysiological target in type I SMA motor neurons. They also suggest the Cajal body-dependent dysfunction of snRNP biogenesis and, therefore, pre-mRNA splicing in these neurons seems to be an essential component for SMA pathogenesis.

  11. Induction of apoptosis by thrombin in the cultured neurons of dorsal motor nucleus of the vagus.

    PubMed

    Wu, X; Zhang, W; Li, J-Y; Chai, B-X; Peng, J; Wang, H; Mulholland, M W

    2011-03-01

    A previous study demonstrated the presence of protease-activated receptor (PAR) 1 and 2 in the dorsal motor nucleus of vagus (DMV). The aim of this study is to characterize the effect of thrombin on the apoptosis of DMV neurons. The dorsal motor nucleus of vagus neurons were isolated from neonatal rat brainstems using micro-dissection and enzymatic digestion and cultured. Apoptosis of DMV neurons were examined in cultured neurons. Apoptotic neuron was examined by TUNEL and ELISA. Data were analyzed using anova and Student's t-test. Exposure of cultured DMV neurons to thrombin (0.1 to 10 U mL(-1)) for 24 h significantly increased apoptosis. Pretreatment of DMV neurons with hirudin attenuated the apoptotic effect of thrombin. Similar induction of apoptosis was observed for the PAR1 receptor agonist SFLLR, but not for the PAR3 agonist TFRGAP, nor for the PAR4 agonist YAPGKF. Protease-activated receptors 1 receptor antagonist Mpr(Cha) abolished the apoptotic effect of thrombin, while YPGKF, a specific antagonist for PAR4, demonstrated no effect. After administration of thrombin, phosphorylation of JNK and P38 occurred as early as 15 min, and remained elevated for up to 45 min. Pretreatment of DMV neurons with SP600125, a specific inhibitor for JNK, or SB203580, a specific inhibitor for P38, significantly inhibited apoptosis induced by thrombin. Thrombin induces apoptosis in DMV neurons through a mechanism involving the JNK and P38 signaling pathways. © 2010 Blackwell Publishing Ltd.

  12. Ensemble Fractional Sensitivity: A Quantitative Approach to Neuron Selection for Decoding Motor Tasks

    PubMed Central

    Singhal, Girish; Aggarwal, Vikram; Acharya, Soumyadipta; Aguayo, Jose; He, Jiping; Thakor, Nitish

    2010-01-01

    A robust method to help identify the population of neurons used for decoding motor tasks is developed. We use sensitivity analysis to develop a new metric for quantifying the relative contribution of a neuron towards the decoded output, called “fractional sensitivity.” Previous model-based approaches for neuron ranking have been shown to largely depend on the collection of training data. We suggest the use of an ensemble of models that are trained on random subsets of trials to rank neurons. For this work, we tested a decoding algorithm on neuronal data recorded from two male rhesus monkeys while they performed a reach to grasp a bar at three orientations (45°, 90°, or 135°). An ensemble approach led to a statistically significant increase of 5% in decoding accuracy and 25% increase in identification accuracy of simulated noisy neurons, when compared to a single model. Furthermore, ranking neurons based on the ensemble fractional sensitivities resulted in decoding accuracies 10%–20% greater than when randomly selecting neurons or ranking based on firing rates alone. By systematically reducing the size of the input space, we determine the optimal number of neurons needed for decoding the motor output. This selection approach has practical benefits for other BMI applications where limited number of electrodes and training datasets are available, but high decoding accuracies are desirable. PMID:20169103

  13. Impaired Autophagy and Defective Mitochondrial Function: Converging Paths on the Road to Motor Neuron Degeneration

    PubMed Central

    Edens, Brittany M.; Miller, Nimrod; Ma, Yong-Chao

    2016-01-01

    Selective motor neuron degeneration is a hallmark of amyotrophic lateral sclerosis (ALS). Around 10% of all cases present as familial ALS (FALS), while sporadic ALS (SALS) accounts for the remaining 90%. Diverse genetic mutations leading to FALS have been identified, but the underlying causes of SALS remain largely unknown. Despite the heterogeneous and incompletely understood etiology, different types of ALS exhibit overlapping pathology and common phenotypes, including protein aggregation and mitochondrial deficiencies. Here, we review the current understanding of mechanisms leading to motor neuron degeneration in ALS as they pertain to disrupted cellular clearance pathways, ATP biogenesis, calcium buffering and mitochondrial dynamics. Through focusing on impaired autophagic and mitochondrial functions, we highlight how the convergence of diverse cellular processes and pathways contributes to common pathology in motor neuron degeneration. PMID:26973461

  14. A plural role for lipids in motor neuron diseases: energy, signaling and structure

    PubMed Central

    Schmitt, Florent; Hussain, Ghulam; Dupuis, Luc; Loeffler, Jean-Philippe; Henriques, Alexandre

    2013-01-01

    Motor neuron diseases (MNDs) are characterized by selective death of motor neurons and include mainly adult-onset amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Neurodegeneration is not the single pathogenic event occurring during disease progression. There are multiple lines of evidence for the existence of defects in lipid metabolism at peripheral level. For instance, hypermetabolism is well characterized in ALS, and dyslipidemia correlates with better prognosis in patients. Lipid metabolism plays also a role in other MNDs. In SMA, misuse of lipids as energetic nutrients is described in patients and in related animal models. The composition of structural lipids in the central nervous system is modified, with repercussion on membrane fluidity and on cell signaling mediated by bioactive lipids. Here, we review the main epidemiologic and mechanistic findings that link alterations of lipid metabolism and motor neuron degeneration, and we discuss the rationale of targeting these modifications for therapeutic management of MNDs. PMID:24600344

  15. Utility of whole exome sequencing in evaluation of juvenile motor neuron disease.

    PubMed

    Agarwal, Sonika; Potocki, Lorraine; Collier, Talia R; Woodbury, Suzanne L; Adesina, Adekunle M; Jones, Jeremy; Lotze, Timothy E

    2016-04-01

    This case report focuses on identifying novel mutations in juvenile motor neuron disease and emphasizes the significance of whole exome sequencing (WES). We report a 13-year-old Hispanic boy with rapidly progressive weakness, muscle atrophy, tremor, and tongue fasciculation, along with upper motor neuron findings of hyperactive gag reflex, hyperreflexia, and cog-wheel rigidity. Electromyography was suggestive of motor neuron disease. After an extensive evaluation, WES was performed. WES identified a heterozygous de novo variant of unknown clinical significance (VUS) in the fused-in-sarcoma gene (FUS) [c.1554_1557del]. Although initially reported as a VUS, the clinical data from our patient and data from the medical literature support that the variant is indeed disease-causing. The genetic etiology of amyotrophic lateral sclerosis (ALS) is heterogeneous and, as clinical sequencing for FUS was not available, WES was the only method by which a diagnosis of juvenile ALS could be made. © 2016 Wiley Periodicals, Inc.

  16. Expression of Carbonic Anhydrase I in Motor Neurons and Alterations in ALS

    PubMed Central

    Liu, Xiaochen; Lu, Deyi; Bowser, Robert; Liu, Jian

    2016-01-01

    Carbonic anhydrase I (CA1) is the cytosolic isoform of mammalian α-CA family members which are responsible for maintaining pH homeostasis in the physiology and pathology of organisms. A subset of CA isoforms are known to be expressed and function in the central nervous system (CNS). CA1 has not been extensively characterized in the CNS. In this study, we demonstrate that CA1 is expressed in the motor neurons in human spinal cord. Unexpectedly, a subpopulation of CA1 appears to be associated with endoplasmic reticulum (ER) membranes. In addition, the membrane-associated CA1s are preferentially upregulated in amyotrophic lateral sclerosis (ALS) and exhibit altered distribution in motor neurons. Furthermore, long-term expression of CA1 in mammalian cells activates apoptosis. Our results suggest a previously unknown role for CA1 function in the CNS and its potential involvement in motor neuron degeneration in ALS. PMID:27809276

  17. TDP-43 A315T Mutation in Familial Motor Neuron Disease

    PubMed Central

    Gitcho, Michael A.; Baloh, Robert H.; Chakraverty, Sumi; Mayo, Kevin; Norton, Joanne B.; Levitch, Denise; Hatanpaa, Kimmo J.; White, Charles L.; Bigio, Eileen H.; Caselli, Richard; Baker, Matt; Al-Lozi, Muhammad T.; Morris, John C.; Pestronk, Alan; Rademakers, Rosa; Goate, Alison M.; Cairns, Nigel J.

    2009-01-01

    To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA-binding protein 43 (TDP-43) proteinopathies to investigate TDP-43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP-43 gene led to the identification of a novel missense mutation, Ala-315-Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration. PMID:18288693

  18. RPM-1 is localized to distinct subcellular compartments and regulates axon length in GABAergic motor neurons

    PubMed Central

    2014-01-01

    Background The PAM/Highwire/RPM-1 (PHR) proteins are conserved signaling proteins that regulate axon length and synapse formation during development. Loss of function in Caenorhabditis elegans rpm-1 results in axon termination and synapse formation defects in the mechanosensory neurons. An explanation for why these two phenotypes are observed in a single neuronal cell has remained absent. Further, it is uncertain whether the axon termination phenotypes observed in the mechanosensory neurons of rpm-1 mutants are unique to this specific type of neuron, or more widespread defects that occur with loss of function in rpm-1. Results Here, we show that RPM-1 is localized to both the mature axon tip and the presynaptic terminals of individual motor neurons and individual mechanosensory neurons. Genetic analysis indicated that GABAergic motor neurons, like the mechanosensory neurons, have both synapse formation and axon termination defects in rpm-1 mutants. RPM-1 functions in parallel with the active zone component SYD-2 (Liprin) to regulate not only synapse formation, but also axon termination in motor neurons. Our analysis of rpm-1−/−; syd-2−/− double mutants also revealed a role for RPM-1 in axon extension. The MAP3K DLK-1 partly mediated RPM-1 function in both axon termination and axon extension, and the relative role of DLK-1 was dictated by the anatomical location of the neuron in question. Conclusions Our findings show that axon termination defects are a core phenotype caused by loss of function in rpm-1, and not unique to the mechanosensory neurons. We show in motor neurons and in mechanosensory neurons that RPM-1 is localized to multiple, distinct subcellular compartments in a single cell. Thus, RPM-1 might be differentially regulated or RPM-1 might differentially control signals in distinct subcellular compartments to regulate multiple developmental outcomes in a single neuron. Our findings provide further support for the previously proposed model that PHR

  19. The Scottish Motor Neuron Disease Register: a prospective study of adult onset motor neuron disease in Scotland. Methodology, demography and clinical features of incident cases in 1989.

    PubMed Central

    1992-01-01

    The Scottish Motor Neuron Disease Register (SMNDR) is a prospective, collaborative, population based study of motor neuron disease (MND) in Scotland. The register started in January 1989 with the aim of studying the clinical and epidemiological features of MND by prospectively identifying incident patients. It is based on a system of registration by recruitment from multiple sources, followed by the collection of complete clinical data and follow up, mainly through general practitioners. In this report the register's methodology and the demography and incidence data for the first year of study are presented. One hundred and fourteen newly diagnosed patients were identified in 1989 giving a crude incidence for Scotland of 2.24/100,000/year. Standardised incidence ratios showed a non-significant trend towards lower rates in north eastern regions and island areas. PMID:1640227

  20. Acetyl L-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos.

    PubMed

    Cuevas, Elvis; Trickler, William J; Guo, Xiaoqing; Ali, Syed F; Paule, Merle G; Kanungo, Jyotshna

    2013-01-01

    Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) type glutamate receptors is commonly used as a pediatric anesthetic. Multiple studies have shown ketamine to be neurotoxic, particularly when administered during the brain growth spurt. Previously, we have shown that ketamine is detrimental to motor neuron development in the zebrafish embryos. Here, using both wild type (WT) and transgenic (hb9:GFP) zebrafish embryos, we demonstrate that ketamine is neurotoxic to both motor and sensory neurons. Drug absorption studies showed that in the WT embryos, ketamine accumulation was approximately 0.4% of the original dose added to the exposure medium. The transgenic embryos express green fluorescent protein (GFP) localized in the motor neurons making them ideal for evaluating motor neuron development and toxicities in vivo. The hb9:GFP zebrafish embryos (28 h post fertilization) treated with 2 mM ketamine for 20 h demonstrated significant reductions in spinal motor neuron numbers, while co-treatment with acetyl L-carnitine proved to be neuroprotective. In whole mount immunohistochemical studies using WT embryos, a similar effect was observed for the primary sensory neurons. In the ketamine-treated WT embryos, the number of primary sensory Rohon-Beard (RB) neurons was significantly reduced compared to that in controls. However, acetyl L-carnitine co-treatment prevented ketamine-induced adverse effects on the RB neurons. These results suggest that acetyl L-carnitine protects both motor and sensory neurons from ketamine-induced neurotoxicity.

  1. Identification and characterization of a cell surface marker for embryonic rat spinal accessory motor neurons.

    PubMed

    Schubert, W; Kaprielian, Z

    2001-10-22

    The developing mammalian spinal cord contains distinct populations of motor neurons that can be distinguished by their cell body positions, by the expression of specific combinations of regulatory genes, and by the paths that their axons take to exit the central nervous system (CNS). Subclasses of spinal motor neurons are also thought to express specific cell surface proteins that function as receptors which control the guidance of their axons. We identified monoclonal antibody (mAb) SAC1 in a screen aimed at generating markers for specific subsets of neurons/axons in the developing rat spinal cord. During early embryogenesis, mAb SAC1 selectively labels a small subset of Isl1-positive motor neurons located exclusively within cervical segments of the spinal cord. Strikingly, these neurons extend mAb SAC1-positive axons along a dorsally directed trajectory toward the lateral exit points. Consistent with the finding that mAb SAC1 also labels spinal accessory nerves, these observations identify mAb SAC1 as a specific marker of spinal accessory motor neurons/axons. During later stages of embryogenesis, mAb SAC1 is transiently expressed on both dorsally and ventrally projecting spinal motor neurons/axons. Interestingly, mAb SAC1 also labels the notochord and floor plate during most stages of spinal cord development. The mAb SAC1 antigen is a 100-kD glycoprotein that is likely to be the rat homolog of SC1/BEN/DM-GRASP, a homophilic adhesion molecule that mediates axon outgrowth and fasciculation.

  2. ALS-related misfolded protein management in motor neurons and muscle cells.

    PubMed

    Galbiati, Mariarita; Crippa, Valeria; Rusmini, Paola; Cristofani, Riccardo; Cicardi, Maria Elena; Giorgetti, Elisa; Onesto, Elisa; Messi, Elio; Poletti, Angelo

    2014-12-01

    Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset motor neuron disease. It is now considered a multi-factorial and multi-systemic disorder in which alterations of the crosstalk between neuronal and non-neuronal cell types might influence the course of the disease. In this review, we will provide evidence that dysfunctions of affected muscle cells are not only a marginal consequence of denervation associated to motor neurons loss, but a direct consequence of cell muscle toxicity of mutant SOD1. In muscle, the misfolded state of mutant SOD1 protein, unlike in motor neurons, does not appear to have direct effects on protein aggregation and mitochondrial functionality. Muscle cells are, in fact, more capable than motor neurons to handle misfolded proteins, suggesting that mutant SOD1 toxicity in muscle is not mediated by classical mechanisms of intracellular misfolded proteins accumulation. Several recent works indicate that a higher activation of molecular chaperones and degradative systems is present in muscle cells, which for this reason are possibly able to better manage misfolded mutant SOD1. However, several alterations in gene expression and regenerative potential of skeletal muscles have also been reported as a consequence of the expression of mutant SOD1 in muscle. Whether these changes in muscle cells are causative of ALS or a consequence of motor neuron alterations is not yet clear, but their elucidation is very important, since the understanding of the mechanisms involved in mutant SOD1 toxicity in muscle may facilitate the design of treatments directed toward this specific tissue to treat ALS or at least to delay disease progression.

  3. Graded synaptic transmission between local interneurones and motor neurones in the metathoracic ganglion of the locust.

    PubMed Central

    Burrows, M; Siegler, M V

    1978-01-01

    1. In the metathoracic ganglion of the locust some neurones can effect changes in the membrane potential of identified post-synaptic motor neurones without themselves spiking. 2. These 'non-spiking' neurones have processes only within the metathoracic ganglion, and therefore are local intraganglionic interneurones. 3. The absence of spikes in the interneurones reflects their normal physiological state and is not due to the experimental conditions. 4. When the interneurones are depolarized by the injection of current pulses lasting several hundred milliseconds, post-synaptic motor neurones are either depolarized, or hyperpolarized, for the duration of the pulse. 5. The magnitude of the change in post-synaptic voltage is graded according to the amount of presynaptic current. 6. A number of physiological tests indicate that the graded effects upon motor neurones are mediated by chemical synaptic transmission. For example, an evoked hyperpolarization of a motor neurone can be reversed in polarity by simultaneously hyperpolarizing the motor neurone with injected current. 7. At their resting potential some interneurones tonically release sufficient transmitter to have a measurable post-synaptic effect. The injection of depolarizing and hyperpolarizing currents into these interneurones effects opposite changes in post-synaptic potential. 8. Other interneurones must be depolarized from resting potential before a post-synaptic effect is observed, and hyperpolarizing currents have no post-synaptic effect. In these interneurones it is estimated that a depolarization of only 2 mV is sufficient to effect the release of transmitter. 9. The membrane potentials of non-spiking interneurones can fluctuate by as much as 15 mV during active movements of the hind legs and individual p.s.p.s as large as 5 mV can be recorded. Therefore, summed p.s.p.s or even single ones are expected to be the electrophysiological signals effecting transmitter release from these interneurones. PMID

  4. Optical control of muscle function by transplantation of stem cell-derived motor neurons in mice.

    PubMed

    Bryson, J Barney; Machado, Carolina Barcellos; Crossley, Martin; Stevenson, Danielle; Bros-Facer, Virginie; Burrone, Juan; Greensmith, Linda; Lieberam, Ivo

    2014-04-04

    Damage to the central nervous system caused by traumatic injury or neurological disorders can lead to permanent loss of voluntary motor function and muscle paralysis. Here, we describe an approach that circumvents central motor circuit pathology to restore specific skeletal muscle function. We generated murine embryonic stem cell-derived motor neurons that express the light-sensitive ion channel channelrhodopsin-2, which we then engrafted into partially denervated branches of the sciatic nerve of adult mice. These engrafted motor neurons not only reinnervated lower hind-limb muscles but also enabled their function to be restored in a controllable manner using optogenetic stimulation. This synthesis of regenerative medicine and optogenetics may be a successful strategy to restore muscle function after traumatic injury or disease.

  5. Rapid Integration of Artificial Sensory Feedback during Operant Conditioning of Motor Cortex Neurons.

    PubMed

    Prsa, Mario; Galiñanes, Gregorio L; Huber, Daniel

    2017-02-22

    Neuronal motor commands, whether generating real or neuroprosthetic movements, are shaped by ongoing sensory feedback from the displacement being produced. Here we asked if cortical stimulation could provide artificial feedback during operant conditioning of cortical neurons. Simultaneous two-photon imaging and real-time optogenetic stimulation were used to train mice to activate a single neuron in motor cortex (M1), while continuous feedback of its activity level was provided by proportionally stimulating somatosensory cortex. This artificial signal was necessary to rapidly learn to increase the conditioned activity, detect correct performance, and maintain the learned behavior. Population imaging in M1 revealed that learning-related activity changes are observed in the conditioned cell only, which highlights the functional potential of individual neurons in the neocortex. Our findings demonstrate the capacity of animals to use an artificially induced cortical channel in a behaviorally relevant way and reveal the remarkable speed and specificity at which this can occur.

  6. Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

    PubMed Central

    Yamashita, Takenari; Aizawa, Hitoshi; Teramoto, Sayaka; Akamatsu, Megumi; Kwak, Shin

    2017-01-01

    Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we investigated the mechanism by which the nuclear pore complex (NPC) is disrupted in dying motor neurons in a mechanistic ALS mouse model (adenosine deaminase acting on RNA 2 (ADAR2) conditional knockout (AR2) mice) and in ALS patients. We showed that nucleoporins (Nups) that constituted the NPC were cleaved by activated calpain via a Ca2+-permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice. In these neurons, nucleo-cytoplasmic transport was disrupted, and the level of the transcript elongation enzyme RNA polymerase II phosphorylated at Ser2 was significantly decreased. Analogous changes were observed in motor neurons lacking ADAR2 immunoreactivity in sporadic ALS patients. Therefore, calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca2+-mediated cell death signals may be a therapeutic strategy for ALS. PMID:28045133

  7. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    PubMed

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed. © 2013 Anatomical Society.

  8. The critical role of membralin in postnatal motor neuron survival and disease

    PubMed Central

    Yang, Bo; Qu, Mingliang; Wang, Rengang; Chatterton, Jon E; Liu, Xiao-Bo; Zhu, Bing; Narisawa, Sonoko; Millan, Jose Luis; Nakanishi, Nobuki; Swoboda, Kathryn; Lipton, Stuart A; Zhang, Dongxian

    2015-01-01

    Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5–6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease. DOI: http://dx.doi.org/10.7554/eLife.06500.001 PMID:25977983

  9. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    PubMed Central

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed. PMID:23876144

  10. Autophagy-mediated stress response in motor neurons after hypothermic spinal cord ischemia in rabbits.

    PubMed

    Fujita, Satoshi; Sakurai, Masahiro; Baba, Hironori; Abe, Koji; Tominaga, Ryuji

    2015-11-01

    The development of spinal cord injury is believed to be related to the vulnerability of spinal motor neurons to ischemia. However, the mechanisms underlying this vulnerability have not been fully investigated. Previously, we reported that spinal motor neurons are lost likely due to autophagy and that local hypothermia prevents such spinal motor neuron death. Therefore, we investigated the role of autophagy in normothermic and hypothermic spinal cord ischemia using an immunohistochemical analysis of Beclin 1 (BCLN1; B-cell leukemia 2 protein [Bcl-2] interacting protein), Bcl-2, and γ-aminobutyric acid type-A receptor-associated protein (GABARAP), which are considered autophagy-related proteins. We used rabbit normothermic and hypothermic transient spinal cord ischemia models using a balloon catheter. Neurologic function was assessed according to the Johnson score, and the spinal cord was removed at 8 hours and 1, 2, and 7 days after reperfusion, and morphologic changes were examined using hematoxylin and eosin staining. A Western blot analysis and histochemical study of BCLN1, Bcl-2, and GABARAP, and double-labeled fluorescent immunocytochemical studies were performed. There were significant differences in the physiologic function between the normothermic model and hypothermic model after the procedure (P < .05). In the normothermic model, most of the motor neurons were selectively lost at 7 days of reperfusion (P < .001 compared with the sham group), and they were preserved in the hypothermic model (P = .574 compared with the sham group). The Western blot analysis revealed that the sustained expression of the autophagy markers, BCLN1 and GABARAP, was observed (P < .001 compared with the sham group) and was associated with neuronal cell death in normothermic ischemic conditions. In hypothermic ischemic conditions, the autophagy inhibitory protein Bcl-2 was powerfully induced (P < .001 compared with the sham group) and was associated with blunted expression

  11. Correlation between discharge timings of pairs of motor units reveals the presence but not the proportion of common synaptic input to motor neurons.

    PubMed

    Rodriguez-Falces, Javier; Negro, Francesco; Farina, Dario

    2017-04-01

    We investigated whether correlation measures derived from pairs of motor unit (MU) spike trains are reliable indicators of the degree of common synaptic input to motor neurons. Several 50-s isometric contractions of the biceps brachii muscle were performed at different target forces ranging from 10 to 30% of the maximal voluntary contraction relying on force feedback. Forty-eight pairs of MUs were examined at various force levels. Motor unit synchrony was assessed by cross-correlation analysis using three indexes: the output correlation as the peak of the cross-histogram (ρ) and the number of synchronous spikes per second (CIS) and per trigger (E). Individual analysis of MU pairs revealed that ρ, CIS, and E were most often positively associated with discharge rate (87, 85, and 76% of the MU pairs, respectively) and negatively with interspike interval variability (69, 65, and 62% of the MU pairs, respectively). Moreover, the behavior of synchronization indexes with discharge rate (and interspike interval variability) varied greatly among the MU pairs. These results were consistent with theoretical predictions, which showed that the output correlation between pairs of spike trains depends on the statistics of the input current and motor neuron intrinsic properties that differ for different motor neuron pairs. In conclusion, the synchronization between MU firing trains is necessarily caused by the (functional) common input to motor neurons, but it is not possible to infer the degree of shared common input to a pair of motor neurons on the basis of correlation measures of their output spike trains.NEW & NOTEWORTHY The strength of correlation between output spike trains is only poorly associated with the degree of common input to the population of motor neurons. The synchronization between motor unit firing trains is necessarily caused by the (functional) common input to motor neurons, but it is not possible to infer the degree of shared common input to a pair of

  12. Regulation of ciliary neurotrophic factor receptor alpha in sciatic motor neurons following axotomy.

    PubMed

    MacLennan, A J; Devlin, B K; Neitzel, K L; McLaurin, D L; Anderson, K J; Lee, N

    1999-01-01

    Spinal motor neurons are one of the few classes of neurons capable of regenerating axons following axotomy. Injury-induced expression of neurotrophic factors and corresponding receptors may play an important role in this rare ability. A wide variety of indirect data suggests that ciliary neurotrophic factor receptor alpha may critically contribute to the regeneration of injured spinal motor neurons. We used immunohistochemistry, in situ hybridization and retrograde tracing techniques to study the regulation of ciliary neurotrophic factor receptor alpha in axotomized sciatic motor neurons. Ciliary neurotrophic factor receptor alpha immunoreactivity, detected with two independent antisera, is increased in a subpopulation of caudal sciatic motor neuron soma one, two and six weeks after sciatic nerve transection and reattachment, while no changes are detected at one day and 15 weeks post-lesion. Ciliary neurotrophic factor receptor alpha messenger RNA levels are augmented in the same classes of neurons following an identical lesion, suggesting that increased synthesis contributes, at least in part, to the additional ciliary neurotrophic factor receptor alpha protein. Separating the proximal and distal nerve stumps with a plastic barrier does not noticeably affect the injury-induced change in ciliary neurotrophic factor receptor alpha regulation, thereby indicating that this injury response is not dependent on signals distal to the lesion traveling retrogradely through the nerve or signals generated by axonal growth through the distal nerve. The prolonged increases in ciliary neurotrophic factor receptor alpha protein and messenger RNA found in regenerating sciatic motor neurons contrast with the responses of non-regenerating central neurons, which are reported to display, at most, a short-lived increase in ciliary neurotrophic factor receptor alpha messenger RNA expression following injury. The present data are the first to demonstrate, in vivo, neuronal regulation of

  13. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

    PubMed Central

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-01-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA. PMID:23208423

  14. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.

    PubMed

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-03-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

  15. HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.

    PubMed

    Heilman, Patrick L; Song, SungWon; Miranda, Carlos J; Meyer, Kathrin; Srivastava, Amit K; Knapp, Amy; Wier, Christopher G; Kaspar, Brian K; Kolb, Stephen J

    2017-11-01

    Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. RetroDISCO: Clearing technique to improve quantification of retrograde labeled motor neurons of intact mouse spinal cords.

    PubMed

    Žygelytė, Emilija; Bernard, Megan E; Tomlinson, Joy E; Martin, Matthew J; Terhorst, Allegra; Bradford, Harriet E; Lundquist, Sarah A; Sledziona, Michael; Cheetham, Jonathan

    2016-09-15

    Quantification of the number of axons reinnervating a target organ is often used to assess regeneration after peripheral nerve repair, but because of axonal branching, this method can overestimate the number of motor neurons regenerating across an injury. Current methods to count the number of regenerated motor neurons include retrograde labeling followed by cryosectioning and counting labeled motor neuron cell bodies, however, the process of sectioning introduces error from potential double counting of cells in adjacent sections. We describe a method, retroDISCO, that optically clears whole mouse spinal cord without loss of fluorescent signal to allow imaging of retrograde labeled motor neurons using confocal microscopy. Complete optical clearing of spinal cords takes four hours and confocal microscopy can obtain z-stacks of labeled motor neuron pools within 3-5min. The technique is able to detect anticipated differences in motor neuron number after cross-suture and conduit repair compared to intact mice and is highly repeatable. RetroDISCO is inexpensive, simple, robust and uses commonly available microscopy techniques to determine the number of motor neurons extending axons across an injury site, avoiding the need for labor-intensive cryosectioning and potential double counting of motor neuron cell bodies in adjacent sections. RetroDISCO allows rapid quantification of the degree of reinnervation without the confounding produced by axonal sprouting. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Global Motor Unit Number Index sum score for assessing the loss of lower motor neurons in amyotrophic lateral sclerosis.

    PubMed

    Grimaldi, Stephan; Duprat, Lauréline; Grapperon, Aude-Marie; Verschueren, Annie; Delmont, Emilien; Attarian, Shahram

    2017-02-06

    Introduction Our objective was to propose a motor unit number index (MUNIX) global sum score in amyotrophic lateral sclerosis (ALS) to estimate the loss of functional motor units. Methods MUNIX was assessed for 18 ALS patients and 17 healthy controls in seven muscles: the abductor pollicis brevis (APB), abductor digiti minimi (ADM), tibialis anterior (TA), deltoid, trapezius, submental complex (SMC) and orbicularis oris. Results MUNIX was significantly lower in ALS patients than in healthy controls for the APB, ADM, TA and the trapezius muscles. The MUNIX sum score of 4 muscles (ADM + APB + Trapezius + TA) was lower in ALS patients (P = 0.01) and was correlated with clinical scores. Discussion The global MUNIX sum score proposed in this study estimates the loss of lower motor neurons in several body regions including the trapezius, and is correlated with clinical impairment in ALS patients. This article is protected by copyright. All rights reserved.

  18. P2X7 receptor-induced death of motor neurons by a peroxynitrite/FAS-dependent pathway

    PubMed Central

    Gandelman, Mandi; Levy, Mark; Cassina, Patricia; Barbeito, Luis; Beckman, Joseph S

    2013-01-01

    The P2X7 receptor/channel responds to extracellular ATP and is associated with neuronal death and neuroinflammation in spinal cord injury and amyotrophic lateral sclerosis (ALS). Whether activation of P2X7 directly causes motor neuron death is unknown. We found that cultured motor neurons isolated from embryonic rat spinal cord express P2X7 and underwent caspase-dependent apoptosis when exposed to exceptionally low concentrations of the P2X7 agonist 3′-O-(4-benzoyl)-ATP (BzATP). The P2X7 inhibitors BBG, oATP and KN-62 prevented BzATP-induced motor neuron death. The endogenous P2X7 agonist ATP induced motor neuron death at low concentrations (1-100 μM). High concentrations of ATP (1 mM) paradoxically became protective due to degradation in the culture media to produce adenosine and activate adenosine receptors. P2X7-induced motor neuron death was dependent on neuronal nitric oxide synthase-mediated production of peroxynitrite, p38 activation and autocrine FAS signaling. Taken together, our results indicate that motor neurons are highly sensitive to P2X7 activation, which triggers apoptosis by activation of the well-established peroxynitrite/FAS death pathway in motor neurons. PMID:23646980

  19. Advance care planning in motor neuron disease: A qualitative study of caregiver perspectives.

    PubMed

    Murray, Leigh; Butow, Phyllis N; White, Kate; Kiernan, Matthew C; D'Abrew, Natalie; Herz, Helen

    2016-05-01

    Motor neuron disease is a fatal disease, characterised by progressive loss of motor function, often associated with cognitive deterioration and, in some, the development of frontotemporal dementia. Life-sustaining technologies are available (e.g. non-invasive ventilation and enteral nutrition) but may compromise quality of life for some patients. Timely commencement of 'Advance Care Planning' enables patients to participate in future care choices; however, this approach has rarely been explored in motor neuron disease. We aimed to investigate caregiver perspectives on the acceptability and impact of advance care planning, documented in a letter format, for patients with motor neuron disease and caregivers. This is a qualitative cross-sectional study. Data were analysed by a narrative synthesis approach. Structured interviews were held with 18 former caregivers of deceased patients with motor neuron disease. A total of 10 patients had created a disease-specific advanced directive, 'Letter of Future Care', and 8 had not. A total of four global themes emerged: Readiness for death, Empowerment, Connections and Clarifying decisions and choices. Many felt the letter of future care was or would be beneficial, engendering autonomy and respect for patients, easing difficult decision-making and enhancing communication within families. However, individuals' 'readiness' to accept encroaching death would influence uptake. Appropriate timing to commence advance care planning may depend on case-based clinical and personal characteristics. Advance care planning can assist patients to achieve a sense of control and 'peace of mind' and facilitates important family discussion. However, the timing and style of its introduction needs to be approached sensitively. Tools and strategies for increasing the efficacy of advance care planning for motor neuron disease should be evaluated and implemented. © The Author(s) 2016.

  20. Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.

    PubMed

    Radunovic, Aleksandar; Annane, Djillali; Rafiq, Muhammad K; Brassington, Ruth; Mustfa, Naveed

    2017-10-06

    Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal neurodegenerative disease. Neuromuscular respiratory failure is the most common cause of death, which usually occurs within two to five years of the disease onset. Supporting respiratory function with mechanical ventilation may improve survival and quality of life. This is the second update of a review first published in 2009. To assess the effects of mechanical ventilation (tracheostomy-assisted ventilation and non-invasive ventilation (NIV)) on survival, functional measures of disease progression, and quality of life in ALS, and to evaluate adverse events related to the intervention. We searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, and AMED on 30 January 2017. We also searched two clinical trials registries for ongoing studies. Randomised controlled trials (RCTs) and quasi-RCTs involving non-invasive or tracheostomy-assisted ventilation in participants with a clinical diagnosis of ALS, independent of the reported outcomes. We included comparisons with no intervention or the best standard care. For the original review, four review authors independently selected studies for assessment. Two review authors reviewed searches for this update. All review authors independently extracted data from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible. We planned to collect adverse event data from the included studies. For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below.Incomplete data were available for one published study comparing early and late initiation of

  1. Symptomatic treatments for amyotrophic lateral sclerosis/motor neuron disease.

    PubMed

    Ng, Louisa; Khan, Fary; Young, Carolyn A; Galea, Mary

    2017-01-10

    Motor neuron disease (MND), which is also known as amyotrophic lateral sclerosis (ALS), causes a wide range of symptoms but the evidence base for the effectiveness of the symptomatic treatment therapies is limited. To summarise the evidence from Cochrane Systematic Reviews of all symptomatic treatments for MND. We searched the Cochrane Database of Systematic Reviews (CDSR) on 15 November 2016 for systematic reviews of symptomatic treatments for MND. We assessed the methodological quality of the included reviews using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the GRADE approach. We followed standard Cochrane study (review) selection and data extraction procedures. We reported findings narratively and in tables. We included nine Cochrane Systematic Reviews of interventions to treat symptoms in people with MND. Three were empty reviews with no included randomised controlled trials (RCTs); however, all three reported on non-RCT evidence and the remaining six included mostly one or two studies. We deemed all of the included reviews of high methodological quality. Drug therapy for painThere is no RCT evidence in a Cochrane Systematic Review exploring the efficacy of drug therapy for pain in MND. Treatment for crampsThere is evidence (13 RCTs, N = 4012) that for the treatment of cramps in MND, compared to placebo:- memantine and tetrahydrocannabinol (THC) are probably ineffective (moderate-quality evidence);- vitamin E may have little or no effect (low-quality evidence); and- the effects of L-threonine, gabapentin, xaliproden, riluzole, and baclofen are uncertain as the evidence is either very low quality or the trial specified the outcome but did not report numerical data.The review reported adverse effects of riluzole, but it is not clear whether other interventions had adverse effects. Treatment for spasticityIt is uncertain whether an endurance-based exercise programme improved spasticity or quality of life, measured at three months after the

  2. Quantification of the proportion of motor neurons recruited by transcranial electrical stimulation during intraoperative motor evoked potential monitoring.

    PubMed

    Tsutsui, Shunji; Yamada, Hiroshi; Hashizume, Hiroshi; Minamide, Akihito; Nakagawa, Yukihiro; Iwasaki, Hiroshi; Yoshida, Munehito

    2013-12-01

    Transcranial motor evoked potentials (TcMEPs) are widely used to monitor motor function during spinal surgery. However, they are much smaller and more variable in amplitude than responses evoked by maximal peripheral nerve stimulation, suggesting that a limited number of spinal motor neurons to the target muscle are excited by transcranial stimulation. The aim of this study was to quantify the proportion of motor neurons recruited during TcMEP monitoring under general anesthesia. In twenty patients who underwent thoracic and/or lumbar spinal surgery with TcMEP monitoring, the triple stimulation technique (TST) was applied to the unilateral upper arm intraoperatively. Total intravenous anesthesia was employed. Trains of four stimuli were delivered with maximal intensity and an inter-pulse interval of 1.5 ms. TST responses were recorded from the abductor digiti minimi muscle, and the negative peak amplitude and area were measured and compared between the TST test (two collisions between transcranial and proximal and distal peripheral stimulation) and control response (two collisions between two proximal and one distal peripheral stimulation). The highest degree of superimposition of the TST test and control responses was chosen from several trials per patient. The average ratios (test:control) were 17.1 % (range 1.8-38 %) for the amplitudes and 21.6 % (range 2.9-40 %) for the areas. The activity of approximately 80 % of the motor units to the target muscle cannot be detected by TcMEP monitoring. Therefore, changes in evoked potentials must be interpreted cautiously when assessing segmental motor function with TcMEP monitoring.

  3. Neuronal injury in the motor cortex after chronic stroke and lower limb motor impairment: a voxel-based lesion symptom mapping study.

    PubMed

    Reynolds, Alexandria M; Peters, Denise M; Vendemia, Jennifer M C; Smith, Lenwood P; Sweet, Raymond C; Baylis, Gordon C; Krotish, Debra; Fritz, Stacy L

    2014-04-01

    Many studies have examined motor impairments using voxel-based lesion symptom mapping, but few are reported regarding the corresponding relationship between cerebral cortex injury and lower limb motor impairment analyzed using this technique. This study correlated neuronal injury in the cerebral cortex of 16 patients with chronic stroke based on a voxel-based lesion symptom mapping analysis. Neuronal injury in the corona radiata, caudate nucleus and putamen of patients with chronic stroke could predict walking speed. The behavioral measure scores were consistent with motor deficits expected after damage to the cortical motor system due to stroke. These findings suggest that voxel-based lesion symptom mapping may provide a more accurate prognosis of motor recovery from chronic stroke according to neuronal injury in cerebral motor cortex.

  4. Neuronal injury in the motor cortex after chronic stroke and lower limb motor impairment: a voxel-based lesion symptom mapping study

    PubMed Central

    Reynolds, Alexandria M.; Peters, Denise M.; Vendemia, Jennifer M. C.; Smith, Lenwood P.; Sweet, Raymond C.; Baylis, Gordon C.; Krotish, Debra; Fritz, Stacy L.

    2014-01-01

    Many studies have examined motor impairments using voxel-based lesion symptom mapping, but few are reported regarding the corresponding relationship between cerebral cortex injury and lower limb motor impairment analyzed using this technique. This study correlated neuronal injury in the cerebral cortex of 16 patients with chronic stroke based on a voxel-based lesion symptom mapping analysis. Neuronal injury in the corona radiata, caudate nucleus and putamen of patients with chronic stroke could predict walking speed. The behavioral measure scores were consistent with motor deficits expected after damage to the cortical motor system due to stroke. These findings suggest that voxel-based lesion symptom mapping may provide a more accurate prognosis of motor recovery from chronic stroke according to neuronal injury in cerebral motor cortex. PMID:25206888

  5. Late onset GM2 gangliosidosis presenting with motor neuron disease: an autopsy case.

    PubMed

    Yokoyama, Teruo; Nakamura, Seigo; Horiuchi, Emiko; Ishiyama, Miyako; Kawashima, Rei; Nakamura, Kazuo; Hasegawa, Kazuko; Yagishita, Saburo

    2014-06-01

    Adult-onset GM2 gangliosidosis is very rare and only three autopsy cases have been reported up to now. We report herein an autopsy case of adult-onset GM2 gangliosidosis. The patient developed slowly progressive motor neuron disease-like symptoms after longstanding mood disorder and cognitive dysfunction. He developed gait disturbance and weakness of lower limbs at age 52 years. Because of progressive muscle weakness and atrophy, he became bed-ridden at age 65. At age of 68, he died. His neurological findings presented slight cognitive disturbance, slight manic state, severe muscle weakness, atrophy of four limbs and no extrapyramidal signs and symptoms, and cerebellar ataxia. Neuropathologically, mild neuronal loss and abundant lipid deposits were noted in the neuronal cytoplasm throughout the nervous system, including peripheral autonomic neurons. The most outstanding findings were marked neuronal loss and distended neurons in the anterior horn of the spinal cord, which supports his clinical symptomatology of lower motor neuron disease in this case. The presence of lipofuscin, zebra bodies and membranous cytoplasmic bodies (MCB) and the increase of GM2 ganglioside by biochemistry led to diagnosis of GM2 gangliosidosis. © 2013 Japanese Society of Neuropathology.

  6. Neurons in Primary Motor Cortex Encode Hand Orientation in a Reach-to-Grasp Task.

    PubMed

    Ma, Chaolin; Ma, Xuan; Fan, Jing; He, Jiping

    2017-04-07

    It is disputed whether those neurons in the primary motor cortex (M1) that encode hand orientation constitute an independent channel for orientation control in reach-to-grasp behaviors. Here, we trained two monkeys to reach forward and grasp objects positioned in the frontal plane at different orientation angles, and simultaneously recorded the activity of M1 neurons. Among the 2235 neurons recorded in M1, we found that 18.7% had a high correlation exclusively with hand orientation, 15.9% with movement direction, and 29.5% with both movement direction and hand orientation. The distributions of neurons encoding hand orientation and those encoding movement direction were not uniform but coexisted in the same region. The trajectory of hand rotation was reproduced by the firing patterns of the orientation-related neurons independent of the hand reaching direction. These results suggest that hand orientation is an independent component for the control of reaching and grasping activity.

  7. Early motor neuron pool identity and muscle nerve trajectory defined by postmitotic restrictions in Nkx6.1 activity.

    PubMed

    De Marco Garcia, Natalia V; Jessell, Thomas M

    2008-01-24

    The fidelity with which spinal motor neurons innervate their limb target muscles helps to coordinate motor behavior, but the mechanisms that determine precise patterns of nerve-muscle connectivity remain obscure. We show that Nkx6 proteins, a set of Hox-regulated homeodomain transcription factors, are expressed by motor pools soon after motor neurons leave the cell cycle, before the formation of muscle nerve side branches in the limb. Using mouse genetics, we show that the status of Nkx6.1 expression in certain motor neuron pools regulates muscle nerve formation, and the pattern of innervation of individual muscles. Our findings provide genetic evidence that neurons within motor pools possess an early transcriptional identity that controls target muscle specificity.

  8. Cathepsin B-dependent motor neuron death after nerve injury in the adult mouse

    SciTech Connect

    Sun, Li; Wu, Zhou; Baba, Masashi; Peters, Christoph; Uchiyama, Yasuo; Nakanishi, Hiroshi

    2010-08-27

    Research highlights: {yields} Cathepsin B (CB), a lysosomal cysteine protease, is expressed in neuron and glia. {yields} CB increased in hypogrossal nucleus neurons after nerve injury in adult mice. {yields} CB-deficiency significantly increased the mean survival ratio of injured neurons. {yields} Thus, CB plays a critical role in axotomy-induced neuronal death in adult mice. -- Abstract: There are significant differences in the rate of neuronal death after peripheral nerve injury between species. The rate of neuronal death of motor neurons after nerve injury in the adult rats is very low, whereas that in adult mice is relatively high. However, the understanding of the mechanism underlying axotomy-induced motor neuron death in adult mice is limited. Cathepsin B (CB), a typical cysteine lysosomal protease, has been implicated in three major morphologically distinct pathways of cell death; apoptosis, necrosis and autophagic cell death. The possible involvement of CB in the neuronal death of hypogrossal nucleus (HGN) neurons after nerve injury in adult mice was thus examined. Quantitative analyses showed the mean survival ratio of HGN neurons in CB-deficient (CB-/-) adult mice after nerve injury was significantly greater than that in the wild-type mice. At the same time, proliferation of microglia in the injured side of the HGN of CB-/- adult mice was markedly reduced compared with that in the wild-type mice. On the injured side of the HGN in the wild-type adult mice, both pro- and mature forms of CB markedly increased in accordance with the increase in the membrane-bound form of LC3 (LC3-II), a marker protein of autophagy. Furthermore, the increase in CB preceded an increase in the expression of Noxa, a major executor for axotomy-induced motor neuron death in the adult mouse. Conversely, expression of neither Noxa or LC3-II was observed in the HGN of adult CB-/- mice after nerve injury. These observations strongly suggest that CB plays a critical role in axotomy

  9. Progressive Apraxia of Speech as a Sign of Motor Neuron Disease

    ERIC Educational Resources Information Center

    Duffy, Joseph R.; Peach, Richard K.; Strand, Edythe A.

    2007-01-01

    Purpose: To document and describe in detail the occurrence of apraxia of speech (AOS) in a group of individuals with a diagnosis of motor neuron disease (MND). Method: Seven individuals with MND and AOS were identified from among 80 patients with a variety of neurodegenerative diseases and AOS (J. R. Duffy, 2006). The history, presenting…

  10. TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy

    PubMed Central

    McKee, Ann C.; Gavett, Brandon E.; Stern, Robert A.; Nowinski, Christopher J.; Cantu, Robert C.; Kowall, Neil W.; Perl, Daniel P.; Hedley-Whyte, E. Tessa; Price, Bruce; Sullivan, Chris; Morin, Peter; Lee, Hyo-Soon; Kubilus, Caroline A.; Daneshvar, Daniel H.; Wulff, Megan; Budson, Andrew E.

    2010-01-01

    Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43 kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43–positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease. PMID:20720505

  11. Conversational Rate of a Non-Vocal Person with Motor Neurone Disease Using the 'TALK' System.

    ERIC Educational Resources Information Center

    Todman, J.; Lewins, E.

    1996-01-01

    This study evaluated the use of TALK, a computer-based augmentative and alternative communication (AAC) system, in the social communications of a nonvocal woman with motor neurone disease. She was able to achieve an average conversational rate of 42 words per minute (wpm) using TALK, compared with 2 to 10 wpm with other AAC systems using…

  12. Indices of free radical activity in the cerebrospinal fluid in motor neuron disease.

    PubMed Central

    Mitchell, J D; Jackson, M J; Pentland, B

    1987-01-01

    Indices of free-radical activity and lipid peroxidation were studied in cerebrospinal fluid samples obtained from 11 patients with motor neuron disease and 11 reference subjects. No differences were found between the two groups. The significance of this finding is discussed in relation to current views of the possible pathogenesis of this disease. PMID:3625217

  13. The AMPA receptor subunit GluR1 regulates dendritic architecture of motor neurons

    NASA Technical Reports Server (NTRS)

    Inglis, Fiona M.; Crockett, Richard; Korada, Sailaja; Abraham, Wickliffe C.; Hollmann, Michael; Kalb, Robert G.

    2002-01-01

    The morphology of the mature motor neuron dendritic arbor is determined by activity-dependent processes occurring during a critical period in early postnatal life. The abundance of the AMPA receptor subunit GluR1 in motor neurons is very high during this period and subsequently falls to a negligible level. To test the role of GluR1 in dendrite morphogenesis, we reintroduced GluR1 into rat motor neurons at the end of the critical period and quantitatively studied the effects on dendrite architecture. Two versions of GluR1 were studied that differed by the amino acid in the "Q/R" editing site. The amino acid occupying this site determines single-channel conductance, ionic permeability, and other essential electrophysiologic properties of the resulting receptor channels. We found large-scale remodeling of dendritic architectures in a manner depending on the amino acid occupying the Q/R editing site. Alterations in the distribution of dendritic arbor were not prevented by blocking NMDA receptors. These observations suggest that the expression of GluR1 in motor neurons modulates a component of the molecular substrate of activity-dependent dendrite morphogenesis. The control of these events relies on subunit-specific properties of AMPA receptors.

  14. Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis.

    PubMed

    Yamashita, Takenari; Akamatsu, Megumi; Kwak, Shin

    2017-02-08

    Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral sclerosis (ALS). Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes GluA2 Q/R site-RNA editing. Furthermore, conditional ADAR2 knockout mice (AR2) exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons, which is the most reliable pathological marker of ALS. Therefore, the evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur in ALS. We discuss the contributors to ADAR2 downregulation and TDP-43 pathology in AR2 mouse motor neurons. We describe mechanisms of exaggerated Ca(2+) influx amelioration via AMPA receptors, which is neuroprotective in ADAR2-deficient motor neurons with normalization of TDP-43 pathology in AR2 mice. Development of drugs to treat diseases requires appropriate animal models and a sensitive method of evaluating efficacy. Therefore, normalization of disrupted intracellular environments resulting from ADAR2 downregulation may be a therapeutic target for ALS. We discuss the development of targeted therapy for ALS using the AR2 mouse model.

  15. Altered mRNA Splicing in SMN-Depleted Motor Neuron-Like Cells.

    PubMed

    Custer, Sara K; Gilson, Timra D; Li, Hongxia; Todd, A Gary; Astroski, Jacob W; Lin, Hai; Liu, Yunlong; Androphy, Elliot J

    2016-01-01

    Spinal muscular atrophy (SMA) is an intractable neurodegenerative disease afflicting 1 in 6-10,000 live births. One of the key functions of the SMN protein is regulation of spliceosome assembly. Reduced levels of the SMN protein that are observed in SMA have been shown to result in aberrant mRNA splicing. SMN-dependent mis-spliced transcripts in motor neurons may cause stresses that are particularly harmful and may serve as potential targets for the treatment of motor neuron disease or as biomarkers in the SMA patient population. We performed deep RNA sequencing using motor neuron-like NSC-34 cells to screen for SMN-dependent mRNA processing changes that occur following acute depletion of SMN. We identified SMN-dependent splicing changes, including an intron retention event that results in the production of a truncated Rit1 transcript. This intron-retained transcript is stable and is mis-spliced in spinal cord from symptomatic SMA mice. Constitutively active Rit1 ameliorated the neurite outgrowth defect in SMN depleted NSC-34 cells, while expression of the truncated protein product of the mis-spliced Rit1 transcript inhibited neurite extension. These results reveal new insights into the biological consequence of SMN-dependent splicing in motor neuron-like cells.

  16. MND2: A new mouse model of inherited motor neuron disease

    SciTech Connect

    Jones, J.M.; Albin, R.L.; Feldman, E.L.; Simin, K.; Schuster, T.G.; Dunnick, W.A.; Collins, J.T.; Chrisp, C.E.; Meisler, M.H. ); Taylor, B.A. )

    1993-06-01

    The autosomal recessive mutation mnd2 results in early onset motor neuron disease with rapidly progressive paralysis, severe muscle wasting, regression of thymus and spleen, and death before 40 days of age. mnd2 has been mapped to mouse chromosome 6 with the gene order: centromere-Tcrb-Ly-2-Sftp-3-D6Mit4-mnd2-D6Mit6, D6Mit9-D6Rck132-Raf-1, D6Mit11-D6Mit12-D6Mit14. mnd2 is located within a conserved linkage group with homologs on human chromosome 2p12-p13. Spinal motor neurons of homozygous affected animals are swollen and stain weakly, and electromyography revealed spontaneous activity characteristic of muscle denervation. Myelin staining was normal throughout the neuraxis. The clinical observations are consistent with a primary abnormality of lower motor neuron function. This new animal model will be of value for identification of a genetic defect responsible for motor neuron disease and for evaluation of new therapies. 36 refs., 7 figs., 2 tabs.

  17. The AMPA receptor subunit GluR1 regulates dendritic architecture of motor neurons

    NASA Technical Reports Server (NTRS)

    Inglis, Fiona M.; Crockett, Richard; Korada, Sailaja; Abraham, Wickliffe C.; Hollmann, Michael; Kalb, Robert G.

    2002-01-01

    The morphology of the mature motor neuron dendritic arbor is determined by activity-dependent processes occurring during a critical period in early postnatal life. The abundance of the AMPA receptor subunit GluR1 in motor neurons is very high during this period and subsequently falls to a negligible level. To test the role of GluR1 in dendrite morphogenesis, we reintroduced GluR1 into rat motor neurons at the end of the critical period and quantitatively studied the effects on dendrite architecture. Two versions of GluR1 were studied that differed by the amino acid in the "Q/R" editing site. The amino acid occupying this site determines single-channel conductance, ionic permeability, and other essential electrophysiologic properties of the resulting receptor channels. We found large-scale remodeling of dendritic architectures in a manner depending on the amino acid occupying the Q/R editing site. Alterations in the distribution of dendritic arbor were not prevented by blocking NMDA receptors. These observations suggest that the expression of GluR1 in motor neurons modulates a component of the molecular substrate of activity-dependent dendrite morphogenesis. The control of these events relies on subunit-specific properties of AMPA receptors.

  18. Conversational Rate of a Non-Vocal Person with Motor Neurone Disease Using the 'TALK' System.

    ERIC Educational Resources Information Center

    Todman, J.; Lewins, E.

    1996-01-01

    This study evaluated the use of TALK, a computer-based augmentative and alternative communication (AAC) system, in the social communications of a nonvocal woman with motor neurone disease. She was able to achieve an average conversational rate of 42 words per minute (wpm) using TALK, compared with 2 to 10 wpm with other AAC systems using…

  19. New Technologies in the Training of Young People with Severe Motor Neurone Disorders.

    ERIC Educational Resources Information Center

    Escoin Homs, Jordi

    1993-01-01

    Reviews the potential use of computer technology for the education, training, and occupational placement of people with severe motor neurone disorders (e.g., cerebral palsy) based on experiences in a program in Spain. Highlights include computer literacy, computer-assisted teaching, quality of output, software development, synthesized speech, and…

  20. Motor Neurone Disease: Disability Profile and Service Needs in an Australian Cohort

    ERIC Educational Resources Information Center

    Ng, Louisa; Talman, Paul; Khan, Fary

    2011-01-01

    Motor neurone disease (MND) places considerable burden upon patients and caregivers. This is the first study, which describes the disability profile and healthcare needs for persons with MND (pwMND) in an Australian sample from the perspective of the patients and caregivers to identify current gaps in the knowledge and service provision. A…

  1. Progressive Apraxia of Speech as a Sign of Motor Neuron Disease

    ERIC Educational Resources Information Center

    Duffy, Joseph R.; Peach, Richard K.; Strand, Edythe A.

    2007-01-01

    Purpose: To document and describe in detail the occurrence of apraxia of speech (AOS) in a group of individuals with a diagnosis of motor neuron disease (MND). Method: Seven individuals with MND and AOS were identified from among 80 patients with a variety of neurodegenerative diseases and AOS (J. R. Duffy, 2006). The history, presenting…

  2. Altered mRNA Splicing in SMN-Depleted Motor Neuron-Like Cells

    PubMed Central

    Todd, A. Gary; Astroski, Jacob W.; Lin, Hai; Liu, Yunlong

    2016-01-01

    Spinal muscular atrophy (SMA) is an intractable neurodegenerative disease afflicting 1 in 6–10,000 live births. One of the key functions of the SMN protein is regulation of spliceosome assembly. Reduced levels of the SMN protein that are observed in SMA have been shown to result in aberrant mRNA splicing. SMN-dependent mis-spliced transcripts in motor neurons may cause stresses that are particularly harmful and may serve as potential targets for the treatment of motor neuron disease or as biomarkers in the SMA patient population. We performed deep RNA sequencing using motor neuron-like NSC-34 cells to screen for SMN-dependent mRNA processing changes that occur following acute depletion of SMN. We identified SMN-dependent splicing changes, including an intron retention event that results in the production of a truncated Rit1 transcript. This intron-retained transcript is stable and is mis-spliced in spinal cord from symptomatic SMA mice. Constitutively active Rit1 ameliorated the neurite outgrowth defect in SMN depleted NSC-34 cells, while expression of the truncated protein product of the mis-spliced Rit1 transcript inhibited neurite extension. These results reveal new insights into the biological consequence of SMN-dependent splicing in motor neuron-like cells. PMID:27736905

  3. Motor Neurone Disease: Disability Profile and Service Needs in an Australian Cohort

    ERIC Educational Resources Information Center

    Ng, Louisa; Talman, Paul; Khan, Fary

    2011-01-01

    Motor neurone disease (MND) places considerable burden upon patients and caregivers. This is the first study, which describes the disability profile and healthcare needs for persons with MND (pwMND) in an Australian sample from the perspective of the patients and caregivers to identify current gaps in the knowledge and service provision. A…

  4. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy.

    PubMed

    McKee, Ann C; Gavett, Brandon E; Stern, Robert A; Nowinski, Christopher J; Cantu, Robert C; Kowall, Neil W; Perl, Daniel P; Hedley-Whyte, E Tessa; Price, Bruce; Sullivan, Chris; Morin, Peter; Lee, Hyo-Soon; Kubilus, Caroline A; Daneshvar, Daniel H; Wulff, Megan; Budson, Andrew E

    2010-09-01

    Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43-positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease.

  5. New Technologies in the Training of Young People with Severe Motor Neurone Disorders.

    ERIC Educational Resources Information Center

    Escoin Homs, Jordi

    1993-01-01

    Reviews the potential use of computer technology for the education, training, and occupational placement of people with severe motor neurone disorders (e.g., cerebral palsy) based on experiences in a program in Spain. Highlights include computer literacy, computer-assisted teaching, quality of output, software development, synthesized speech, and…

  6. Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis

    PubMed Central

    Yamashita, Takenari; Akamatsu, Megumi; Kwak, Shin

    2017-01-01

    Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral sclerosis (ALS). Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes GluA2 Q/R site-RNA editing. Furthermore, conditional ADAR2 knockout mice (AR2) exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons, which is the most reliable pathological marker of ALS. Therefore, the evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur in ALS. We discuss the contributors to ADAR2 downregulation and TDP-43 pathology in AR2 mouse motor neurons. We describe mechanisms of exaggerated Ca2+ influx amelioration via AMPA receptors, which is neuroprotective in ADAR2-deficient motor neurons with normalization of TDP-43 pathology in AR2 mice. Development of drugs to treat diseases requires appropriate animal models and a sensitive method of evaluating efficacy. Therefore, normalization of disrupted intracellular environments resulting from ADAR2 downregulation may be a therapeutic target for ALS. We discuss the development of targeted therapy for ALS using the AR2 mouse model. PMID:28208729

  7. Cell-type-specific miR-431 dysregulation in a motor neuron model of spinal muscular atrophy.

    PubMed

    Wertz, Mary H; Winden, Kellen; Neveu, Pierre; Ng, Shi-Yan; Ercan, Ebru; Sahin, Mustafa

    2016-06-01

    Spinal muscular atrophy (SMA) is an autosomal-recessive pediatric neurodegenerative disease characterized by selective loss of spinal motor neurons. It is caused by mutation in the survival of motor neuron 1, SMN1, gene and leads to loss of function of the full-length SMN protein. microRNAs (miRNAs) are small RNAs that are involved in post-transcriptional regulation of gene expression. Prior studies have implicated miRNAs in the pathogenesis of motor neuron disease. We hypothesized that motor neuron-specific miRNA expression changes are involved in their selective vulnerability in SMA. Therefore, we sought to determine the effect of SMN loss on miRNAs and their target mRNAs in spinal motor neurons. We used microarray and RNAseq to profile both miRNA and mRNA expression in primary spinal motor neuron cultures after acute SMN knockdown. By integrating the miRNA:mRNA profiles, a number of dysregulated miRNAs were identified with enrichment in differentially expressed putative mRNA targets. miR-431 expression was highly increased, and a number of its putative mRNA targets were significantly downregulated in motor neurons after SMN loss. Further, we found that miR-431 regulates motor neuron neurite length by targeting several molecules previously identified to play a role in motor neuron axon outgrowth, including chondrolectin. Together, our findings indicate that cell-type-specific dysregulation of miR-431 plays a role in the SMA motor neuron phenotype. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Decreased Motor Neuron Support by SMA Astrocytes due to Diminished MCP1 Secretion.

    PubMed

    Martin, Jasmin E; Nguyen, TrangKimberly T; Grunseich, Christopher; Nofziger, Jonathan H; Lee, Philip R; Fields, Douglas; Fischbeck, Kenneth H; Foran, Emily

    2017-05-24

    Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by severe, often fatal muscle weakness due to loss of motor neurons. SMA patients have deletions and other mutations of the survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein. Astrocytes are the primary support cells of the CNS and are responsible for glutamate clearance, metabolic support, response to injury, and regulation of signal transmission. Astrocytes have been implicated in SMA as in in other neurodegenerative disorders. Astrocyte-specific rescue of SMN protein levels has been shown to mitigate disease manifestations in mice. However, the mechanism by which SMN deficiency in astrocytes may contribute to SMA is unclear and what aspect of astrocyte activity is lacking is unknown. Therefore, it is worthwhile to identify defects in SMN-deficient astrocytes that compromise normal function. We show here that SMA astrocyte cultures derived from mouse spinal cord of both sexes are deficient in supporting both WT and SMN-deficient motor neurons derived from male, female, and mixed-sex sources and that this deficiency may be mitigated with secreted factors. In particular, SMN-deficient astrocytes have decreased levels of monocyte chemoactive protein 1 (MCP1) secretion compared with controls and MCP1 restoration stimulates outgrowth of neurites from cultured motor neurons. Correction of MCP1 deficiency may thus be a new therapeutic approach to SMA.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is caused by the loss of motor neurons, but astrocyte dysfunction also contributes to the disease in mouse models. Monocyte chemoactive protein 1 (MCP1) has been shown to be neuroprotective and is released by astrocytes. Here, we report that MCP1 levels are decreased in SMA mice and that replacement of deficient MCP1 increases differentiation and neurite length of WT and SMN-deficient motor-neuron-like cells in cell culture. This study reveals a novel aspect of astrocyte

  9. Bee Venom Protects against Rotenone-Induced Cell Death in NSC34 Motor Neuron Cells.

    PubMed

    Jung, So Young; Lee, Kang-Woo; Choi, Sun-Mi; Yang, Eun Jin

    2015-09-21

    Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV) extracted from honey bees has been widely used in oriental medicine and contains melittin, apamin, adolapin, mast cell-degranulating peptide, and phospholipase A₂. In this study, we tested the effects of BV on neuronal cell death by examining rotenone-induced mitochondrial dysfunction. NSC34 motor neuron cells were pretreated with 2.5 μg/mL BV and stimulated with 10 μM rotenone to induce cell toxicity. We assessed cell death by Western blotting using specific antibodies, such as phospho-ERK1/2, phospho-JNK, and cleaved capase-3 and performed an MTT assay for evaluation of cell death and mitochondria staining. Pretreatment with 2.5 μg/mL BV had a neuroprotective effect against 10 μM rotenone-induced cell death in NSC34 motor neuron cells. Pre-treatment with BV significantly enhanced cell viability and ameliorated mitochondrial impairment in rotenone-treated cellular model. Moreover, BV treatment inhibited the activation of JNK signaling and cleaved caspase-3 related to cell death and increased ERK phosphorylation involved in cell survival in rotenone-treated NSC34 motor neuron cells. Taken together, we suggest that BV treatment can be useful for protection of neurons against oxidative stress or neurotoxin-induced cell death.

  10. Bee Venom Protects against Rotenone-Induced Cell Death in NSC34 Motor Neuron Cells

    PubMed Central

    Jung, So Young; Lee, Kang-Woo; Choi, Sun-Mi; Yang, Eun Jin

    2015-01-01

    Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV) extracted from honey bees has been widely used in oriental medicine and contains melittin, apamin, adolapin, mast cell-degranulating peptide, and phospholipase A2. In this study, we tested the effects of BV on neuronal cell death by examining rotenone-induced mitochondrial dysfunction. NSC34 motor neuron cells were pretreated with 2.5 μg/mL BV and stimulated with 10 μM rotenone to induce cell toxicity. We assessed cell death by Western blotting using specific antibodies, such as phospho-ERK1/2, phospho-JNK, and cleaved capase-3 and performed an MTT assay for evaluation of cell death and mitochondria staining. Pretreatment with 2.5 μg/mL BV had a neuroprotective effect against 10 μM rotenone-induced cell death in NSC34 motor neuron cells. Pre-treatment with BV significantly enhanced cell viability and ameliorated mitochondrial impairment in rotenone-treated cellular model. Moreover, BV treatment inhibited the activation of JNK signaling and cleaved caspase-3 related to cell death and increased ERK phosphorylation involved in cell survival in rotenone-treated NSC34 motor neuron cells. Taken together, we suggest that BV treatment can be useful for protection of neurons against oxidative stress or neurotoxin-induced cell death. PMID:26402700

  11. Normal dendrite growth in Drosophila motor neurons requires the AP-1 transcription factor.

    PubMed

    Hartwig, Cortnie L; Worrell, Jason; Levine, Richard B; Ramaswami, Mani; Sanyal, Subhabrata

    2008-09-01

    During learning and memory formation, information flow through networks is regulated significantly through structural alterations in neurons. Dendrites, sites of signal integration, are key targets of activity-mediated modifications. Although local mechanisms of dendritic growth ensure synapse-specific changes, global mechanisms linking neural activity to nuclear gene expression may have profound influences on neural function. Fos, being an immediate-early gene, is ideally suited to be an initial transducer of neural activity, but a precise role for the AP-1 transcription factor in dendrite growth remains to be elucidated. Here we measure changes in the dendritic fields of identified Drosophila motor neurons in vivo and in primary culture to investigate the role of the immediate-early transcription factor AP-1 in regulating endogenous and activity-induced dendrite growth. Our data indicate that (a) increased neural excitability or depolarization stimulates dendrite growth, (b) AP-1 (a Fos, Jun hetero-dimer) is required for normal motor neuron dendritic growth during development and in response to activity induction, and (c) neuronal Fos protein levels are rapidly but transiently induced in motor neurons following neural activity. Taken together, these results show that AP-1 mediated transcription is important for dendrite growth, and that neural activity influences global dendritic growth through a gene-expression dependent mechanism gated by AP-1.

  12. Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis.

    PubMed

    Riancho, J; Gonzalo, I; Ruiz-Soto, M; Berciano, J

    2016-02-04

    Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration. ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established. Copyright © 2016 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  13. Repurposing Reelin: the new role of radial glia, Reelin and Notch in motor neuron migration.

    PubMed

    Hawthorne, Alicia L

    2014-06-01

    The role of Reelin during cerebral cortical neuron migration has long been studied, but the Reelin signaling pathway and its possible interactions are just beginning to be unraveled. Reelin is not only important in cerebral cortical migration, but has recently been shown to interact with the Notch signaling pathway and to be critical for radial glial cell number and morphology. Lee and Song (2013) show a new Notch- and Reelin-dependent role for radial glia in the mouse spinal cord: to act as a fine filter that allows somatic motor neuron axons but not cell bodies to traverse out of the CNS. Here, the types of neuronal migration are discussed, focusing on motor neurons and cues for proper localization. The interaction of Reelin signaling with the Notch pathway is reviewed, which dictates the proper formation of radial glia in the spinal cord in order to prevent ectopic motor neuron migration (Lee and Song, 2013). Future studies may reveal novel interactions and further insights as to how Reelin functions throughout the developing nervous system. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Putamen neurons process both sensory and motor information during a complex task.

    PubMed

    Vicente, Ana F; Bermudez, Maria A; Romero, Maria Del Carmen; Perez, Rogelio; Gonzalez, Francisco

    2012-07-23

    The putamen has classically been considered to be primarily a motor structure. It is involved in a broad range of roles and its neurons have been postulated to function as pattern classifiers of behaviourally significant events. However, its specific role in motor and sensory processing is still unclear. For the purpose of better categorizing putamen neurons, we trained two rhesus monkeys to perform multisensory operant tasks by using complex stimuli such as short videoclips. Trials involved image or soundtrack or both. Some stimuli required a motor response associated to reward, whereas others did not require response and produced no reward. We found that neurons in the putamen showed pure visual responses, action-related activity, and reward responses. Insofar as action-related activity, preparation of movement, movement execution, and withholding of movement involved three different putamen neuron populations. Moreover, our data suggest an involvement of putamen neurons in processing primary rewards and visual events in a complex task, which may contribute to reinforcement learning through stimulus-reward association.

  15. Plastic Changes in the Spinal Cord in Motor Neuron Disease

    PubMed Central

    Fornai, Francesco; Ferrucci, Michela; Lenzi, Paola; Falleni, Alessandra; Biagioni, Francesca; Flaibani, Marina; Siciliano, Gabriele; Giannessi, Francesco; Paparelli, Antonio

    2014-01-01

    In the present paper, we analyze the cell number within lamina X at the end stage of disease in a G93A mouse model of ALS; the effects induced by lithium; the stem-cell like phenotype of lamina X cells during ALS; the differentiation of these cells towards either a glial or neuronal phenotype. In summary we found that G93A mouse model of ALS produces an increase in lamina X cells which is further augmented by lithium administration. In the absence of lithium these nestin positive stem-like cells preferentially differentiate into glia (GFAP positive), while in the presence of lithium these cells differentiate towards a neuron-like phenotype (βIII-tubulin, NeuN, and calbindin-D28K positive). These effects of lithium are observed concomitantly with attenuation in disease progression and are reminiscent of neurogenetic effects induced by lithium in the subependymal ventricular zone of the hippocampus. PMID:24829911

  16. Lower Motor Control Modeled by Neuron With Fuzzy Synapses

    DTIC Science & Technology

    2007-11-02

    seen in parkinsonism , chorea, cerebellar disorders, and spasticity. In most cases, muscles work in opposing pairs: one muscle opens or extends a joint...performances of predictor schemes based on neurons with fuzzy synapses of order P = 3 in tremor prediction applications. The rules of these particular...Chelaru, A. Kandel, I. Tofan, M. Irimia, “Fuzzy methods in tremor assessment, prediction, and rehabilitation”, Artificial Intelligence in Medicine

  17. Morphological Characteristics of Motor Neurons Do Not Determine Their Relative Susceptibility to Degeneration in a Mouse Model of Severe Spinal Muscular Atrophy

    PubMed Central

    Mutsaers, Chantal A.; Thomson, Derek; Hamilton, Gillian; Parson, Simon H.; Gillingwater, Thomas H.

    2012-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice – including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA. PMID:23285108

  18. Tissue Plasminogen Activator Induction in Purkinje Neurons After Cerebellar Motor Learning

    NASA Astrophysics Data System (ADS)

    Seeds, Nicholas W.; Williams, Brian L.; Bickford, Paula C.

    1995-12-01

    The cerebellar cortex is implicated in the learning of complex motor skills. This learning may require synaptic remodeling of Purkinje cell inputs. An extracellular serine protease, tissue plasminogen activator (tPA), is involved in remodeling various nonneural tissues and is associated with developing and regenerating neurons. In situ hybridization showed that expression of tPA messenger RNA was increased in the Purkinje neurons of rats within an hour of their being trained for a complex motor task. Antibody to tPA also showed the induction of tPA protein associated with cerebellar Purkinje cells. Thus, the induction of tPA during motor learning may play a role in activity-dependent synaptic plasticity.

  19. Physiological basis and image processing in functional magnetic resonance imaging: Neuronal and motor activity in brain

    PubMed Central

    Sharma, Rakesh; Sharma, Avdhesh

    2004-01-01

    Functional magnetic resonance imaging (fMRI) is recently developing as imaging modality used for mapping hemodynamics of neuronal and motor event related tissue blood oxygen level dependence (BOLD) in terms of brain activation. Image processing is performed by segmentation and registration methods. Segmentation algorithms provide brain surface-based analysis, automated anatomical labeling of cortical fields in magnetic resonance data sets based on oxygen metabolic state. Registration algorithms provide geometric features using two or more imaging modalities to assure clinically useful neuronal and motor information of brain activation. This review article summarizes the physiological basis of fMRI signal, its origin, contrast enhancement, physical factors, anatomical labeling by segmentation, registration approaches with examples of visual and motor activity in brain. Latest developments are reviewed for clinical applications of fMRI along with other different neurophysiological and imaging modalities. PMID:15125779

  20. Coculture of Primary Motor Neurons and Schwann Cells as a Model for In Vitro Myelination.

    PubMed

    Hyung, Sujin; Yoon Lee, Bo; Park, Jong-Chul; Kim, Jinseok; Hur, Eun-Mi; Francis Suh, Jun-Kyo

    2015-10-12

    A culture system that can recapitulate myelination in vitro will not only help us better understand the mechanism of myelination and demyelination, but also find out possible therapeutic interventions for treating demyelinating diseases. Here, we introduce a simple and reproducible myelination culture system using mouse motor neurons (MNs) and Schwann cells (SCs). Dissociated motor neurons are plated on a feeder layer of SCs, which interact with and wrap around the axons of MNs as they differentiate in culture. In our MN-SC coculture system, MNs survived over 3 weeks and extended long axons. Both viability and axon growth of MNs in the coculture were markedly enhanced as compared to those of MN monoculture. Co-labeling of myelin basic proteins (MBPs) and neuronal microtubules revealed that SC formed myelin sheaths by wrapping around the axons of MNs. Furthermore, using the coculture system we found that treatment of an antioxidant substance coenzyme Q10 (Co-Q10) markedly facilitated myelination.

  1. Coculture of Primary Motor Neurons and Schwann Cells as a Model for In Vitro Myelination

    PubMed Central

    Hyung, Sujin; Yoon Lee, Bo; Park, Jong-Chul; Kim, Jinseok; Hur, Eun-Mi; Francis Suh, Jun-Kyo

    2015-01-01

    A culture system that can recapitulate myelination in vitro will not only help us better understand the mechanism of myelination and demyelination, but also find out possible therapeutic interventions for treating demyelinating diseases. Here, we introduce a simple and reproducible myelination culture system using mouse motor neurons (MNs) and Schwann cells (SCs). Dissociated motor neurons are plated on a feeder layer of SCs, which interact with and wrap around the axons of MNs as they differentiate in culture. In our MN-SC coculture system, MNs survived over 3 weeks and extended long axons. Both viability and axon growth of MNs in the coculture were markedly enhanced as compared to those of MN monoculture. Co-labeling of myelin basic proteins (MBPs) and neuronal microtubules revealed that SC formed myelin sheaths by wrapping around the axons of MNs. Furthermore, using the coculture system we found that treatment of an antioxidant substance coenzyme Q10 (Co-Q10) markedly facilitated myelination. PMID:26456300

  2. Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment.

    PubMed

    Matusica, Dusan; Alfonsi, Fabienne; Turner, Bradley J; Butler, Tim J; Shepheard, Stephanie R; Rogers, Mary-Louise; Skeldal, Sune; Underwood, Clare K; Mangelsdorf, Marie; Coulson, Elizabeth J

    2016-02-01

    The p75 neurotrophin receptor (p75(NTR); also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75(NTR)-derived trophic cell-permeable peptide, c29, to inhibit p75(NTR)-mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1(G93A) mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75(NTR) cleavage products. Although c29 treatment inhibited mature- and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75(NTR) in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75(NTR) cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1(G93A) mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo. © 2016. Published by The Company of Biologists Ltd.

  3. Induction of parkinsonism-related proteins in the spinal motor neurons of transgenic mouse carrying a mutant SOD1 gene.

    PubMed

    Morimoto, Nobutoshi; Nagai, Makiko; Miyazaki, Kazunori; Ohta, Yasuyuki; Kurata, Tomoko; Takehisa, Yasushi; Ikeda, Yoshio; Matsuura, Tohru; Asanuma, Masato; Abe, Koji

    2010-06-01

    Amyotrophic lateral sclerosis is a progressive and fatal disease caused by selective death of motor neurons, and a number of these patients carry mutations in the superoxide dismutase 1 (SOD1) gene involved in ameliorating oxidative stress. Recent studies indicate that oxidative stress and disruption of mitochondrial homeostasis is a common mechanism for motor neuron degeneration in amyotrophic lateral sclerosis and the loss of midbrain dopamine neurons in Parkinson's disease. Therefore, the present study investigated the presence and alterations of familial Parkinson's disease-related proteins, PINK1 and DJ-1, in spinal motor neurons of G93ASOD1 transgenic mouse model of amyotrophic lateral sclerosis. Following onset of disease, PINK1 and DJ-1 protein expression increased in the spinal motor neurons. The activated form of p53 also increased and translocated to the nuclei of spinal motor neurons, followed by increased expression of p53-activated gene 608 (PAG608). This is the first report demonstrating that increased expression of PAG608 correlates with activation of phosphorylated p53 in spinal motor neurons of an amyotrophic lateral sclerosis model. These results provide further evidence of the profound correlations between spinal motor neurons of amyotrophic lateral sclerosis and parkinsonism-related proteins.

  4. Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex

    PubMed Central

    Kida, Hiroyuki; Tsuda, Yasumasa; Ito, Nana; Yamamoto, Yui; Owada, Yuji; Kamiya, Yoshinori; Mitsushima, Dai

    2016-01-01

    Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats—while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training. PMID:27193420

  5. The Relationship of Neuronal Activity within the Sensori-Motor Region of the Subthalamic Nucleus to Speech

    ERIC Educational Resources Information Center

    Watson, Peter; Montgomery, Erwin B., Jr.

    2006-01-01

    Microelectrode recordings of human sensori-motor subthalamic neuronal activity during spoken sentence and syllable-repetition tasks provided an opportunity to evaluate the relationship between changes in neuronal activities and specific aspects of these vocal behaviors. Observed patterns of neuronal activity included a build up of activity in…

  6. Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2

    PubMed Central

    Foran, Emily; Bogush, Alex; Goffredo, Michael; Roncaglia, Paola; Gustincich, Stefano; Pasinelli, Piera; Trotti, Davide

    2013-01-01

    Dysregulation of glutamate handling ensuing downregulation of expression and activity levels of the astroglial glutamate transporter EAAT2 is implicated in excitotoxic degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). We previously reported that EAAT2 (a.k.a. GLT-1) is cleaved by caspase-3 at its cytosolic carboxy-terminus domain. This cleavage results in impaired glutamate transport activity and generates a proteolytic fragment (CTE) that we found to be post-translationally conjugated by SUMO1. We show here that this sumoylated CTE fragment accumulates in the nucleus of spinal cord astrocytes of the SOD1-G93A mouse model of ALS at symptomatic stages of disease. Astrocytic expression of CTE, artificially tagged with SUMO1 (CTE-SUMO1) to mimic the native sumoylated fragment, recapitulates the nuclear accumulation pattern of the endogenous EAAT2-derived proteolytic fragment. Moreover, in a co-culture binary system, expression of CTE-SUMO1 in spinal cord astrocytes initiates extrinsic toxicity by inducing caspase-3 activation in motor neuron-derived NSC-34 cells or axonal growth impairment in primary motor neurons. Interestingly, prolonged nuclear accumulation of CTE-SUMO1 is intrinsically toxic to spinal cord astrocytes, although this gliotoxic effect of CTE-SUMO1 occurs later than the indirect, non-cell autonomous toxic effect on motor neurons. As more evidence on the implication of SUMO substrates in neurodegenerative diseases emerges, our observations strongly suggest that the nuclear accumulation in spinal cord astrocytes of a sumoylated proteolytic fragment of the astroglial glutamate transporter EAAT2 could participate to the pathogenesis of ALS and suggest a novel, unconventional role for EAAT2 in motor neuron degeneration. PMID:21769946

  7. Effects of cerebrolysin on motor-neuron-like NSC-34 cells

    SciTech Connect

    Keilhoff, Gerburg; Lucas, Benjamin; Pinkernelle, Josephine; Steiner, Michael; Fansa, Hisham

    2014-10-01

    Although the peripheral nervous system is capable of regeneration, this capability is limited. As a potential means of augmenting nerve regeneration, the effects of cerebrolysin (CL) – a proteolytic peptide fraction – were tested in vitro on the motor-neuron-like NSC-34 cell line and organotypic spinal cord cultures. Therefore, NSC-34 cells were subjected to mechanical stress by changing media and metabolic stress by oxygen glucose deprivation. Afterwards, cell survival/proliferation using MTT and BrdU-labeling (FACS) and neurite sprouting using ImageJ analysis were evaluated. Calpain-1, Src and α-spectrin protein expression were analyzed by Western blot. In organotypic cultures, the effect of CL on motor neuron survival and neurite sprouting was tested by immunohistochemistry. CL had a temporary anti-proliferative but initially neuroprotective effect on OGD-stressed NSC-34 cells. High-dosed or repeatedly applied CL was deleterious for cell survival. CL amplified neurite reconstruction to limited extent, affected calpain-1 protein expression and influenced calpain-mediated spectrin cleavage as a function of Src expression. In organotypic spinal cord slice cultures, CL was not able to support motor neuron survival/neurite sprouting. Moreover, it hampered astroglia and microglia activities. The data suggest that CL may have only isolated positive effects on injured spinal motor neurons. High-dosed or accumulated CL seemed to have adverse effects in treatment of spinal cord injury. Further experiments are required to optimize the conditions for a safe clinical administration of CL in spinal cord injuries. - Highlights: • Cerebrolysin (CL) is anti-proliferative but initially neuroprotective in OGD-stressed NSC-34 cells. • CL amplified neurite reconstruction of NSC-34 cells. • CL affected calpain-1 expression and calpain-mediated spectrin cleavage as function of Src expression. • In organotypic spinal cord cultures, CL hampered motor neuron survival and

  8. Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.

    PubMed

    Do-Ha, Dzung; Buskila, Yossi; Ooi, Lezanne

    2017-02-03

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K(+) concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

  9. Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons

    PubMed Central

    Choi, Won-Seok; Kim, Hyung-Wook; Tronche, François; Palmiter, Richard D.; Storm, Daniel R.; Xia, Zhengui

    2017-01-01

    Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson’s disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of the Ndufs4 gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson’s disease using conditional knockout (cKO) mice in which Ndufs4 was selectively deleted in dopaminergic neurons (Ndufs4 cKO). This conditional deletion of Ndufs4, which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However, Ndufs4 cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected, Ndufs4 cKO mice showed non-motor symptoms experienced by many Parkinson’s disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson’s disease and reduces dopamine content in the absence of dopamine neuron loss. PMID:28327638

  10. Motor control may support mirror neuron research with new hypotheses and methods. Reply to comments on "Grasping synergies: A motor-control approach to the mirror neuron mechanism"

    NASA Astrophysics Data System (ADS)

    D'Ausilio, Alessandro; Bartoli, Eleonora; Maffongelli, Laura

    2015-03-01

    We are grateful to all commentators for their insightful commentaries and observations that enrich our proposal. One of our aims was indeed to bridge the gap between fields of research that, progressing independently, are facing similar issues regarding the neural representation of motor knowledge. In this respect, we were pleased to receive feedback from eminent researchers on both the mirror neuron as well as the motor control fields. Their expertise covers animal and human neurophysiology, as well as the computational modeling of neural and behavioral processes. Given their heterogeneous cultural perspectives and research approaches, a number of important open questions were raised. For simplicity we separated these issues into four sections. In the first section we present methodological aspects regarding how synergies can be measured in paradigms investigating the human mirror system. The second section regards the fundamental definition of what exactly synergies might be. The third concerns how synergies can generate testable predictions in mirror neuron research. Finally, the fourth section deals with the ultimate question regarding the function of the mirror neuron system.

  11. Intracortical Microstimulation (ICMS) Activates Motor Cortex Layer 5 Pyramidal Neurons Mainly Transsynaptically.

    PubMed

    Hussin, Ahmed T; Boychuk, Jeffery A; Brown, Andrew R; Pittman, Quentin J; Teskey, G Campbell

    2015-01-01

    Intracortical microstimulation (ICMS) is a technique used for a number of purposes including the derivation of cortical movement representations (motor maps). Its application can activate the output layer 5 of motor cortex and can result in the elicitation of body movements depending upon the stimulus parameters used. The extent to which pyramidal tract projection neurons of the motor cortex are activated transsynaptically or directly by ICMS remains an open question. Given this uncertainty in the mode of activation, we used a preparation that combined patch clamp whole-cell recordings from single layer 5 pyramidal neurons and extracellular ICMS in slices of motor cortex as well as a standard in vivo mapping technique to ask how ICMS activated motor cortex pyramidal neurons. We measured changes in synaptic spike threshold and spiking rate to ICMS in vitro and movement threshold in vivo in the presence or absence of specific pharmacological blockers of glutamatergic (AMPA, NMDA and Kainate) receptors and GABAA receptors. With major excitatory and inhibitory synaptic transmission blocked (with DNQX, APV and bicuculline methiodide), we observed a significant increase in the ICMS current intensity required to elicit a movement in vivo as well as to the first spike and an 85% reduction in spiking responses in vitro. Subsets of neurons were still responsive after the synaptic block, especially at higher current intensities, suggesting a modest direct activation. Taken together our data indicate a mainly synaptic mode of activation to ICMS in layer 5 of rat motor cortex. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Actions of motor neurons and leg muscles in jumping by planthopper insects (hemiptera, issidae).

    PubMed

    Burrows, Malcolm; Bräunig, Peter

    2010-04-15

    To understand the catapult mechanism that propels jumping in a planthopper insect, the innervation and action of key muscles were analyzed. The large trochanteral depressor muscle, M133b,c, is innervated by two motor neurons and by two dorsal unpaired median (DUM) neurons, all with axons in N3C. A smaller depressor muscle, M133a, is innervated by two neurons, one with a large-diameter cell body, a large, blind-ending dendrite, and a giant ovoid, axon measuring 50 microm by 30 microm in nerve N5A. The trochanteral levator muscles (M132) and (M131) are innervated by N4 and N3B, respectively. The actions of these muscles in a restrained jump were divisible into a three-phase pattern. First, both hind legs were moved into a cocked position by high-frequency bursts of spikes in the levator muscles lasting about 0.5 seconds. Second, and once both legs were cocked, M133b,c received a long continuous sequence of motor spikes, but the two levators spiked only sporadically. The spikes in the two motor neurons to M133b,c on one side were closely coupled to each other and to the spikes on the other side. If one hind leg was cocked then the spikes only occurred in motor neurons to that side. The final phase was the jump movement itself, which occurred when the depressor spikes ceased and which lasted 1 ms. Muscles 133b,c activated synchronously on both sides, are responsible for generating the power, and M133a and its giant neuron may play a role in triggering the release of a jump.

  13. Selective Gating of Neuronal Activity by Intrinsic Properties in Distinct Motor Rhythms

    PubMed Central

    2015-01-01

    Many neural circuits show fast reconfiguration following altered sensory or modulatory inputs to generate stereotyped outputs. In the motor circuit of Xenopus tadpoles, I study how certain voltage-dependent ionic currents affect firing thresholds and contribute to circuit reconfiguration to generate two distinct motor patterns, swimming and struggling. Firing thresholds of excitatory interneurons [i.e., descending interneurons (dINs)] in the swimming central pattern generator are raised by depolarization due to the inactivation of Na+ currents. In contrast, the thresholds of other types of neurons active in swimming or struggling are raised by hyperpolarization from the activation of fast transient K+ currents. The firing thresholds are then compared with the excitatory synaptic drives, which are revealed by blocking action potentials intracellularly using QX314 during swimming and struggling. During swimming, transient K+ currents lower neuronal excitability and gate out neurons with weak excitation, whereas their inactivation by strong excitation in other neurons increases excitability and enables fast synaptic potentials to drive reliable firing. During struggling, continuous sensory inputs lead to high levels of network excitation. This allows the inactivation of Na+ currents and suppression of dIN activity while inactivating transient K+ currents, recruiting neurons that are not active in swimming. Therefore, differential expression of these currents between neuron types can explain why synaptic strength does not predict firing reliability/intensity during swimming and struggling. These data show that intrinsic properties can override fast synaptic potentials, mediate circuit reconfiguration, and contribute to motor–pattern switching. PMID:26156983

  14. Sensorimotor experience and verb-category mapping in human sensory, motor and parietal neurons.

    PubMed

    Yang, Ying; Dickey, Michael Walsh; Fiez, Julie; Murphy, Brian; Mitchell, Tom; Collinger, Jennifer; Tyler-Kabara, Elizabeth; Boninger, Michael; Wang, Wei

    2017-07-01

    Semantic grounding is the process of relating meaning to symbols (e.g., words). It is the foundation for creating a representational symbolic system such as language. Semantic grounding for verb meaning is hypothesized to be achieved through two mechanisms: sensorimotor mapping, i.e., directly encoding the sensorimotor experiences the verb describes, and verb-category mapping, i.e., encoding the abstract category a verb belongs to. These two mechanisms were investigated by examining neuronal-level spike (i.e. neuronal action potential) activities from the motor, somatosensory and parietal areas in two human participants. Motor and a portion of somatosensory neurons were found to be involved in primarily sensorimotor mapping, while parietal and some somatosensory neurons were found to be involved in both sensorimotor and verb-category mapping. The time course of the spike activities and the selective tuning pattern of these neurons indicate that they belong to a large neural network used for semantic processing. This study is the first step towards understanding how words are processed by neurons. Published by Elsevier Ltd.

  15. IPLEX administration improves motor neuron survival and ameliorates motor functions in a severe mouse model of spinal muscular atrophy.

    PubMed

    Murdocca, Michela; Malgieri, Arianna; Luchetti, Andrea; Saieva, Luciano; Dobrowolny, Gabriella; de Leonibus, Elvira; Filareto, Antonio; Quitadamo, Maria Chiara; Novelli, Giuseppe; Musarò, Antonio; Sangiuolo, Federica

    2012-09-25

    Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder and the first genetic cause of death in childhood. SMA is caused by low levels of survival motor neuron (SMN) protein that induce selective loss of α-motor neurons (MNs) in the spinal cord, resulting in progressive muscle atrophy and consequent respiratory failure. To date, no effective treatment is available to counteract the course of the disease. Among the different therapeutic strategies with potential clinical applications, the evaluation of trophic and/or protective agents able to antagonize MNs degeneration represents an attractive opportunity to develop valid therapies. Here we investigated the effects of IPLEX (recombinant human insulinlike growth factor 1 [rhIGF-1] complexed with recombinant human IGF-1 binding protein 3 [rhIGFBP-3]) on a severe mouse model of SMA. Interestingly, molecular and biochemical analyses of IGF-1 carried out in SMA mice before drug administration revealed marked reductions of IGF-1 circulating levels and hepatic mRNA expression. In this study, we found that perinatal administration of IPLEX, even if does not influence survival and body weight of mice, results in reduced degeneration of MNs, increased muscle fiber size and in amelioration of motor functions in SMA mice. Additionally, we show that phenotypic changes observed are not SMN-dependent, since no significant SMN modification was addressed in treated mice. Collectively, our data indicate IPLEX as a good therapeutic candidate to hinder the progression of the neurodegenerative process in SMA.

  16. Substratum preferences of motor and sensory neurons in postnatal and adult rats.

    PubMed

    Gonzalez-Perez, Francisco; Alé, Albert; Santos, Daniel; Barwig, Christina; Freier, Thomas; Navarro, Xavier; Udina, Esther

    2016-02-01

    After peripheral nerve injuries, damaged axons can regenerate but functional recovery is limited by the specific reinnervation of targets. In this study we evaluated if motor and sensory neurites have a substrate preference for laminin and fibronectin in postnatal and adult stages. In postnatal dorsal root ganglia (DRG) explants, sensory neurons extended longer neurites on collagen matrices enriched with laminin (~50%) or fibronectin (~35%), whereas motoneurons extended longer neurites (~100%) in organotypic spinal cord slices embedded in fibronectin-enriched matrix. An increased percentage of parvalbumin-positive neurites (presumptive proprioceptive) vs. neurofilament-positive neurites was also found in DRG in fibronectin-enriched matrix. To test if the different preference of neurons for extracellular matrix components was maintained in vivo, these matrices were used to fill a chitosan guide to repair a 6-mm gap in the sciatic nerve of adult rats. However, the number of regenerating motor and sensory neurons after 1 month was similar between groups. Moreover, none of the retrotraced sensory neurons in DRG was positive for parvalbumin, suggesting that presumptive proprioceptive neurons had poor regenerative capabilities compared with other peripheral neurons. Using real-time PCR we evaluated the expression of α5β1 (receptor for fibronectin) and α7β1 integrin (receptor for laminin) in spinal cord and DRG 2 days after injury. Postnatal animals showed a higher increase of α5β1 integrin, whereas both integrins were similarly expressed in adult neurons. Therefore, we conclude that motor and sensory axons have a different substrate preference at early postnatal stages but this difference is lost in the adult. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  17. The C. elegans NeuroD homolog cnd-1 functions in multiple aspects of motor neuron fate specification.

    PubMed

    Hallam, S; Singer, E; Waring, D; Jin, Y

    2000-10-01

    The basic helix-loop-helix transcription factor NeuroD (Neurod1) has been implicated in neuronal fate determination, differentiation and survival. Here we report the expression and functional analysis of cnd-1, a C. elegans NeuroD homolog. cnd-1 expression was first detected in neuroblasts of the AB lineage in 14 cell embryos and maintained in many neuronal descendants of the AB lineage during embryogenesis, diminishing in most terminally differentiated neurons prior to hatching. Specifically, cnd-1 reporter genes were expressed in the precursors of the embryonic ventral cord motor neurons and their progeny. A loss-of-function mutant, cnd-1(ju29), exhibited multiple defects in the ventral cord motor neurons. First, the number of motor neurons was reduced, possibly caused by the premature withdrawal of the precursors from mitotic cycles. Second, the strict correlation between the fate of a motor neuron with respect to its lineage and position in the ventral cord was disrupted, as manifested by the variable expression pattern of motor neuron fate specific markers. Third, motor neurons also exhibited defects in terminal differentiation characteristics including axonal morphology and synaptic connectivity. Finally, the expression patterns of three neuronal type-specific transcription factors, unc-3, unc-4 and unc-30, were altered. Our data suggest that cnd-1 may specify the identity of ventral cord motor neurons both by maintaining the mitotic competence of their precursors and by modulating the expression of neuronal type-specific determination factors. cnd-1 appears to have combined the functions of several vertebrate neurogenic bHLH proteins and may represent an ancestral form of this protein family.

  18. Network feedback regulates motor output across a range of modulatory neuron activity.

    PubMed

    Spencer, Robert M; Blitz, Dawn M

    2016-06-01

    Modulatory projection neurons alter network neuron synaptic and intrinsic properties to elicit multiple different outputs. Sensory and other inputs elicit a range of modulatory neuron activity that is further shaped by network feedback, yet little is known regarding how the impact of network feedback on modulatory neurons regulates network output across a physiological range of modulatory neuron activity. Identified network neurons, a fully described connectome, and a well-characterized, identified modulatory projection neuron enabled us to address this issue in the crab (Cancer borealis) stomatogastric nervous system. The modulatory neuron modulatory commissural neuron 1 (MCN1) activates and modulates two networks that generate rhythms via different cellular mechanisms and at distinct frequencies. MCN1 is activated at rates of 5-35 Hz in vivo and in vitro. Additionally, network feedback elicits MCN1 activity time-locked to motor activity. We asked how network activation, rhythm speed, and neuron activity levels are regulated by the presence or absence of network feedback across a physiological range of MCN1 activity rates. There were both similarities and differences in responses of the two networks to MCN1 activity. Many parameters in both networks were sensitive to network feedback effects on MCN1 activity. However, for most parameters, MCN1 activity rate did not determine the extent to which network output was altered by the addition of network feedback. These data demonstrate that the influence of network feedback on modulatory neuron activity is an important determinant of network output and feedback can be effective in shaping network output regardless of the extent of network modulation. Copyright © 2016 the American Physiological Society.

  19. Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

    PubMed Central

    Liu, Ying Hsiu; Sahashi, Kentaro; Rigo, Frank; Bennett, C. Frank

    2015-01-01

    Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice. PMID:25583329

  20. Adult rat motor neurons do not re-establish electrical coupling during axonal regeneration and muscle reinnervation.

    PubMed

    Favero, Morgana; Cangiano, Alberto; Busetto, Giuseppe

    2015-01-01

    Gap junctions (GJs) between neurons are present in both the newborn and the adult nervous system, and although important roles have been suggested or demonstrated in a number of instances, in many other cases a full understanding of their physiological role is still missing. GJs are expressed in the rodent lumbar cord at birth and mediate both dye and electrical coupling between motor neurons. This expression has been proposed to mediate: (i) fast synchronization of motoneuronal spike activity, in turn linked to the process of refinement of neuromuscular connections, and (ii) slow synchronization of locomotor-like oscillatory activity. Soon after birth this coupling disappears. Since in the adult rat regeneration of motor fibers after peripheral nerve injury leads to a recapitulation of synaptic refinement at the target muscles, we tested whether GJs between motor neurons are transiently re-expressed. We found that in conditions of maximal responsiveness of lumbar motor neurons (such as no depression by anesthetics, decerebrate release of activity of subsets of motor neurons, use of temporal and spatial summation by antidromic and orthodromic stimulations, testing of large ensembles of motor neurons) no firing is observed in ventral root axons in response to antidromic spike invasion of nearby counterparts. We conclude that junctional coupling between motor neurons is not required for the refinement of neuromuscular innervation in the adult.

  1. Specification of individual adult motor neuron morphologies by combinatorial transcription factor codes

    PubMed Central

    Enriquez, Jonathan; Venkatasubramanian, Lalanti; Baek, Myungin; Peterson, Meredith; Aghayeva, Ulkar; Mann, Richard S.

    2015-01-01

    Summary How the highly stereotyped morphologies of individual neurons are genetically specified is not well understood. We identify six transcription factors (TFs) expressed in a combinatorial manner in seven post-mitotic adult leg motor neurons (MNs) that are derived from a single neuroblast in Drosophila. Unlike TFs expressed in mitotically active neuroblasts, these TFs do not regulate each other's expression. Removing the activity of a single TF resulted in specific morphological defects, including muscle targeting and dendritic arborization, and in a highly specific walking defect in adult flies. In contrast, when the expression of multiple TFs was modified nearly complete transformations in MN morphologies were generated. These results show that the morphological characteristics of a single neuron are dictated by a combinatorial code of morphology TFs (mTFs). mTFs function at a previously unidentified regulatory tier downstream of factors acting in the NB, but independently of factors that act in terminally differentiated neurons. PMID:25959734

  2. Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury

    NASA Technical Reports Server (NTRS)

    Murashov, A. K.; Ul Haq, I.; Hill, C.; Park, E.; Smith, M.; Wang, X.; Wang, X.; Goldberg, D. J.; Wolgemuth, D. J.

    2001-01-01

    The p38 stress-activated protein kinase pathway is involved in regulation of phosphorylation of Hsp25, which in turn regulates actin filament dynamic in non-neuronal cells. We report that p38, Hsp25 and Akt signaling pathways were specifically activated in spinal motor neurons after sciatic nerve axotomy. The activation of the p38 kinase was required for induction of Hsp25 expression. Furthermore, Hsp25 formed a complex with Akt, a member of PI-3 kinase pathway that prevents neuronal cell death. Together, our observations implicate Hsp25 as a central player in a complex system of signaling that may both promote regeneration of nerve fibers and prevent neuronal cell death in the injured spinal cord.

  3. Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury

    NASA Technical Reports Server (NTRS)

    Murashov, A. K.; Ul Haq, I.; Hill, C.; Park, E.; Smith, M.; Wang, X.; Wang, X.; Goldberg, D. J.; Wolgemuth, D. J.

    2001-01-01

    The p38 stress-activated protein kinase pathway is involved in regulation of phosphorylation of Hsp25, which in turn regulates actin filament dynamic in non-neuronal cells. We report that p38, Hsp25 and Akt signaling pathways were specifically activated in spinal motor neurons after sciatic nerve axotomy. The activation of the p38 kinase was required for induction of Hsp25 expression. Furthermore, Hsp25 formed a complex with Akt, a member of PI-3 kinase pathway that prevents neuronal cell death. Together, our observations implicate Hsp25 as a central player in a complex system of signaling that may both promote regeneration of nerve fibers and prevent neuronal cell death in the injured spinal cord.

  4. Specification of individual adult motor neuron morphologies by combinatorial transcription factor codes.

    PubMed

    Enriquez, Jonathan; Venkatasubramanian, Lalanti; Baek, Myungin; Peterson, Meredith; Aghayeva, Ulkar; Mann, Richard S

    2015-05-20

    How the highly stereotyped morphologies of individual neurons are genetically specified is not well understood. We identify six transcription factors (TFs) expressed in a combinatorial manner in seven post-mitotic adult leg motor neurons (MNs) that are derived from a single neuroblast in Drosophila. Unlike TFs expressed in mitotically active neuroblasts, these TFs do not regulate each other's expression. Removing the activity of a single TF resulted in specific morphological defects, including muscle targeting and dendritic arborization, and in a highly specific walking defect in adult flies. In contrast, when the expression of multiple TFs was modified, nearly complete transformations in MN morphologies were generated. These results show that the morphological characteristics of a single neuron are dictated by a combinatorial code of morphology TFs (mTFs). mTFs function at a previously unidentified regulatory tier downstream of factors acting in the NB but independently of factors that act in terminally differentiated neurons.

  5. Electrophysiological recording from neurons controlling sensory and motor functions of the esophagus.

    PubMed

    Sengupta, J N

    2001-12-03

    contractions of the distal esophagus. This response undergoes inhibition in response to proximal distension. In addition, there is a second, nonrhythmic firing response that occurs both proximal and distal esophageal distension. This observation suggests that swallow-induced inhibition of the distal esophagus is controlled by the preganglionic motor neurons in the brain stem. Electrophysiological studies allow direct understanding of neuronal activities regulating esophageal functions. In vivo recording has an advantage for studying functional roles of the neurons in regulatory reflexes, whereas in vitro recording is useful for more accurate study of receptor pharmacology. Recordings from the central nervous system allow study of the neurotransmitters involved in neuronal function and the circuitry of different reflex mechanisms.

  6. AMPA receptor activation causes preferential mitochondrial Ca²⁺ load and oxidative stress in motor neurons.

    PubMed

    Joshi, Dinesh C; Tewari, Bhanu P; Singh, Mahendra; Joshi, Preeti G; Joshi, Nanda B

    2015-08-07

    It is well established that motor neurons are highly vulnerable to glutamate induced excitotoxicity. The selective vulnerability of these neurons has been attributed to AMPA receptor mediated excessive rise in cytosolic calcium and consequent mitochondrial Ca(2+) loading. Earlier we have reported that in motor neurons a generic rise in [Ca(2+)]i does not always lead to mitochondrial Ca(2+) loading and membrane depolarization but it occurs upon AMPA receptor activation. The mechanism of such specific mitochondrial involvement upon AMPA receptor activation is not known. The present study examines the mitochondrial Ca(2+) regulation and oxidative stress in spinal cord neurons upon AMPA subtype of glutamate receptor activation. Stimulating the spinal neurons with AMPA exhibited a sharp rise in [Ca(2+)]m in both motor and other spinal neurons that was sustained up to the end of recording time of 30min. The rise in [Ca(2+)]m was substantially higher in motor neurons than in other spinal neurons which could be due to the differential mitochondrial homeostasis in two types of neurons. To examine this possibility, we measured AMPA induced [Ca(2+)]m loading in the presence of mitochondrial inhibitors. In both cell types the AMPA induced [Ca(2+)]m loading was blocked by mitochondrial calcium uniporter blocker ruthenium red. In motor neurons it was also inhibited substantially by CGP37157 and cyclosporine-A, the blockers of Na(+)/Ca(2+) exchanger and mitochondrial permeability transition pore (MPTP) respectively, whereas no effect of these agents was observed in other spinal neurons. Thus in motor neurons the Ca(2+) sequestration by mitochondria occurs through mitochondrial calcium uniporter as well as due to reversal of Na(+)/Ca(2+) exchanger, in contrast the latter pathway does not contribute in other spinal neurons. The ROS formation was inhibited by nitric oxide synthase (NOS) inhibitor L-NAME in both types of neurons, however the mitochondrial complex-I inhibitor rotenone

  7. Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

    PubMed

    Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z

    2017-07-01

    Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

  8. Functional Dopaminergic Neurons in Substantia Nigra are Required for Transcranial Magnetic Stimulation-Induced Motor Plasticity.

    PubMed

    Hsieh, Tsung-Hsun; Huang, Ying-Zu; Rotenberg, Alexander; Pascual-Leone, Alvaro; Chiang, Yung-Hsiao; Wang, Jia-Yi; Chen, Jia-Jin J

    2015-07-01

    Repetitive magnetic stimulation (rTMS), including theta burst stimulation (TBS), is capable of modulating motor cortical excitability through plasticity-like mechanisms and might have therapeutic potential for Parkinson's disease (PD). An animal model would be helpful for elucidating the mechanism of rTMS that remain unclear and controversial. Here, we have established a TMS model in rat and applied this model to study the impact of substantia nigra dopamine neuron on TBS-induced motor plasticity in PD rats. In parallel with human results, continuous TBS (cTBS) successfully suppressed motor evoked potentials (MEPs), while MEPs increased after intermittent TBS (iTBS) in healthy rats. We then tested the effect of iTBS in early and advanced 6-hydroxydopamine (6-OHDA)-lesioned PD. Moreover, dopaminergic neurons in substantia nigra and rotation behavior were assessed to correlate with the amount of iTBS-induced plasticity. In results, iTBS-induced potentiation was reduced in early PD rats and was absent in advanced PD rats. Such reduction in plasticity strongly correlated with the dopaminergic cell loss and the count of rotation in PD rats. In conclusion, we have established a TMS PD rat model. With the help of this model, we confirmed the loss of domaninergic neurons in substantia nigra resulting in reduced rTMS-induced motor plasticity in PD.

  9. Nonlinear integration of visual and haltere inputs in fly neck motor neurons.

    PubMed

    Huston, Stephen J; Krapp, Holger G

    2009-10-21

    Animals use information from multiple sensory organs to generate appropriate behavior. Exactly how these different sensory inputs are fused at the motor system is not well understood. Here we study how fly neck motor neurons integrate information from two well characterized sensory systems: visual information from the compound eye and gyroscopic information from the mechanosensory halteres. Extracellular recordings reveal that a subpopulation of neck motor neurons display "gating-like" behavior: they do not fire action potentials in response to visual stimuli alone but will do so if the halteres are coactivated. Intracellular recordings show that these motor neurons receive small, sustained subthreshold visual inputs in addition to larger inputs that are phase locked to haltere movements. Our results suggest that the nonlinear gating-like effect results from summation of these two inputs with the action potential threshold providing the nonlinearity. As a result of this summation, the sustained visual depolarization is transformed into a temporally structured train of action potentials synchronized to the haltere beating movements. This simple mechanism efficiently fuses two different sensory signals and may also explain the context-dependent effects of visual inputs on fly behavior.

  10. Slow active potentials in ventral inhibitory motor neurons of the nematode Ascaris.

    PubMed

    Angstadt, J D; Stretton, A O

    1989-12-01

    The ability of ventral inhibitory motor neurons of the nematode Ascaris to generate slow depolarizing potentials was investigated using intracellular recording and current injection. In quiescent cells, regenerative depolarizations with peak amplitudes of approximately 20 mV and durations of several 100 ms were evoked in response to brief depolarizing current pulses. Repetitive slow potentials were produced in response to sustained depolarizing currents in a threshold-dependent manner. Repetitive slow potentials also occurred spontaneously, exhibiting cycle periods of about 700 ms. The ability of inhibitory motor neurons to generate slow potentials was blocked by addition of Co++, Cd++, or other Ca-channel blockers to the saline but not by TTX or substitution of Na+ with Tris. The amplitude and duration of slow potentials were increased in the presence of Ba++, Sr++, and TEA. Spontaneous slow potentials exhibited characteristics expected of intrinsically generated oscillations, including frequency modulation by injection of prolonged offset currents, phase resetting by brief current pulses, and suppression by strong hyperpolarization. Slow potentials appear to be generated in the ventral nerve cord processes and/or cell body of the motor neuron, and they produce rhythmic inhibitory postsynaptic potentials in ventral muscle cells. Slow potentials may therefore contribute to locomotory or other motor behaviors of the animal.

  11. Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

    PubMed Central

    Tomassy, Giulio Srubek; De Leonibus, Elvira; Jabaudon, Denis; Lodato, Simona; Alfano, Christian; Mele, Andrea; Macklis, Jeffrey D.; Studer, Michèle

    2010-01-01

    Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise. PMID:20133588

  12. GABA and 5-HT chitosan nanoparticles decrease striatal neuronal degeneration and motor deficits during liver injury.

    PubMed

    Shilpa, J; Paulose, C S

    2014-07-01

    The metabolic alterations resulted from hepatic injury and cell loss lead to synaptic defects and neurodegeneration that undoubtedly contribute motor deficits. In the present study, GABA and 5-HT chitosan nanoparticles mediated liver cell proliferation influenced by growth factor and cytokines and neuronal survival in corpus striatum of partially hepatectomised rats was evaluated. Liver cell proliferation was initiated and progressed by the combined effect of increased expression of growth factor, insulin like growth factor-1 and decreased expressions of cytokines, tumor necrosis factor-α and Akt-1. This was confirmed by the extent of incorporation of thymidine analogue, BrdU, in the DNA of rapidly dividing cells. Inappropriate influx of compounds to corpus striatum resulting from incomplete metabolism elevated GABAB and 5-HT2A neurotransmissions compared to those treated with nanoparticles. This directly influenced cyclic AMP response element binding protein, glial cell derived neurotrophic factor and brain derived neurotrophic factor in the corpus striatum that facilitate neurogenesis, neuronal survival, development, differentiation and neuroprotection. Motor deficits due to liver injury followed striatal neuronal damage were scored by grid walk and rotarod studies, which confirmed the regain of motor activity by GABA and 5-HT chitosan nanoparticle treatment. The present study revealed the therapeutic significance of GABA and 5-HT chitosan nanoparticles in liver based diseases and related striatal neuronal damage that influenced by GABA and 5-HT.

  13. Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

    PubMed Central

    Fee, Lanette; Tao, Yazhong; Redler, Rachel L.; Fay, James M.; Zhang, Yuliang; Lv, Zhengjian; Mercer, Ian P.; Deshmukh, Mohanish; Lyubchenko, Yuri L.; Dokholyan, Nikolay V.

    2016-01-01

    Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions. Here, we definitively link cytotoxicity associated with SOD1 aggregation in ALS to a nonnative trimeric SOD1 species. We develop methodology for the incorporation of low-resolution experimental data into simulations toward the structural modeling of metastable, multidomain aggregation intermediates. We apply this methodology to derive the structure of a SOD1 trimer, which we validate in vitro and in hybridized motor neurons. We show that SOD1 mutants designed to promote trimerization increase cell death. Further, we demonstrate that the cytotoxicity of the designed mutants correlates with trimer stability, providing a direct link between the presence of misfolded oligomers and neuron death. Identification of cytotoxic species is the first and critical step in elucidating the molecular etiology of ALS, and the ability to manipulate formation of these species will provide an avenue for the development of future therapeutic strategies. PMID:26719414

  14. Neurofilament RNA causes neurodegeneration with accumulation of ubiquitinated aggregates in cultured motor neurons.

    PubMed

    Lin, Hong; Zhai, Jinbin; Nie, Zhenying; Wu, Junhua; Meinkoth, Judy L; Schlaepfer, William W; Cañete-Soler, Rafaela

    2003-09-01

    The mechanisms whereby mutant gene expression triggers neurodegeneration are poorly understood but have generally been attributed to translated gene products. We now demonstrate direct neuropathic effects of untranslated RNA on cultured motor neurons. We show that expression of untranslated light neurofilament (NF-L) RNA sequence in the 3'UTR of an EGFP transgene (pEGFP/NF-L RNA) or in a separate expression vector (pRc/NF-L RNA) causes dose-dependent, neuron-specific motor neuron degeneration. Neither unfused EGFP protein (pEGFP/wt) nor EGFP-tagged NF-L protein (pEGFP/NF-L protein) has similar neuropathic effects. The findings are the first demonstration of a direct RNA-mediated neurotoxic effect. Moreover, the resulting neuropathological changes show that untranslated RNA can lead to early degeneration of neuritic processes and accumulations of ubiquitinated aggregates in the perikarya and nuclei of degenerating motor neurons. The latter findings are hallmark neuropathological features of neurodegenerative diseases and their occurrence as a result of altered RNA expression raises the prospects of an RNA-mediated component in the pathogenesis of neurodegenerative states.

  15. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

    PubMed

    Naryshkin, Nikolai A; Weetall, Marla; Dakka, Amal; Narasimhan, Jana; Zhao, Xin; Feng, Zhihua; Ling, Karen K Y; Karp, Gary M; Qi, Hongyan; Woll, Matthew G; Chen, Guangming; Zhang, Nanjing; Gabbeta, Vijayalakshmi; Vazirani, Priya; Bhattacharyya, Anuradha; Furia, Bansri; Risher, Nicole; Sheedy, Josephine; Kong, Ronald; Ma, Jiyuan; Turpoff, Anthony; Lee, Chang-Sun; Zhang, Xiaoyan; Moon, Young-Choon; Trifillis, Panayiota; Welch, Ellen M; Colacino, Joseph M; Babiak, John; Almstead, Neil G; Peltz, Stuart W; Eng, Loren A; Chen, Karen S; Mull, Jesse L; Lynes, Maureen S; Rubin, Lee L; Fontoura, Paulo; Santarelli, Luca; Haehnke, Daniel; McCarthy, Kathleen D; Schmucki, Roland; Ebeling, Martin; Sivaramakrishnan, Manaswini; Ko, Chien-Ping; Paushkin, Sergey V; Ratni, Hasane; Gerlach, Irene; Ghosh, Anirvan; Metzger, Friedrich

    2014-08-08

    Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA. Copyright © 2014, American Association for the Advancement of Science.

  16. Temperature manipulation of neuronal dynamics in a forebrain motor control nucleus.

    PubMed

    Goldin, Matías A; Mindlin, Gabriel B

    2017-08-01

    Different neuronal types within brain motor areas contribute to the generation of complex motor behaviors. A widely studied songbird forebrain nucleus (HVC) has been recognized as fundamental in shaping the precise timing characteristics of birdsong. This is based, among other evidence, on the stretching and the "breaking" of song structure when HVC is cooled. However, little is known about the temperature effects that take place in its neurons. To address this, we investigated the dynamics of HVC both experimentally and computationally. We developed a technique where simultaneous electrophysiological recordings were performed during temperature manipulation of HVC. We recorded spontaneous activity and found three effects: widening of the spike shape, decrease of the firing rate and change in the interspike interval distribution. All these effects could be explained with a detailed conductance based model of all the neurons present in HVC. Temperature dependence of the ionic channel time constants explained the first effect, while the second was based in the changes of the maximal conductance using single synaptic excitatory inputs. The last phenomenon, only emerged after introducing a more realistic synaptic input to the inhibitory interneurons. Two timescales were present in the interspike distributions. The behavior of one timescale was reproduced with different input balances received form the excitatory neurons, whereas the other, which disappears with cooling, could not be found assuming poissonian synaptic inputs. Furthermore, the computational model shows that the bursting of the excitatory neurons arises naturally at normal brain temperature and that they have an intrinsic delay at low temperatures. The same effect occurs at single synapses, which may explain song stretching. These findings shed light on the temperature dependence of neuronal dynamics and present a comprehensive framework to study neuronal connectivity. This study, which is based on

  17. Temperature manipulation of neuronal dynamics in a forebrain motor control nucleus

    PubMed Central

    Mindlin, Gabriel B.

    2017-01-01

    Different neuronal types within brain motor areas contribute to the generation of complex motor behaviors. A widely studied songbird forebrain nucleus (HVC) has been recognized as fundamental in shaping the precise timing characteristics of birdsong. This is based, among other evidence, on the stretching and the “breaking” of song structure when HVC is cooled. However, little is known about the temperature effects that take place in its neurons. To address this, we investigated the dynamics of HVC both experimentally and computationally. We developed a technique where simultaneous electrophysiological recordings were performed during temperature manipulation of HVC. We recorded spontaneous activity and found three effects: widening of the spike shape, decrease of the firing rate and change in the interspike interval distribution. All these effects could be explained with a detailed conductance based model of all the neurons present in HVC. Temperature dependence of the ionic channel time constants explained the first effect, while the second was based in the changes of the maximal conductance using single synaptic excitatory inputs. The last phenomenon, only emerged after introducing a more realistic synaptic input to the inhibitory interneurons. Two timescales were present in the interspike distributions. The behavior of one timescale was reproduced with different input balances received form the excitatory neurons, whereas the other, which disappears with cooling, could not be found assuming poissonian synaptic inputs. Furthermore, the computational model shows that the bursting of the excitatory neurons arises naturally at normal brain temperature and that they have an intrinsic delay at low temperatures. The same effect occurs at single synapses, which may explain song stretching. These findings shed light on the temperature dependence of neuronal dynamics and present a comprehensive framework to study neuronal connectivity. This study, which is based on

  18. Robust neuronal dynamics in premotor cortex during motor planning

    PubMed Central

    Li, Nuo; Daie, Kayvon; Svoboda, Karel; Druckmann, Shaul

    2016-01-01

    Neural activity maintains representations that bridge past and future events, often over many seconds. Network models can produce persistent and ramping activity, but the positive feedback that is critical for these slow dynamics can cause sensitivity to perturbations. Here we use electrophysiology and optogenetic perturbations in mouse premotor cortex to probe robustness of persistent neural representations during motor planning. Preparatory activity is remarkably robust to large-scale unilateral silencing: detailed neural dynamics that drive specific future movements were quickly and selectively restored by the network. Selectivity did not recover after bilateral silencing of premotor cortex. Perturbations to one hemisphere are thus corrected by information from the other hemisphere. Corpus callosum bisections demonstrated that premotor cortex hemispheres can maintain preparatory activity independently. Redundancy across selectively coupled modules, as we observed in premotor cortex, is a hallmark of robust control systems. Network models incorporating these principles show robustness that is consistent with data. PMID:27074502

  19. Imaging Flow Cytometry Analysis to Identify Differences of Survival Motor Neuron Protein Expression in Patients With Spinal Muscular Atrophy.

    PubMed

    Arakawa, Reiko; Arakawa, Masayuki; Kaneko, Kaori; Otsuki, Noriko; Aoki, Ryoko; Saito, Kayoko

    2016-08-01

    Spinal muscular atrophy is a neurodegenerative disorder caused by the deficient expression of survival motor neuron protein in motor neurons. A major goal of disease-modifying therapy is to increase survival motor neuron expression. Changes in survival motor neuron protein expression can be monitored via peripheral blood cells in patients; therefore we tested the sensitivity and utility of imaging flow cytometry for this purpose. After the immortalization of peripheral blood lymphocytes from a human healthy control subject and two patients with spinal muscular atrophy type 1 with two and three copies of SMN2 gene, respectively, we used imaging flow cytometry analysis to identify significant differences in survival motor neuron expression. A bright detail intensity analysis was used to investigate differences in the cellular localization of survival motor neuron protein. Survival motor neuron expression was significantly decreased in cells derived from patients with spinal muscular atrophy relative to those derived from a healthy control subject. Moreover, survival motor neuron expression correlated with the clinical severity of spinal muscular atrophy according to SMN2 copy number. The cellular accumulation of survival motor neuron protein was also significantly decreased in cells derived from patients with spinal muscular atrophy relative to those derived from a healthy control subject. The benefits of imaging flow cytometry for peripheral blood analysis include its capacities for analyzing heterogeneous cell populations; visualizing cell morphology; and evaluating the accumulation, localization, and expression of a target protein. Imaging flow cytometry analysis should be implemented in future studies to optimize its application as a tool for spinal muscular atrophy clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy.

    PubMed

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M; Yang, Ben; Shi, Han; Sze, Christie C; Hong, Benjamin Taige; Su, Susan C; Cantu, Jorge A; Topczewski, Jacek; Crawford, Thomas O; Ko, Chien-Ping; Sumner, Charlotte J; Ma, Long; Ma, Yong-Chao

    2015-04-15

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35(-/-) compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration. Copyright © 2015 the authors 0270-6474/15/356038-13$15.00/0.

  1. SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA

    PubMed Central

    McGovern, Vicki L.; Iyer, Chitra C.; Arnold, W. David; Gombash, Sara E.; Zaworski, Phillip G.; Blatnik, Anton J.; Foust, Kevin D.; Burghes, Arthur H.M.

    2015-01-01

    Proximal spinal muscular atrophy (SMA) is the most frequent cause of hereditary infant mortality. SMA is an autosomal recessive neuromuscular disorder that results from the loss of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The SMN2 gene produces an insufficient amount of full-length SMN protein that results in loss of motor neurons in the spinal cord and subsequent muscle paralysis. Previously we have shown that overexpression of human SMN in neurons in the SMA mouse ameliorates the SMA phenotype while overexpression of human SMN in skeletal muscle had no effect. Using Cre recombinase, here we show that either deletion or replacement of Smn in motor neurons (ChAT-Cre) significantly alters the functional output of the motor unit as measured with compound muscle action potential and motor unit number estimation. However ChAT-Cre alone did not alter the survival of SMA mice by replacement and did not appreciably affect survival when used to deplete SMN. However replacement of Smn in both neurons and glia in addition to the motor neuron (Nestin-Cre and ChAT-Cre) resulted in the greatest improvement in survival of the mouse and in some instances complete rescue was achieved. These findings demonstrate that high expression of SMN in the motor neuron is both necessary and sufficient for proper function of the motor unit. Furthermore, in the mouse high expression of SMN in neurons and glia, in addition to motor neurons, has a major impact on survival. PMID:26206889

  2. Non-Aggregating Tau Phosphorylation by Cyclin-Dependent Kinase 5 Contributes to Motor Neuron Degeneration in Spinal Muscular Atrophy

    PubMed Central

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M.; Yang, Ben; Shi, Han; Sze, Christie C.; Hong, Benjamin Taige; Su, Susan C.; Cantu, Jorge A.; Topczewski, Jacek; Crawford, Thomas O.; Ko, Chien-Ping; Sumner, Charlotte J.; Ma, Long

    2015-01-01

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35−/− compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration. PMID:25878277

  3. SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA.

    PubMed

    McGovern, Vicki L; Iyer, Chitra C; Arnold, W David; Gombash, Sara E; Zaworski, Phillip G; Blatnik, Anton J; Foust, Kevin D; Burghes, Arthur H M

    2015-10-01

    Proximal spinal muscular atrophy (SMA) is the most frequent cause of hereditary infant mortality. SMA is an autosomal recessive neuromuscular disorder that results from the loss of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The SMN2 gene produces an insufficient amount of full-length SMN protein that results in loss of motor neurons in the spinal cord and subsequent muscle paralysis. Previously we have shown that overexpression of human SMN in neurons in the SMA mouse ameliorates the SMA phenotype while overexpression of human SMN in skeletal muscle had no effect. Using Cre recombinase, here we show that either deletion or replacement of Smn in motor neurons (ChAT-Cre) significantly alters the functional output of the motor unit as measured with compound muscle action potential and motor unit number estimation. However ChAT-Cre alone did not alter the survival of SMA mice by replacement and did not appreciably affect survival when used to deplete SMN. However replacement of Smn in both neurons and glia in addition to the motor neuron (Nestin-Cre and ChAT-Cre) resulted in the greatest improvement in survival of the mouse and in some instances complete rescue was achieved. These findings demonstrate that high expression of SMN in the motor neuron is both necessary and sufficient for proper function of the motor unit. Furthermore, in the mouse high expression of SMN in neurons and glia, in addition to motor neurons, has a major impact on survival. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  4. Regulation of motor patterns by the central spike-initiation zone of a sensory neuron.

    PubMed

    Daur, Nelly; Nadim, Farzan; Stein, Wolfgang

    2009-09-01

    Sensory feedback from muscles and peripheral sensors acts to initiate, tune or reshape motor activity according to the state of the body. Yet, sensory neurons often show low levels of activity even in the absence of sensory input. Here we examine the functional role of spontaneous low-frequency activity of such a sensory neuron. The anterior gastric receptor (AGR) is a muscle-tendon organ in the crab stomatogastric nervous system whose phasic activity shapes the well-characterized gastric mill (chewing) and pyloric (filtering) motor rhythms. Phasic activity is driven by a spike-initiation zone near the innervated muscle. We demonstrate that AGR possesses a second spike-initiation zone, which is located spatially distant from the innervated muscle in a central section of the axon. This initiation zone generates tonic activity and is responsible for the spontaneous activity of AGR in vivo, but does not code sensory information. Rather, it is sensitive to the neuromodulator octopamine. A computational model indicates that the activity at this initiation zone is not caused by excitatory input from another neuron, but generated intrinsically. This tonic activity is functionally relevant, because it modifies the activity state of the gastric mill motor circuit and changes the pyloric rhythm. The sensory function of AGR is not impaired as phasic activity suppresses spiking at the central initiation zone. Our results thus demonstrate that sensory neurons are not mere reporters of sensory signals. Neuromodulators can elicit non-sensory coding activity in these neurons that shapes the state of the motor system.

  5. Alterations in the motor