Science.gov

Sample records for microglial-mediated motoneuron injury

  1. Extracellular Mutant SOD1 Induces Microglial-Mediated Motoneuron Injury

    PubMed Central

    Zhao, Weihua; Beers, David R.; Henkel, Jenny S.; Zhang, Wei; Urushitani, Makoto; Julien, Jean-Pierre; Appel, Stanley H.

    2009-01-01

    Through undefined mechanisms, dominant mutations in (Cu/Zn) superoxide dismutase-1 (mSOD1) cause the non-cell-autonomous death of motoneurons in inherited amyotrophic lateral sclerosis (ALS). Microgliosis at sites of motoneuron injury is a neuropathological hallmark of ALS. Extracellular mSOD1 causes motoneuron injury and triggers microgliosis in spinal cord cultures, but it is unclear whether the injury results from extracellular mSOD1 directly interacting with motoneurons or is mediated through mSOD1-activated microglia. To dissociate these potential mSOD1-mediated neurotoxic mechanisms, the effects of extracellular human mSOD1G93A or mSOD1G85R were assayed using primary cultures of motoneurons and microglia. The data demonstrate that exogenous mSOD1G93A did not cause detectable direct killing of motoneurons. In contrast, mSOD1G93A or mSOD1G85R did induce the morphological and functional activation of microglia, increasing their release of pro-inflammatory cytokines and free radicals. Furthermore, only when microglia were co-cultured with motoneurons did extracellular mSOD1G93A injure motoneurons. The microglial activation mediated by mSOD1G93A was attenuated using toll-like receptors (TLR) 2, TLR4 and CD14 blocking antibodies, or when microglia lacked CD14 expression. These data suggest that extracellular mSOD1G93A is not directly toxic to motoneurons but requires microglial activation for toxicity, utilizing CD14 and TLR pathways. This link between mSOD1 and innate immunity may offer novel therapeutic targets in ALS. PMID:19672969

  2. Activity dependent therapies modulate the spinal changes that motoneurons suffer after a peripheral nerve injury.

    PubMed

    Arbat-Plana, Ariadna; Torres-Espín, Abel; Navarro, Xavier; Udina, Esther

    2015-01-01

    Injury of a peripheral nerve not only leads to target denervation, but also induces massive stripping of spinal synapses on axotomized motoneurons, with disruption of spinal circuits. Even when regeneration is successful, unspecific reinnervation and the limited reconnection of the spinal circuits impair functional recovery. The aim of this study was to describe the changes that axotomized motoneurons suffer after peripheral nerve injury and how activity-dependent therapies and neurotrophic factors can modulate these events. We observed a marked decrease in glutamatergic synapses, with a maximum peak at two weeks post-axotomy, which was only partially reversed with time. This decrease was accompanied by an increase in gephyrin immunoreactivity and a disintegration of perineuronal nets (PNNs) surrounding the motoneurons. Direct application of neurotrophins at the proximal stump was not able to reverse these effects. In contrast, activity-dependent treatment, in the form of treadmill running, reduced the observed destructuring of perineuronal nets and the loss of glutamatergic synapses two weeks after injury. These changes were proportional to the intensity of the exercise protocol. Blockade of sensory inputs from the homolateral hindlimb also reduced PNN immunoreactivity around intact motoneurons, and in that case treadmill running did not reverse that loss, suggesting that the effects of exercise on motoneuron PNN depend on increased sensory activity. Preservation of motoneuron PNN and reduction of synaptic stripping by exercise could facilitate the maintenance of the spinal circuitry and benefit functional recovery after peripheral nerve injury. PMID:25448160

  3. Functional recovery after cervical spinal cord injury: Role of neurotrophin and glutamatergic signaling in phrenic motoneurons.

    PubMed

    Gill, Luther C; Gransee, Heather M; Sieck, Gary C; Mantilla, Carlos B

    2016-06-01

    Cervical spinal cord injury (SCI) interrupts descending neural drive to phrenic motoneurons causing diaphragm muscle (DIAm) paralysis. Recent studies using a well-established model of SCI, unilateral spinal hemisection of the C2 segment of the cervical spinal cord (SH), provide novel information regarding the molecular and cellular mechanisms of functional recovery after SCI. Over time post-SH, gradual recovery of rhythmic ipsilateral DIAm activity occurs. Recovery of ipsilateral DIAm electromyogram (EMG) activity following SH is enhanced by increasing brain-derived neurotrophic factor (BDNF) in the region of the phrenic motoneuron pool. Delivery of exogenous BDNF either via intrathecal infusion or via mesenchymal stem cells engineered to release BDNF similarly enhance recovery. Conversely, recovery after SH is blunted by quenching endogenous BDNF with the fusion-protein TrkB-Fc in the region of the phrenic motoneuron pool or by selective inhibition of TrkB kinase activity using a chemical-genetic approach in TrkB(F616A) mice. Furthermore, the importance of BDNF signaling via TrkB receptors at phrenic motoneurons is highlighted by the blunting of recovery by siRNA-mediated downregulation of TrkB receptor expression in phrenic motoneurons and by the enhancement of recovery evident following virally-induced increases in TrkB expression specifically in phrenic motoneurons. BDNF/TrkB signaling regulates synaptic plasticity in various neuronal systems, including glutamatergic pathways. Glutamatergic neurotransmission constitutes the main inspiratory-related, excitatory drive to motoneurons, and following SH, spontaneous neuroplasticity is associated with increased expression of ionotropic N-methyl-d-aspartate (NMDA) receptors in phrenic motoneurons. Evidence for the role of BDNF/TrkB and glutamatergic signaling in recovery of DIAm activity following cervical SCI is reviewed. PMID:26506253

  4. Neuroprotective Effects of Testosterone on Motoneuron and Muscle Morphology Following Spinal Cord Injury

    PubMed Central

    Byers, James S.; Huguenard, Anna L.; Kuruppu, Dulanji; Liu, Nai-Kui; Xu, Xiao-Ming; Sengelaub, Dale R.

    2014-01-01

    Treatment with testosterone is neuroprotective/neurotherapeutic after a variety of motoneuron injuries. Here we assessed whether testosterone might have similar beneficial effects after spinal cord injury (SCI). Young adult female rats received either sham or T9 spinal cord contusion injuries and were implanted with blank or testosterone-filled Silastic capsules. Four weeks later, motoneurons innervating the vastus lateralis muscle of the quadriceps were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Soma volume, motoneuron number, lesion volume, and tissue sparing were also assessed, as were muscle weight, fiber cross-sectional area, and motor endplate size and density. Contusion injury resulted in large lesions, with no significant differences in lesion volume, percent total volume of lesion, or spared white or gray matter between SCI groups. SCI with or without testosterone treatment also had no effect on the number or soma volume of quadriceps motoneurons. However, SCI resulted in a decrease in dendritic length of quadriceps motoneurons in untreated animals, and this decrease was completely prevented by treatment with testosterone. Similarly, the vastus lateralis muscle weights and fiber cross-sectional areas of untreated SCI animals were smaller than those of sham-surgery controls, and these reductions were both prevented by testosterone treatment. No effects on motor endplate area or density were observed across treatment groups. These findings suggest that regressive changes in motoneuron and muscle morphology seen after SCI can be prevented by testosterone treatment, further supporting a role for testosterone as a neurotherapeutic agent in the injured nervous system. PMID:22314886

  5. Locomotor training modifies soleus monosynaptic motoneuron responses in human spinal cord injury

    PubMed Central

    Smith, Andrew C.; Rymer, William Zev

    2015-01-01

    The objective of this study was to assess changes in monosynaptic motoneuron responses to stimulation of Ia afferents after locomotor training in individuals with chronic spinal cord injury (SCI). We hypothesized that locomotor training modifies the amplitude of the soleus monosynaptic motoneuron responses in a body position-dependent manner. Fifteen individuals with chronic clinical motor complete or incomplete SCI received an average of 45 locomotor training sessions. The soleus H-reflex and M-wave recruitment curves were assembled using data collected in both the right and left legs, with subjects seated and standing, before and after training. The soleus H-reflexes and M-waves, measured as peak-to-peak amplitudes, were normalized to the maximal M-wave (Mmax). Stimulation intensities were normalized to 50 % Mmax stimulus intensity. A sigmoid function was also fitted to the normalized soleus H-reflexes on the ascending limb of the recruitment curve. After training, soleus H-reflex excitability was increased in both legs in AIS C subjects, and remained unchanged in AIS A-B and AIS D subjects during standing. When subjects were seated, soleus H-reflex excitability was decreased after training in many AIS C and D subjects. Changes in reflex excitability coincided with changes in stimulation intensities at H-threshold, 50 % maximal H-reflex, and at maximal H-reflex, while an interaction between leg side and AIS scale for the H-reflex slope was also found. Adaptations of the intrinsic properties of soleus motoneurons and Ia afferents, the excitability profile of the soleus motoneuron pool, oligosynaptic inputs, and corticospinal inputs may all contribute to these changes. The findings of this study demonstrate that locomotor training impacts the amplitude of the monosynaptic motoneuron responses based on the demands of the motor task in people with chronic SCI. PMID:25205562

  6. Redistribution of Kv2.1 ion channels on spinal motoneurons following peripheral nerve injury.

    PubMed

    Romer, Shannon H; Dominguez, Kathleen M; Gelpi, Marc W; Deardorff, Adam S; Tracy, Robert C; Fyffe, Robert E W

    2014-02-14

    Pathophysiological responses to peripheral nerve injury include alterations in the activity, intrinsic membrane properties and excitability of spinal neurons. The intrinsic excitability of α-motoneurons is controlled in part by the expression, regulation, and distribution of membrane-bound ion channels. Ion channels, such as Kv2.1 and SK, which underlie delayed rectifier potassium currents and afterhyperpolarization respectively, are localized in high-density clusters at specific postsynaptic sites (Deardorff et al., 2013; Muennich and Fyffe, 2004). Previous work has indicated that Kv2.1 channel clustering and kinetics are regulated by a variety of stimuli including ischemia, hypoxia, neuromodulator action and increased activity. Regulation occurs via channel dephosphorylation leading to both declustering and alterations in channel kinetics, thus normalizing activity (Misonou et al., 2004; Misonou et al., 2005; Misonou et al., 2008; Mohapatra et al., 2009; Park et al., 2006). Here we demonstrate using immunohistochemistry that peripheral nerve injury is also sufficient to alter the surface distribution of Kv2.1 channels on motoneurons. The dynamic changes in channel localization include a rapid progressive decline in cluster size, beginning immediately after axotomy, and reaching maximum within one week. With reinnervation, the organization and size of Kv2.1 clusters do not fully recover. However, in the absence of reinnervation Kv2.1 cluster sizes fully recover. Moreover, unilateral peripheral nerve injury evokes parallel, but smaller effects bilaterally. These results suggest that homeostatic regulation of motoneuron Kv2.1 membrane distribution after axon injury is largely independent of axon reinnervation. PMID:24355600

  7. Treadmill training induced lumbar motoneuron dendritic plasticity and behavior recovery in adult rats after a thoracic contusive spinal cord injury.

    PubMed

    Wang, Hongxing; Liu, Nai-Kui; Zhang, Yi Ping; Deng, Lingxiao; Lu, Qing-Bo; Shields, Christopher B; Walker, Melissa J; Li, Jianan; Xu, Xiao-Ming

    2015-09-01

    Spinal cord injury (SCI) is devastating, causing sensorimotor impairments and paralysis. Persisting functional limitations on physical activity negatively affect overall health in individuals with SCI. Physical training may improve motor function by affecting cellular and molecular responses of motor pathways in the central nervous system (CNS) after SCI. Although motoneurons form the final common path for motor output from the CNS, little is known concerning the effect of exercise training on spared motoneurons below the level of injury. Here we examined the effect of treadmill training on morphological, trophic, and synaptic changes in the lumbar motoneuron pool and on behavior recovery after a moderate contusive SCI inflicted at the 9th thoracic vertebral level (T9) using an Infinite Horizon (IH, 200 kDyne) impactor. We found that treadmill training significantly improved locomotor function, assessed by Basso-Beattie-Bresnahan (BBB) locomotor rating scale, and reduced foot drops, assessed by grid walking performance, as compared with non-training. Additionally, treadmill training significantly increased the total neurite length per lumbar motoneuron innervating the soleus and tibialis anterior muscles of the hindlimbs as compared to non-training. Moreover, treadmill training significantly increased the expression of a neurotrophin brain-derived neurotrophic factor (BDNF) in the lumbar motoneurons as compared to non-training. Finally, treadmill training significantly increased synaptic density, identified by synaptophysin immunoreactivity, in the lumbar motoneuron pool as compared to non-training. However, the density of serotonergic terminals in the same regions did not show a significant difference between treadmill training and non-training. Thus, our study provides a biological basis for exercise training as an effective medical practice to improve recovery after SCI. Such an effect may be mediated by synaptic plasticity, and neurotrophic modification in the

  8. Role of HSP70 in motoneuron survival after excitotoxic stress in a rat spinal cord injury model in vitro.

    PubMed

    Shabbir, Ayisha; Bianchetti, Elena; Cargonja, Renato; Petrovic, Antonela; Mladinic, Miranda; Pilipović, Kristina; Nistri, Andrea

    2015-12-01

    The outcome for gait recovery from paralysis due to spinal lesion remains uncertain even when damage is limited. One critical factor is the survival of motoneurons, which are very vulnerable cells. To clarify the early pathophysiological mechanisms of spinal damage, an in vitro injury model of the rat spinal cord caused by moderate excitotoxicity was used. With this preparation we investigated whether motoneuron survival was dependent on the expression of the neuroprotective protein HSP70. In the present study excitotoxicity evoked by kainate induced delayed (24 h) loss (35%) of motoneurons, which became pyknotic with translocation of the cell death biomarker apoptosis-inducing factor (AIF) to the nucleus. This process was concomitant with suppression of locomotor network electrical activity. Surviving cells showed strong expression of HSP70 without nuclear AIF. The HSP70 inhibitor VER155008 per se induced neurotoxicity similar to that of kainate, while the HSP90 inhibitor geldanamycin did not damage spinal tissue. Electrophysiological recording following kainate or VER155008 indicated depression of motoneuron field potentials, with decreased excitability and impaired synaptic transmission. When these two drugs were applied together, more intense neurotoxicity emerged. Our data indicate that HSP70 was one important contributor to motoneuron survival and suggest that enhancing HSP70 activity is a potential future strategy for neuroprotecting these cells. PMID:26490753

  9. Motoneuron Intrinsic Properties, but Not Their Receptive Fields, Recover in Chronic Spinal Injury

    PubMed Central

    Kajtaz, Elma; Cain, Charlette M.; Heckman, C.J.

    2013-01-01

    Proper movement execution relies on precise input processing by spinal motoneurons (MNs). Spinal MNs are activated by limb joint rotations. Typically, their movement-related receptive fields (MRRFs) are sharply focused and joint-specific. After acute spinal transection MRRFs become wide, but their manifestation is not apparent, as intrinsic excitability, primarily resulting from the loss of persistent inward currents (PICs), dramatically decreases. PICs undergo a remarkable recovery with time after injury. Here we investigate whether MRRFs undergo a recovery that parallels that of the PIC. Using the chronic spinal cat in acute terminal decerebrate preparations, we found that MRRFs remain expanded 1 month after spinal transaction, whereas PICs recovered to >80% of their preinjury amplitudes. These recovered PICs substantially amplified the expanded inputs underlying the MRRFs. As a result, we show that single joint rotations lead to the activation of muscles across the entire limb. These results provide a potential mechanism for the propagation of spasms throughout the limb. PMID:24285887

  10. Delaying the onset of treadmill exercise following peripheral nerve injury has different effects on axon regeneration and motoneuron synaptic plasticity

    PubMed Central

    Brandt, Jaclyn; Evans, Jonathan T.; Mildenhall, Taylor; Mulligan, Amanda; Konieczny, Aimee; Rose, Samuel J.

    2015-01-01

    Transection of a peripheral nerve results in withdrawal of synapses from motoneurons. Some of the withdrawn synapses are restored spontaneously, but those containing the vesicular glutamate transporter 1 (VGLUT1), and arising mainly from primary afferent neurons, are withdrawn permanently. If animals are exercised immediately after nerve injury, regeneration of the damaged axons is enhanced and no withdrawal of synapses from injured motoneurons can be detected. We investigated whether delaying the onset of exercise until after synapse withdrawal had occurred would yield similar results. In Lewis rats, the right sciatic nerve was cut and repaired. Reinnervation of the soleus muscle was monitored until a direct muscle (M) response was observed to stimulation of the tibial nerve. At that time, rats began 2 wk of daily treadmill exercise using an interval training protocol. Both M responses and electrically-evoked H reflexes were monitored weekly for an additional seven wk. Contacts made by structures containing VGLUT1 or glutamic acid decarboxylase (GAD67) with motoneurons were studied from confocal images of retrogradely labeled cells. Timing of full muscle reinnervation was similar in both delayed and immediately exercised rats. H reflex amplitude in delayed exercised rats was only half that found in immediately exercised animals. Unlike immediately exercised animals, motoneuron contacts containing VGLUT1 in delayed exercised rats were reduced significantly, relative to intact rats. The therapeutic window for application of exercise as a treatment to promote restoration of synaptic inputs onto motoneurons following peripheral nerve injury is different from that for promoting axon regeneration in the periphery. PMID:25632080

  11. Delaying the onset of treadmill exercise following peripheral nerve injury has different effects on axon regeneration and motoneuron synaptic plasticity.

    PubMed

    Brandt, Jaclyn; Evans, Jonathan T; Mildenhall, Taylor; Mulligan, Amanda; Konieczny, Aimee; Rose, Samuel J; English, Arthur W

    2015-04-01

    Transection of a peripheral nerve results in withdrawal of synapses from motoneurons. Some of the withdrawn synapses are restored spontaneously, but those containing the vesicular glutamate transporter 1 (VGLUT1), and arising mainly from primary afferent neurons, are withdrawn permanently. If animals are exercised immediately after nerve injury, regeneration of the damaged axons is enhanced and no withdrawal of synapses from injured motoneurons can be detected. We investigated whether delaying the onset of exercise until after synapse withdrawal had occurred would yield similar results. In Lewis rats, the right sciatic nerve was cut and repaired. Reinnervation of the soleus muscle was monitored until a direct muscle (M) response was observed to stimulation of the tibial nerve. At that time, rats began 2 wk of daily treadmill exercise using an interval training protocol. Both M responses and electrically-evoked H reflexes were monitored weekly for an additional seven wk. Contacts made by structures containing VGLUT1 or glutamic acid decarboxylase (GAD67) with motoneurons were studied from confocal images of retrogradely labeled cells. Timing of full muscle reinnervation was similar in both delayed and immediately exercised rats. H reflex amplitude in delayed exercised rats was only half that found in immediately exercised animals. Unlike immediately exercised animals, motoneuron contacts containing VGLUT1 in delayed exercised rats were reduced significantly, relative to intact rats. The therapeutic window for application of exercise as a treatment to promote restoration of synaptic inputs onto motoneurons following peripheral nerve injury is different from that for promoting axon regeneration in the periphery. PMID:25632080

  12. [REACTIVE CHANGES IN SPINAL CORD MOTONEURONS AFTER SCIATIC NERVE INJURY AFTER HIGH-FREQUENCY ELECTROSURGICAL INSTRUMENT APPLICATION].

    PubMed

    Korsak, A; Chaikovsky, Yu; Sokurenko, L; Likhodiievskyi, V; Neverovskyi, A

    2016-02-01

    A new experimental model for tissues connection at peripheral nerve injury site in form of tissues welding was designed. In current study we investigated motoneuron state 1, 3, 6 and 12 weeks after peripheral nerve injury and surgical repair with high-frequency electrosurgical technology. Spinal cord sections was stained by Nissl method and observed with light microscopy. We found that postoperative period in animals from experimental groups characterized by qualitative changes in neurons from spinal motor centers that can be interpreted as compensatory processes as response to alteration. In animals from group with high-frequency electrosurgical technology usage stabilization processes passes more quickly comparatively to animals with epineural sutures. High-frequency electrosurgical technology usage provides less harmful effects on motoneurons than epineural suturing. PMID:27001790

  13. Locomotor training improves reciprocal and nonreciprocal inhibitory control of soleus motoneurons in human spinal cord injury

    PubMed Central

    Smith, Andrew C.; Mummidisetty, Chaithanya K.

    2015-01-01

    Pathologic reorganization of spinal networks and activity-dependent plasticity are common neuronal adaptations after spinal cord injury (SCI) in humans. In this work, we examined changes of reciprocal Ia and nonreciprocal Ib inhibition after locomotor training in 16 people with chronic SCI. The soleus H-reflex depression following common peroneal nerve (CPN) and medial gastrocnemius (MG) nerve stimulation at short conditioning-test (C-T) intervals was assessed before and after training in the seated position and during stepping. The conditioned H reflexes were normalized to the unconditioned H reflex recorded during seated. During stepping, both H reflexes were normalized to the maximal M wave evoked at each bin of the step cycle. In the seated position, locomotor training replaced reciprocal facilitation with reciprocal inhibition in all subjects, and Ib facilitation was replaced by Ib inhibition in 13 out of 14 subjects. During stepping, reciprocal inhibition was decreased at early stance and increased at midswing in American Spinal Injury Association Impairment Scale C (AIS C) and was decreased at midstance and midswing phases in AIS D after training. Ib inhibition was decreased at early swing and increased at late swing in AIS C and was decreased at early stance phase in AIS D after training. The results of this study support that locomotor training alters postsynaptic actions of Ia and Ib inhibitory interneurons on soleus motoneurons at rest and during stepping and that such changes occur in cases with limited or absent supraspinal inputs. PMID:25609110

  14. Hypoxia triggers short term potentiation of phrenic motoneuron discharge after chronic cervical spinal cord injury

    PubMed Central

    Lee, Kun-Ze; Sandhu, Milapjit S.; Dougherty, Brendan J.; Reier, Paul J.; Fuller, David D.

    2014-01-01

    Repeated exposure to hypoxia can induce spinal neuroplasticity as well as respiratory and somatic motor recovery after spinal cord injury (SCI). The purpose of the present study was to define the capacity for a single bout of hypoxia to trigger short-term plasticity in phrenic output after cervical SCI, and to determine the phrenic motoneuron (PhrMN) bursting and recruitment patterns underlying the response. Hypoxia-induced short term potentiation (STP) of phrenic motor output was quantified in anesthetized rats 11 wks following lateral spinal hemisection at C2 (C2Hx). A 3-min hypoxic episode (12–14% O2) always triggered STP of inspiratory burst amplitude, the magnitude of which was greater in phrenic bursting ipsilateral vs. contralateral to C2Hx. We next determined if STP could be evoked in recruited (silent) PhrMNs ipsilateral to C2Hx. Individual PhrMN action potentials were recorded during and following hypoxia using a “single fiber” approach. STP of bursting activity did not occur in cells initiating bursting at inspiratory onset, but was robust in recruited PhrMNs as well as previously active cells initiating bursting later in the inspiratory effort. We conclude that following chronic C2Hx, a single bout of hypoxia triggers recruitment of PhrMNs in the ipsilateral spinal cord with bursting that persists beyond the hypoxic exposure. The results provide further support for the use of short bouts of hypoxia as a neurorehabilitative training modality following SCI. PMID:25448009

  15. Ventral root re-implantation is better than peripheral nerve transplantation for motoneuron survival and regeneration after spinal root avulsion injury

    PubMed Central

    2013-01-01

    Background Peripheral nerve (PN) transplantation and ventral root implantation are the two common types of recovery operations to restore the connection between motoneurons and their target muscles after brachial plexus injury. Despite experience accumulated over the past decade, fundamental knowledge is still lacking concerning the efficacy of the two microsurgical interventions. Methods Thirty-eight adult female Sprague–Dawley rats were divided into 5 groups. Immediately following root avulsion, animals in the first group (n = 8) and the second group (n = 8) received PN graft and ventral root implantation respectively. The third group (n = 8) and the fourth group (n = 8) received PN graft and ventral root implantation respectively at one week after root avulsion. The fifth group received root avulsion only as control (n = 6). The survival and axonal regeneration of severed motoneurons were investigated at 6 weeks post-implantation. Results Re-implantation of ventral roots, both immediately after root avulsion and in delay, significantly increased the survival and regeneration of motoneurons in the avulsed segment of the spinal cord as compared with PN graft transplantation. Conclusions The ventral root re-implantation is a better surgical repairing procedure than PN graft transplantation for brachial plexus injury because of its easier manipulation for re-implanting avulsed ventral roots to the preferred site, less possibility of causing additional damage and better effects on motoneuron survival and axonal regeneration. PMID:23799915

  16. Melatonin preserves superoxide dismutase activity in hypoglossal motoneurons of adult rats following peripheral nerve injury.

    PubMed

    Chang, Hung-Ming; Huang, Yi-Lun; Lan, Chyn-Tair; Wu, Un-In; Hu, Ming-E; Youn, Su-Chung

    2008-03-01

    Peripheral nerve injury (PNI) produces functional changes in lesioned neurons in which oxidative stress is considered to be the main cause of neuronal damage. As superoxide dismutase (SOD) is an important antioxidative enzyme involved in redox regulation of oxidative stress, the present study determined whether melatonin would exert its beneficial effects by preserving the SOD reactivity following PNI. Adult rats subjected to hypoglossal nerve transection were intraperitoneally injected with melatonin at ones for 3, 7, 14, 30 and 60 days successively. The potential neuroprotective effects of melatonin were quantitatively demonstrated by neuronal nitric oxide synthase (nNOS), mitochondrial manganese SOD (Mn-SOD), and cytosolic copper-zinc SOD (Cu/Zn-SOD) immunohistochemistry. The functional recovery of the lesioned neurons was evaluated by choline acetyltransferase (ChAT) immunohistochemistry along with the electromyographic (EMG) recordings of denervation-induced fibrillation activity. The results indicate that following PNI, the nNOS immunoreactivity was significantly increased in lesioned neurons peaking at 14 days. The up-regulation of nNOS temporally coincided with the reduction of ChAT and SOD in which the Cu/Zn-SOD showed a greater diminution than Mn-SOD. However, following melatonin administration, the nNOS augmentation was successfully suppressed and the activities of Mn-SOD, Cu/Zn-SOD, and ChAT were effectively preserved at all postaxotomy periods. EMG data also showed a decreased fibrillation in melatonin-treated groups, suggesting a potential effect of melatonin in promoting functional recovery. In association with its significant capacity in preserving SOD reactivity, melatonin is suggested to serve as a powerful therapeutic agent for treating PNI-relevant oxidative damage. PMID:18289169

  17. Bilateral Bulbospinal Projections to Pudendal Motoneuron Circuitry after Chronic Spinal Cord Hemisection Injury as Revealed by Transsynaptic Tracing with Pseudorabies Virus

    PubMed Central

    Chadha, Harpreet K.; Dugan, Victoria P.; Gupta, Daya S.; Ferrero, Sunny L.; Hubscher, Charles H.

    2011-01-01

    Abstract Complications of spinal cord injury in males include losing brainstem control of pudendal nerve–innervated perineal muscles involved in erection and ejaculation. We previously described, in adult male rats, a bulbospinal pathway originating in a discrete area within the medullary gigantocellularis (GiA/Gi), and lateral paragigantocellularis (LPGi) nuclei, which when electrically microstimulated unilaterally, produces a bilateral inhibition of pudendal motoneuron reflex circuitry after crossing to the contralateral spinal cord below T8. Microstimulation following a long-term lateral hemisection, however, revealed reflex inhibition from both sides of the medulla, suggesting the development or unmasking of an injury-induced bulbospinal pathway crossing the midline cranial to the spinal lesion. In the present study, we investigated this pathway anatomically using the transsynaptic neuronal tracer pseudorabies virus (PRV) injected unilaterally into the bulbospongiosus muscle in uninjured controls, and ipsilateral to a chronic (1–2 months) unilateral lesion of the lateral funiculus. At 4.75 days post-injection, PRV-labeled cells were found bilaterally in the GiA/Gi/LPGi with equal side-to-side labeling in uninjured controls, and with significantly greater labeling contralateral to the lesion/injection in lesioned animals. The finding of PRV-labeled neurons on both sides of the medulla after removing the mid-thoracic spinal pathway on one side provides anatomical evidence for the bilaterality in both the brainstem origin and the lumbosacral pudendal circuit termination of the spared lateral funicular bulbospinal pathway. This also suggests that this bilaterality may contribute to the quick functional recovery of bladder and sexual functions observed in animals and humans with lateral hemisection injury. PMID:21265606

  18. Bilateral bulbospinal projections to pudendal motoneuron circuitry after chronic spinal cord hemisection injury as revealed by transsynaptic tracing with pseudorabies virus.

    PubMed

    Johnson, Richard D; Chadha, Harpreet K; Dugan, Victoria P; Gupta, Daya S; Ferrero, Sunny L; Hubscher, Charles H

    2011-04-01

    Complications of spinal cord injury in males include losing brainstem control of pudendal nerve-innervated perineal muscles involved in erection and ejaculation. We previously described, in adult male rats, a bulbospinal pathway originating in a discrete area within the medullary gigantocellularis (GiA/Gi), and lateral paragigantocellularis (LPGi) nuclei, which when electrically microstimulated unilaterally, produces a bilateral inhibition of pudendal motoneuron reflex circuitry after crossing to the contralateral spinal cord below T8. Microstimulation following a long-term lateral hemisection, however, revealed reflex inhibition from both sides of the medulla, suggesting the development or unmasking of an injury-induced bulbospinal pathway crossing the midline cranial to the spinal lesion. In the present study, we investigated this pathway anatomically using the transsynaptic neuronal tracer pseudorabies virus (PRV) injected unilaterally into the bulbospongiosus muscle in uninjured controls, and ipsilateral to a chronic (1-2 months) unilateral lesion of the lateral funiculus. At 4.75 days post-injection, PRV-labeled cells were found bilaterally in the GiA/Gi/LPGi with equal side-to-side labeling in uninjured controls, and with significantly greater labeling contralateral to the lesion/injection in lesioned animals. The finding of PRV-labeled neurons on both sides of the medulla after removing the mid-thoracic spinal pathway on one side provides anatomical evidence for the bilaterality in both the brainstem origin and the lumbosacral pudendal circuit termination of the spared lateral funicular bulbospinal pathway. This also suggests that this bilaterality may contribute to the quick functional recovery of bladder and sexual functions observed in animals and humans with lateral hemisection injury. PMID:21265606

  19. Testing the excitability of human motoneurons

    PubMed Central

    McNeil, Chris J.; Butler, Jane E.; Taylor, Janet L.; Gandevia, Simon C.

    2013-01-01

    The responsiveness of the human central nervous system can change profoundly with exercise, injury, disuse, or disease. Changes occur at both cortical and spinal levels but in most cases excitability of the motoneuron pool must be assessed to localize accurately the site of adaptation. Hence, it is critical to understand, and employ correctly, the methods to test motoneuron excitability in humans. Several techniques exist and each has its advantages and disadvantages. This review examines the most common techniques that use evoked compound muscle action potentials to test the excitability of the motoneuron pool and describes the merits and limitations of each. The techniques discussed are the H-reflex, F-wave, tendon jerk, V-wave, cervicomedullary motor evoked potential (CMEP), and motor evoked potential (MEP). A number of limitations with these techniques are presented. PMID:23630483

  20. Phase relation changes between the firings of alpha and gamma-motoneurons and muscle spindle afferents in the sacral micturition centre during continence functions in brain-dead human and patients with spinal cord injury.

    PubMed

    Schalow, G

    2010-01-01

    1. Single-nerve fibre action potentials (APs) were recorded with 2 pairs of wire electrodes from lower sacral nerve roots during surgery in patients with spinal cord injury and in a brain-dead human. Conduction velocity distribution histograms were constructed for afferent and efferent fibres, nerve fibre groups were identified and simultaneous impulse patterns of alpha and gamma-motoneurons and secondary muscle spindle afferents (SP2) were constructed. Temporal relations between afferent and efferent APs were analyzed by interspike interval (II) and phase relation changes to explore the coordinated self-organization of somatic and parasympathetic neuronal networks in the sacral micturition centre during continence functions under physiologic (brain-dead) and pathophysiologic conditions (spinal cord injury). 2. In a paraplegic with hyperreflexia of the bladder, urinary bladder stretch (S1) and tension receptor afferents (ST) fired already when the bladder was empty, and showed a several times higher bladder afferent activity increase upon retrograde bladder filling than observed in the brain-dead individual. Two alpha2-motoneurons (FR) innervating the external bladder sphincter were already oscillatory firing to generate high activity levels when the bladder was empty. They showed activity levels with no bladder filling, comparable to those measured at a bladder filling of 600 ml in the brain-dead individual. A bladder storage volume of 600 ml was thus lost in the paraplegic, due to a too high bladder afferent input to the sacral micturition center, secondary to inflammation and hypertrophy of the detrusor. 3. In a brain-dead human, 2 phase relations existed per oscillation period of 160 ms between the APs of a sphincteric oscillatory firing alpha2-motoneuron, a dynamic fusimotor and a secondary muscle spindle afferent fibre. Following stimulation of mainly somatic afferent fibres, the phase relations changed only little. 4. In a paraplegic with dyssynergia of the

  1. Synaptic Control of Motoneuronal Excitability

    PubMed Central

    Rekling, Jens C.; Funk, Gregory D.; Bayliss, Douglas A.; Dong, Xiao-Wei; Feldman, Jack L.

    2016-01-01

    Movement, the fundamental component of behavior and the principal extrinsic action of the brain, is produced when skeletal muscles contract and relax in response to patterns of action potentials generated by motoneurons. The processes that determine the firing behavior of motoneurons are therefore important in understanding the transformation of neural activity to motor behavior. Here, we review recent studies on the control of motoneuronal excitability, focusing on synaptic and cellular properties. We first present a background description of motoneurons: their development, anatomical organization, and membrane properties, both passive and active. We then describe the general anatomical organization of synaptic input to motoneurons, followed by a description of the major transmitter systems that affect motoneuronal excitability, including ligands, receptor distribution, pre- and postsynaptic actions, signal transduction, and functional role. Glutamate is the main excitatory, and GABA and glycine are the main inhibitory transmitters acting through ionotropic receptors. These amino acids signal the principal motor commands from peripheral, spinal, and supraspinal structures. Amines, such as serotonin and norepinephrine, and neuropeptides, as well as the glutamate and GABA acting at metabotropic receptors, modulate motoneuronal excitability through pre- and postsynaptic actions. Acting principally via second messenger systems, their actions converge on common effectors, e.g., leak K+ current, cationic inward current, hyperpolarization-activated inward current, Ca2+ channels, or presynaptic release processes. Together, these numerous inputs mediate and modify incoming motor commands, ultimately generating the coordinated firing patterns that underlie muscle contractions during motor behavior. PMID:10747207

  2. Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS mice

    PubMed Central

    Kieran, Dairín; Woods, Ina; Villunger, Andreas; Strasser, Andreas; Prehn, Jochen H. M.

    2007-01-01

    BH3-only proteins couple diverse stress signals to the evolutionarily conserved mitochondrial apoptosis pathway. Previously, we reported that the activation of the BH3-only protein p53-up-regulated mediator of apoptosis (Puma) was necessary and sufficient for endoplasmic reticulum (ER) stress- and proteasome inhibition-induced apoptosis in neuroblastoma and other cancer cells. Defects in protein quality control have also been suggested to be a key event in ALS, a fatal neurodegenerative condition characterized by motoneuron degeneration. Using the SOD1G93A mouse model as well as human post mortem samples from ALS patients, we show evidence for increased ER stress and defects in protein degradation in motoneurons during disease progression. Before symptom onset, we detected a significant up-regulation of Puma in motoneurons of SOD1G93A mice. Genetic deletion of puma significantly improved motoneuron survival and delayed disease onset and motor dysfunction in SOD1G93A mice. However, it had no significant effect on lifespan, suggesting that other ER stress-related cell-death proteins or other factors, such as excitotoxicity, necrosis, or inflammatory injury, may contribute at later disease stages. Indeed, further experiments using cultured motoneurons revealed that genetic deletion of puma protected motoneurons against ER stress-induced apoptosis but showed no effect against excitotoxic injury. These findings demonstrate that a single BH3-only protein, the ER stress-associated protein Puma, plays an important role during the early stages of chronic neurodegeneration in vivo. PMID:18077368

  3. Single motoneuron succinate dehydrogenase activity.

    PubMed

    Chalmers, G R; Edgerton, V R

    1989-07-01

    We have developed a quantitative histochemical assay for measurement of succinate dehydrogenase (SDH) activity in single motoneurons. A computer image processing system was used to quantify the histochemical enzyme reaction product and to follow the time course of the reaction. The optimal concentration for each of the ingredients of the incubation medium for the SDH reaction was determined and the importance of using histochemical "blanks" in the determination of enzymatic activity was demonstrated. The enzymatic activity was linear with respect to reaction time and tissue thickness. The procedure described meets the criteria generally considered essential for establishment of a quantitative histochemical assay. The assay was then used to examine the SDH activity of cat and rat motoneurons. It was found that motoneurons with a small soma size had a wide range of SDH activity, whereas those with a large soma size were restricted to low SDH activity. PMID:2732457

  4. Different discharge properties of facial nucleus motoneurons following neurotmesis in a rat model.

    PubMed

    Shi, Suming; Xu, Lei; Li, Jianfeng; Han, Yuechen; Wang, Haibo

    2016-08-26

    Facial nucleus motoneurons innervating the facial expressive muscles are involved in a wide range of motor activities, however, the types of movement related neurons and their electrophysiological transformation after peripheral facial nerve injury haven't been revealed. This study was designed to elucidate the types of facial nucleus motoneurons and their alterations of discharge parameters following peripheral facial nerve injury in vivo. Here we set up a rat model by implanting electrode arrays into the brainstem and recorded the electrophysiological signals of facial nucleus neurons in the intact rats for 5 days, then transected the trunk of facial nerve (TF), and continued the record for 4 weeks. At the 4th week post-surgery, the morphological changes of TFs were analyzed. In this paper, we described two types of putative facial nucleus motoneurons based on their electrophysiological properties and their firing frequency adaptation. Type I motoneurons (n=57.6%) were characterized by a sustained spike adaptation, Type II motoneurons (n=26.2%) were identified by a phasic fast spike firing. Facial palsy and synkinesia, caused by neurotmesis of TF, were accompanied by firing rates reduction and firing pattern alteration of motoneurons. Our findings suggest the presence of two types of facial nucleus motorneurons, and their response patterns after neurotmesis support the notion that the discharge pattern of motorneurons may play an important role in the facial nerve function. PMID:27423319

  5. Neural control of phrenic motoneuron discharge

    PubMed Central

    Lee, Kun-Ze; Fuller, David D.

    2011-01-01

    Phrenic motoneurons (PMNs) provide a synaptic relay between bulbospinal respiratory pathways and the diaphragm muscle. PMNs also receive propriospinal inputs, although the functional role of these interneuronal projections has not been established. Here we review the literature regarding PMN discharge patterns during breathing and the potential mechanisms that underlie PMN recruitment. Anatomical and neurophysiological studies indicate that PMNs form a heterogeneous pool, with respiratory-related PMN discharge and recruitment patterns likely determined by a balance between intrinsic MN properties and extrinsic synaptic inputs. We also review the limited literature regarding PMN bursting during respiratory plasticity. Differential recruitment or rate modulation of PMN subtypes may underlie phrenic motor plasticity following neural injury and/or respiratory stimulation; however this possibility remains relatively unexplored. PMID:21376841

  6. Insulin-like growth factors: putative muscle-derived trophic agents that promote motoneuron survival.

    PubMed

    Neff, N T; Prevette, D; Houenou, L J; Lewis, M E; Glicksman, M A; Yin, Q W; Oppenheim, R W

    1993-12-01

    Treatment of chick embryos in ovo with IGF-I during the period of normal, developmentally regulated neuronal death (embryonic days 5-10) resulted in a dose-dependent rescue of a significant number of lumbar motoneurons from degeneration and death. IGF-II and two variants of IGF-I with reduced affinity for IGF binding proteins, des(1-3) IGF-I and long R3 IGF-I, also elicited enhanced survival of motoneurons equal to that seen in IGF-I-treated embryos. IGF-I did not enhance mitogenic activity in motoneuronal populations when applied to embryos during the period of normal neuronal proliferation (E2-5). Treatment of embryos with IGF-I also reduced two types of injury-induced neuronal death. Following either deafferentation or axotomy, treatment of embryos with IGF-I rescued approximately 75% and 50%, respectively, of the motoneurons that die in control embryos as a result of these procedures. Consistent with the survival-promoting activity on motoneurons in ovo, IGF-I, -II, and des(1-3) IGF-I elevated choline acetyltransferase activity in embryonic rat spinal cord cultures, with des(1-3) IGF-I demonstrating 2.5 times greater potency than did IGF-I. A single addition of IGF-I at culture initiation resulted in the maintenance of 80% of the initial ChAT activity for up to 5 days, during which time ChAT activity in untreated control cultures fell to 9%. In summary, these results demonstrate clear motoneuronal trophic activity for the IGFs. These findings, together with previous reports that IGFs are synthesized in muscle and may participate in motoneuron axonal regeneration and sprouting, indicate that these growth factors may have an important role in motoneuron development, maintenance, and recovery from injury. PMID:8301266

  7. Acute Stimulation of Transplanted Neurons Improves Motoneuron Survival, Axon Growth, and Muscle Reinnervation

    PubMed Central

    Grumbles, Robert M.; Liu, Yang; Thomas, Christie M.; Wood, Patrick M.

    2013-01-01

    Abstract Few options exist for treatment of pervasive motoneuron death after spinal cord injury or in neurodegenerative diseases such as amyotrophic lateral sclerosis. Local transplantation of embryonic motoneurons into an axotomized peripheral nerve is a promising approach to arrest the atrophy of denervated muscles; however, muscle reinnervation is limited by poor motoneuron survival. The aim of the present study was to test whether acute electrical stimulation of transplanted embryonic neurons promotes motoneuron survival, axon growth, and muscle reinnervation. The sciatic nerve of adult Fischer rats was transected to mimic the widespread denervation seen after disease or injury. Acutely dissociated rat embryonic ventral spinal cord cells were transplanted into the distal tibial nerve stump as a neuron source for muscle reinnervation. Immediately post-transplantation, the cells were stimulated at 20 Hz for 1 h. Other groups were used to control for the cell transplantation and stimulation. When neurons were stimulated acutely, there were significantly more neurons, including cholinergic neurons, 10 weeks after transplantation. This led to enhanced numbers of myelinated axons, reinnervation of more muscle fibers, and more medial and lateral gastrocnemius muscles were functionally connected to the transplant. Reinnervation reduced muscle atrophy significantly. These data support the concept that electrical stimulation rescues transplanted motoneurons and facilitates muscle reinnervation. PMID:23544978

  8. Motoneurons Derived from Induced Pluripotent Stem Cells Develop Mature Phenotypes Typical of Endogenous Spinal Motoneurons

    PubMed Central

    Toma, Jeremy S.; Shettar, Basavaraj C.; Chipman, Peter H.; Pinto, Devanand M.; Borowska, Joanna P.; Ichida, Justin K.; Fawcett, James P.; Zhang, Ying; Eggan, Kevin

    2015-01-01

    Induced pluripotent cell-derived motoneurons (iPSCMNs) are sought for use in cell replacement therapies and treatment strategies for motoneuron diseases such as amyotrophic lateral sclerosis (ALS). However, much remains unknown about the physiological properties of iPSCMNs and how they compare with endogenous spinal motoneurons or embryonic stem cell-derived motoneurons (ESCMNs). In the present study, we first used a proteomic approach and compared protein expression profiles between iPSCMNs and ESCMNs to show that <4% of the proteins identified were differentially regulated. Like ESCs, we found that mouse iPSCs treated with retinoic acid and a smoothened agonist differentiated into motoneurons expressing the LIM homeodomain protein Lhx3. When transplanted into the neural tube of developing chick embryos, iPSCMNs selectively targeted muscles normally innervated by Lhx3 motoneurons. In vitro studies showed that iPSCMNs form anatomically mature and functional neuromuscular junctions (NMJs) when cocultured with chick myofibers for several weeks. Electrophysiologically, iPSCMNs developed passive membrane and firing characteristic typical of postnatal motoneurons after several weeks in culture. Finally, iPSCMNs grafted into transected mouse tibial nerve projected axons to denervated gastrocnemius muscle fibers, where they formed functional NMJs, restored contractile force. and attenuated denervation atrophy. Together, iPSCMNs possess many of the same cellular and physiological characteristics as ESCMNs and endogenous spinal motoneurons. These results further justify using iPSCMNs as a source of motoneurons for cell replacement therapies and to study motoneuron diseases such as ALS. PMID:25609642

  9. Posthatching development of spinal motoneurons in the angelfish Pterophyllum scalare.

    PubMed

    Yoshida, M; Fudoji, M; Sakamoto, H; Uematsu, K

    1999-01-01

    We investigated the posthatching developmental sequence of spinal motoneurons innervating the axial muscles in the teleost angelfish, Pterophyllum scalare, by means of retrograde labeling with horseradish peroxidase. Two discrete types of spinal motoneurons, primary-type motoneurons and secondary motoneurons were labeled in a temporally different sequence during the course of larval development. These two types of motoneurons were morphologically distinguishable from one other. Primary-type motoneurons are generated by day 1 posthatching and do not increase in number over the observed period (to day 12 posthatching). In contrast, the secondary motoneurons increase in number through posthatching day 3. Differentiation of the spinal motoneurons appears to be nearly complete a few days before the onset of free swimming. In addition, the data suggest that the differentiation of secondary motoneurons precedes the development of the red muscle that is to be innervated by the motoneurons. PMID:10343084

  10. Adaptability of the oxidative capacity of motoneurons

    NASA Technical Reports Server (NTRS)

    Chalmers, G. R.; Roy, R. R.; Edgerton, V. R.

    1992-01-01

    Previous studies have demonstrated that a chronic change in neuronal activation can produce a change in soma oxidative capacity, suggesting that: (i) these 2 variables are directly related in neurons and (ii) ion pumping is an important energy requiring activity of a neuron. Most of these studies, however, have focused on reduced activation levels of sensory systems. In the present study the effect of a chronic increase or decrease in motoneuronal activity on motoneuron oxidative capacity and soma size was studied. In addition, the effect of chronic axotomy was studied as an indicator of whether cytoplasmic volume may also be related to the oxidative capacity of motoneurons. A quantitative histochemical assay for succinate dehydrogenase activity was used as a measure of motoneuron oxidative capacity in experimental models in which chronic electromyography has been used to verify neuronal activity levels. Spinal transection reduced, and spinal isolation virtually eliminated lumbar motoneuron electrical activity. Functional overload of the plantaris by removal of its major synergists was used to chronically increase neural activity of the plantaris motor pool. No change in oxidative capacity or soma size resulted from either a chronic increase or decrease in neuronal activity level. These data indicate that the chronic modulation of ionic transport and neurotransmitter turnover associated with action potentials do not induce compensatory metabolic responses in the metabolic capacity of the soma of lumbar motoneurons. Soma oxidative capacity was reduced in the axotomized motoneurons, suggesting that a combination of axoplasmic transport, intracellular biosynthesis and perhaps neurotransmitter turnover represent the major energy demands on a motoneuron. While soma oxidative capacity may be closely related to neural activity in some neural systems, e.g. visual and auditory, lumbar motoneurons appear to be much less sensitive to modulations in chronic activity levels.

  11. Neonatal motoneurons overexpressing the bcl-2 protooncogene in transgenic mice are protected from axotomy-induced cell death.

    PubMed Central

    Dubois-Dauphin, M; Frankowski, H; Tsujimoto, Y; Huarte, J; Martinou, J C

    1994-01-01

    In vitro, the overexpression of the bcl-2 protooncogene in cultured neurons has been shown to prevent apoptosis induced by neurotrophic factor deprivation. We have generated transgenic mice overexpressing the Bcl-2 protein in neurons, including motoneurons of the facial nucleus. We have tested whether Bcl-2 could protect these motoneurons from experimentally induced cell death in new born mice. To address this question, we performed unilateral lesion of the facial nerve of wild-type and transgenic 2-day-old mice. In wild-type mice, the lesioned nerve and the corresponding motoneuron cell bodies in the facial nucleus underwent rapid degeneration. In contrast, in transgenic mice, facial motoneurons survived axotomy. Not only their cell bodies but also their axons were protected up to the lesion site. These results demonstrate that in vivo Bcl-2 protects neonatal motoneurons from degeneration after axonal injury. A better understanding of the mechanisms by which Bcl-2 prevents neuronal cell death in vivo could lead to the development of strategies for the treatment of motoneuron degenerative diseases. Images PMID:8159744

  12. Delayed riluzole treatment is able to rescue injured rat spinal motoneurons.

    PubMed

    Nógrádi, A; Szabó, A; Pintér, S; Vrbová, G

    2007-01-19

    The effect of delayed 2-amino-6-trifluoromethoxy-benzothiazole (riluzole) treatment on injured motoneurons was studied. The L4 ventral root of adult rats was avulsed and reimplanted into the spinal cord. Immediately after the operation or with a delay of 5, 10, 14 or 16 days animals were treated with riluzole (n=5 in each group) while another four animals remained untreated. Three months after the operation the fluorescent dye Fast Blue was applied to the proximal end of the cut ventral ramus of the L4 spinal nerve to retrogradely label reinnervating neurons. Three days later the spinal cords were processed for counting the retrogradely labeled cells and choline acetyltransferase immunohistochemistry was performed to reveal the cholinergic cells in the spinal cords. In untreated animals there were 20.4+/-1.6 (+/-S.E.M.) retrogradely labeled neurons while in animals treated with riluzole immediately or 5 and 10 days after ventral root avulsion the number of labeled motoneurons ranged between 763+/-36 and 815+/-50 (S.E.M.). Riluzole treatment starting at 14 and 16 days after injury resulted in significantly lower number of reinnervating motoneurons (67+/-4 and 52+/-3 S.E.M., respectively). Thus, riluzole dramatically enhanced the survival and reinnervating capacity of injured motoneurons not only when treatment started immediately after injury but also in cases when riluzole treatment was delayed for up to 10 days. These results suggest that motoneurons destined to die after ventral root avulsion are programmed to survive for some time after injury and riluzole is able to rescue them during this period of time. PMID:17084537

  13. Specificity in monosynaptic and disynaptic bulbospinal connections to thoracic motoneurones in the rat

    PubMed Central

    de Almeida, Anoushka T R; Kirkwood, Peter A

    2013-01-01

    The respiratory activity in the intercostal nerves of the rat is unusual, in that motoneurones of both branches of the intercostal nerves, internal and external, are activated during expiration. Here, the pathways involved in that activation were investigated in anaesthetised and in decerebrate rats by cross-correlation and by intracellular spike-triggered averaging from expiratory bulbospinal neurones (EBSNs), with a view to revealing specific connections that could be used in studies of experimental spinal cord injury. Decerebrate preparations, which showed the strongest expiratory activity, were found to be the most suitable for these measurements. Cross-correlations in these preparations showed monosynaptic connections from 16/19 (84%) of EBSNs, but only to internal intercostal nerve motoneurones (24/37, 65% of EBSN/nerve pairs), whereas disynaptic connections were seen for external intercostal nerve motoneurones (4/19, 21% of EBSNs or 7/25, 28% of EBSN/nerve pairs). There was evidence for additional disynaptic connections to internal intercostal nerve motoneurones. Intracellular spike-triggered averaging revealed excitatory postsynaptic potentials, which confirmed these connections. This is believed to be the first report of single descending fibres that participate in two different pathways to two different groups of motoneurones. It is of interest compared with the cat, where only one group of motoneurones is activated during expiration and only one of the pathways has been detected. The specificity of the connections could be valuable in studies of plasticity in pathological situations, but care will be needed in studying connections in such situations, because their strength was found here to be relatively weak. PMID:23774278

  14. Hypocretinergic control of spinal cord motoneurons.

    PubMed

    Yamuy, Jack; Fung, Simon J; Xi, Mingchu; Chase, Michael H

    2004-06-01

    Hypocretinergic (orexinergic) neurons in the lateral hypothalamus project to motor columns in the lumbar spinal cord. Consequently, we sought to determine whether the hypocretinergic system modulates the electrical activity of motoneurons. Using in vivo intracellular recording techniques, we examined the response of spinal motoneurons in the cat to electrical stimulation of the lateral hypothalamus. In addition, we examined the membrane potential response to orthodromic stimulation and intracellular current injection before and after both hypothalamic stimulation and the juxtacellular application of hypocretin-1. It was found that (1) hypothalamic stimulation produced a complex sequence of depolarizing- hyperpolarizing potentials in spinal motoneurons; (2) the depolarizing potentials decreased in amplitude after the application of SB-334867, a hypocretin type 1 receptor antagonist; (3) the EPSP induced by dorsal root stimulation was not affected by the application of SB-334867; (4) subthreshold stimulation of dorsal roots and intracellular depolarizing current steps produced spike potentials when applied in concert to stimulation of the hypothalamus or after the local application of hypocretin-1; (5) the juxtacellular application of hypocretin-1 induced motoneuron depolarization and, frequently, high-frequency discharge; (6) hypocretin-1 produced a significant decrease in rheobase (36%), membrane time constant (16.4%), and the equalizing time constant (23.3%); (7) in a small number of motoneurons, hypocretin-1 produced an increase in the synaptic noise; and (8) the input resistance was not affected after hypocretin-1. The juxtacellular application of vehicle (saline) and denatured hypocretin-1 did not produce changes in the preceding electrophysiological properties. We conclude that hypothalamic hypocretinergic neurons are capable of modulating the activity of lumbar motoneurons through presynaptic and postsynaptic mechanisms. The lack of hypocretin

  15. Identification of common excitatory motoneurons in Drosophila melanogaster larvae.

    PubMed

    Takizawa, Eiji; Komatsu, Akira; Tsujimura, Hidenobu

    2007-05-01

    In insects, four types of motoneurons have long been known, including fast motoneurons, slow motoneurons, common inhibitory motoneurons, and DUM neurons. They innervate the same muscle and control its contraction together. Recent studies in Drosophila have suggested the existence of another type of motoneuron, the common excitatory motoneuron. Here, we found that shakB-GAL4 produced by labels this type of motoneuron in Drosophila larvae. We found that Drosophila larvae have two common excitatory motoneurons in each abdominal segment, RP2 for dorsal muscles and MNSNb/d-Is for ventral muscles. They innervate most of the internal longitudinal or oblique muscles on the dorsal or ventral body wall with type-Is terminals and use glutamate as a transmitter. Electrophysiological recording indicated that stimulation of the RP2 axon evoked excitatory junctional potential in a dorsal muscle. PMID:17867850

  16. Relations among passive electrical properties of lumbar alpha-motoneurones of the cat.

    PubMed Central

    Gustafsson, B; Pinter, M J

    1984-01-01

    The relations among passive membrane properties have been examined in cat motoneurones utilizing exclusively electrophysiological techniques. A significant relation was found to exist between the input resistance and the membrane time constant. The estimated electrotonic length showed no evident tendency to vary with input resistance but did show a tendency to decrease with increasing time constant. Detailed analysis of this trend suggests, however, that a variation in dendritic geometry is likely to exist among cat motoneurones, such that the dendritic trees of motoneurones projecting to fast-twitch muscle units are relatively more expansive than those of motoneurones projecting to slow-twitch units. Utilizing an expression derived from the Rall neurone model, the total capacitance of the equivalent cylinder corresponding to a motoneurone has been estimated. With the assumption of a constant and uniform specific capacitance of 1 mu F/cm2, the resulting values have been used as estimates of cell surface area. These estimates agree well with morphologically obtained measurements from cat motoneurones reported by others. Both membrane time constant (and thus likely specific membrane resistivity) and electrotonic length showed little tendency to vary with surface area. However, after-hyperpolarization (a.h.p.) duration showed some tendency to vary such that cells with brief a.h.p. duration were, on average, larger than those with longer a.h.p. durations. Apart from motoneurones with the lowest values, axonal conduction velocity was only weakly related to variations in estimated surface area. Input resistance and membrane time constant were found to vary systematically with the a.h.p. duration. Analysis suggested that the major part of the increase in input resistance with a.h.p. duration was related to an increase in membrane resistivity and a variation in dendritic geometry rather than to differences in surface area among the motoneurones. The possible effects of

  17. Factors influencing the spinal motoneurons in development

    PubMed Central

    Wiese, Stefan

    2015-01-01

    The development of the spinal cord needs a concerted interaction of transcription factors activating diverse genes and signals from outside acting on the specification of the different cells. Signals have to act on the segments of the embryo as well as on the cranial-caudal axis and the dorso-ventral axis. Additionally the axons of the motoneurons have to cross the central nervous system barrier to connect to the periphery. Intensive anatomical studies have been followed by molecular characterization of the different subsets of transcription factors that are expressed by cells of the developing spinal cord. Here, intensive studies for the most important appearing cells, the motoneurons, have resulted in a good knowledge on the expression patterns of these proteins. Nonetheless motoneurons are by far not the only important cells and the concert activity of all cells besides them is necessary for the correct function and integrity of motoneurons within the spinal cord. This article will briefly summarize the different aspects on spinal cord development and focuses on the differentiation as well as the functionalization of motoneurons. PMID:26807112

  18. Evidence for reversible motoneurone dysfunction in thyrotoxicosis

    PubMed Central

    McComas, A. J.; Sica, R. E. P.; McNabb, A. R.; Goldberg, W. M.; Upton, A. R. M.

    1974-01-01

    Motor unit estimating techniques have been employed as part of a comprehensive electrophysiological survey of peripheral nerve and muscle in 20 patients with thyrotoxicosis. In all patients there was evidence of a loss of operational motor units; the selective nature of this involvement suggested that the motoneurone soma was the site of the primary lesion. The reversible nature of the postulated motoneurone dysfunction was demonstrated by the increased motor unit counts in six patients who were studied again after treatment of their thyrotoxicosis. PMID:4836749

  19. Motoneuron Programmed Cell Death in Response to proBDNF

    PubMed Central

    Taylor, AR; Gifondorwa, DJ; Robinson, MB; Strupe, JL; Prevette, D; Johnson, JE; Hempstead, BL; Oppenheim, RW; Milligan, CE

    2011-01-01

    Motoneurons (MN) as well as most neuronal populations undergo a temporally and spatially specific period of programmed cell death (PCD). Several factors have been considered to regulate the survival of MNs during this period, including availability of muscle-derived trophic support and activity. The possibility that target-derived factors may also negatively regulate MN survival has been considered, but not pursued. Neurotrophin precursors, through their interaction with p75NTR and sortilin receptors have been shown to induce cell death during development and following injury in the CNS. In this study, we find that muscle cells produce and secrete proBDNF. ProBDNF through its interaction with p75NTR and sortilin, promotes a caspase-dependent death of MNs in culture. We also provide data to suggest that proBDNF regulates MN PCD during development in vivo. PMID:21834083

  20. EGb761 protects motoneurons against avulsion-induced oxidative stress in rats

    PubMed Central

    2010-01-01

    Background Root avulsion of the brachial plexus causes an oxidative stress reaction in the spinal cord and induces dramatic spinal motoneuron death, while EGb761 is a natural free radical cleaning agent. This study was designed to investigate the protective effects of intraperitoneally injected EGb761 against neural damage following brachial root avulsion. Methods The effect of EGb761 on avulsion-induced motoneuron injury was studied in 26 total groups of (n) rats, treated as follows. Animals in singular number groups received EGb761(50 mg/kg.d) and those in complex number groups received normal saline solution (i.p.), serving as controls. Groups 1-8 were used for the determination of nitric oxide (NO) levels in the serum and injured spinal cord at the 5 d, 2 w, 4 w, and 6 w time points. Groups 9-16 were used for determination of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) levels in injured spinal cord at the 5 d, 2 w, 4 w, and 6 w time points. Groups 17-26 were used for determination of the number of neuronal nitric oxide synthase (nNOS)-positive and surviving motoneurons in injured C7 ventral horn at the 5 d, 2 w, 4 w, 6 w and 8 w time points. Results Compared to control groups, the EGb761 treatment group not only had significant decreased levels of NO in serum at 2 w and 6 w after avulsion, but also had reduced levels of NO specifically in the spinal cord at 2 w, 4 w and 6 w. The cNOS activity in the spinal cord was also significant decreased at 2 w and 4 w, while the iNOS activity in injured C6-T1 spinal segments was reduced at 2 w, 4 w and 6 w. All together, the percentages of NADPH-d positive motoneurons in an injured C7 segment were down-regulated and the number of surviving motoneurons in injured C7 ventral horn was increased at 2 w, 4 w, 6 w and 8 w in treated versus untreated animals. Conclusions Intraperitoneal administration of EGb761 after root avulsion of the brachial plexus exerted protective effects by

  1. Androgenic, But Not Estrogenic, Protection of Motoneurons from Somal and Dendritic Atrophy Induced by the Death of Neighboring Motoneurons

    PubMed Central

    Fargo, Keith N.; Sengelaub, Dale R.

    2009-01-01

    Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have been investigating the effects of motoneuron loss on surviving motoneurons in a lumbar motor nucleus, the spinal nucleus of the bulbocavernosus (SNB). SNB motoneurons undergo marked dendritic and somal atrophy following the experimentally induced death of other nearby SNB motoneurons. However, treatment with testosterone at the time of lesioning attenuates this atrophy. Because testosterone can be metabolized into the estrogen estradiol (as well as other physiologically active steroid hormones), it was unknown whether the protective effect of testosterone was an androgen effect, an estrogen effect, or both. In the present experiment, we used a retrogradely transported neurotoxin to kill the majority of SNB motoneurons on one side of the spinal cord only in adult male rats. Some animals were also treated with either testosterone, the androgen dihydrotestosterone (which cannot be converted into estradiol), or the estrogen estradiol. As seen previously, partial motoneuron loss led to reductions in soma area and in dendritic length and extent in surviving motoneurons. Testosterone and dihydrotestosterone attenuated these reductions, but estradiol had no protective effect. These results indicate that the neuroprotective effect of testosterone on the morphology of SNB motoneurons following partial motoneuron depletion is an androgen effect rather than an estrogen effect. PMID:17565709

  2. Neuroprotective effects of testosterone on the morphology and function of somatic motoneurons following the death of neighboring motoneurons

    PubMed Central

    Little, Christine M.; Coons, Kellie D.; Sengelaub, Dale R.

    2008-01-01

    Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have previously shown that partial depletion of motoneurons from sexually dimorphic, highly androgen-sensitive spinal motor populations induces dendritic atrophy in remaining motoneurons, and this atrophy is attenuated by treatment with testosterone. To test whether testosterone has similar effects in more typical motoneurons, we examined potential neuroprotective effects in motoneurons innervating muscles of the quadriceps. Motoneurons innervating the vastus medialis muscle were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, some saporin-injected rats were given implants containing testosterone or left untreated. Four weeks later, motoneurons innervating the ipsilateral vastus lateralis muscle were labeled with cholera toxin-conjugated HRP, and dendritic arbors were reconstructed in 3 dimensions. Compared to intact normal males, partial motoneuron depletion resulted in decreased dendritic length in remaining quadriceps motoneurons, and this atrophy was attenuated by testosterone treatment. To examine the functional consequences of the induced dendritic atrophy, and its attenuation with testosterone treatment, the activation of remaining quadriceps motoneurons was assessed using peripheral nerve recording. Partial motoneuron depletion resulted in decreased amplitudes of motor nerve activity, and these changes were attenuated by treatment with testosterone, providing a functional correlate to the neuroprotective effects of testosterone treatment on quadriceps motoneuron morphology. Together, these findings suggest that testosterone has neuroprotective effects on morphology and function in both highly androgen-sensitive as well as more typical motoneuron populations, further supporting a role for testosterone as a neurotherapeutic agent in the injured nervous system. PMID:19003970

  3. Electrical Stimulation of Low-Threshold Proprioceptive Fibers in the Adult Rat Increases Density of Glutamatergic and Cholinergic Terminals on Ankle Extensor α-Motoneurons.

    PubMed

    Gajewska-Woźniak, Olga; Grycz, Kamil; Czarkowska-Bauch, Julita; Skup, Małgorzata

    2016-01-01

    The effects of stimulation of low-threshold proprioceptive afferents in the tibial nerve on two types of excitatory inputs to α-motoneurons were tested. The first input is formed by glutamatergic Ia sensory afferents contacting monosynaptically α-motoneurons. The second one is the cholinergic input originating from V0c-interneurons, located in lamina X of the spinal cord, modulating activity of α-motoneurons via C-terminals. Our aim was to clarify whether enhancement of signaling to ankle extensor α-motoneurons, via direct electrical stimulation addressed predominantly to low-threshold proprioceptive fibers in the tibial nerve of awake rats, will affect Ia glutamatergic and cholinergic innervation of α-motoneurons of lateral gastrocnemius (LG). LG motoneurons were identified with True Blue tracer injected intramuscularly. Tibial nerve was stimulated for 7 days with continuous bursts of three pulses applied in four 20 min sessions daily. The Hoffmann reflex and motor responses recorded from the soleus muscle, LG synergist, allowed controlling stimulation. Ia terminals and C-terminals abutting on LG-labeled α-motoneurons were detected by immunofluorescence (IF) using input-specific anti- VGLUT1 and anti-VAChT antibodies, respectively. Quantitative analysis of confocal images revealed that the number of VGLUT1 IF and VAChT IF terminals contacting the soma of LG α-motoneurons increased after stimulation by 35% and by 26%, respectively, comparing to the sham-stimulated side. The aggregate volume of VGLUT1 IF and VAChT IF terminals increased by 35% and by 30%, respectively. Labeling intensity of boutons was also increased, suggesting an increase of signaling to LG α-motoneurons after stimulation. To conclude, one week of continuous burst stimulation of proprioceptive input to LG α-motoneurons is effective in enrichment of their direct glutamatergic but also indirect cholinergic inputs. The effectiveness of such and longer stimulation in models of injury is a

  4. Electrical Stimulation of Low-Threshold Proprioceptive Fibers in the Adult Rat Increases Density of Glutamatergic and Cholinergic Terminals on Ankle Extensor α-Motoneurons

    PubMed Central

    Gajewska-Woźniak, Olga; Grycz, Kamil; Czarkowska-Bauch, Julita; Skup, Małgorzata

    2016-01-01

    The effects of stimulation of low-threshold proprioceptive afferents in the tibial nerve on two types of excitatory inputs to α-motoneurons were tested. The first input is formed by glutamatergic Ia sensory afferents contacting monosynaptically α-motoneurons. The second one is the cholinergic input originating from V0c—interneurons, located in lamina X of the spinal cord, modulating activity of α-motoneurons via C-terminals. Our aim was to clarify whether enhancement of signaling to ankle extensor α-motoneurons, via direct electrical stimulation addressed predominantly to low-threshold proprioceptive fibers in the tibial nerve of awake rats, will affect Ia glutamatergic and cholinergic innervation of α-motoneurons of lateral gastrocnemius (LG). LG motoneurons were identified with True Blue tracer injected intramuscularly. Tibial nerve was stimulated for 7 days with continuous bursts of three pulses applied in four 20 min sessions daily. The Hoffmann reflex and motor responses recorded from the soleus muscle, LG synergist, allowed controlling stimulation. Ia terminals and C-terminals abutting on LG-labeled α-motoneurons were detected by immunofluorescence (IF) using input-specific anti- VGLUT1 and anti-VAChT antibodies, respectively. Quantitative analysis of confocal images revealed that the number of VGLUT1 IF and VAChT IF terminals contacting the soma of LG α-motoneurons increased after stimulation by 35% and by 26%, respectively, comparing to the sham-stimulated side. The aggregate volume of VGLUT1 IF and VAChT IF terminals increased by 35% and by 30%, respectively. Labeling intensity of boutons was also increased, suggesting an increase of signaling to LG α-motoneurons after stimulation. To conclude, one week of continuous burst stimulation of proprioceptive input to LG α-motoneurons is effective in enrichment of their direct glutamatergic but also indirect cholinergic inputs. The effectiveness of such and longer stimulation in models of injury is a

  5. Motoneurons are essential for vascular pathfinding

    PubMed Central

    Lim, Amy H.; Suli, Arminda; Yaniv, Karina; Weinstein, Brant; Li, Dean Y.; Chien, Chi-Bin

    2011-01-01

    The neural and vascular systems share common guidance cues that have direct and independent signaling effects on nerves and endothelial cells. Here, we show that zebrafish Netrin 1a directs Dcc-mediated axon guidance of motoneurons and that this neural guidance function is essential for lymphangiogenesis. Specifically, Netrin 1a secreted by the muscle pioneers at the horizontal myoseptum (HMS) is required for the sprouting of dcc-expressing rostral primary motoneuron (RoP) axons and neighboring axons along the HMS, adjacent to the future trajectory of the parachordal chain (PAC). These axons are required for the formation of the PAC and, subsequently, the thoracic duct. The failure to form the PAC in netrin 1a or dcc morphants is phenocopied by laser ablation of motoneurons and is rescued both by cellular transplants and overexpression of dcc mRNA. These results provide a definitive example of the requirement of axons in endothelial guidance leading to the parallel patterning of nerves and vessels in vivo. PMID:21828101

  6. Infrahyoid and accessory motoneurons in the Japanese monkey (Macaca fuscata).

    PubMed

    Ueyama, T; Satoda, T; Tashiro, T; Sugimoto, T; Matsushima, R; Mizuno, N

    1990-01-15

    The segmental and topographical organization of motoneurons innervating the infrahyoid (IH) and the spinal accessory (AC) muscles was studied in the Japanese monkey (Macaca fuscata) with the retrograde horseradish peroxidase (HRP) method after application of HRP to the peripheral nerve branches supplying the IH and AC muscles. IH motoneurons constitute two distinct slender cell columns, a longer medial and a shorter lateral one. The medial cell column extends from the most caudal level of the hypoglossal nucleus to the lower levels of the second cervical (C2) cord segment. In the medial column, motoneurons supplying the sternohyoid and sternothyroid muscles are distributed at the medullary and C1 levels, while those innervating the omohyoid muscle are primarily distributed at the C2 level. The lateral cell column consists of motoneurons supplying the thyrohyoid muscle and extends from the most caudal level of the hypoglossal nucleus to the middle levels of the C1 cord segment. Axons of thyrohyoid motoneurons follow a dorsomedially directed bent emergent course, making a hairpin turn. AC motoneurons supplying the sternocleidomastoid (SC) and trapezius (TZ) muscles form a single slender cell column extending from the most rostral level of the pyramidal decussation to the middle levels of the C6 cord segment. SC motoneurons are distributed from the most rostral level of the pyramidal decussation to the middle levels of the C3 cord segment, while TZ motoneurons are distributed from the upper levels of the C2 cord segment to the lower levels of the C6 cord segment. At the levels of the C2 and C3 cord segments, both SC and TZ motoneurons are distributed in the AC cell column; the cluster of SC motoneurons is located dorsomedial to that of TZ motoneurons. PMID:2152765

  7. Transient down-regulation and restoration of glycogen synthase levels in axotomized rat facial motoneurons.

    PubMed

    Takezawa, Yosuke; Kohsaka, Shinichi; Nakajima, Kazuyuki

    2014-10-24

    In adult rats, transection of the facial nerve causes a functional down-regulation of motoneurons and glial activation/proliferation. It has not been clear how energy-supplying systems are regulated in an axotomized facial nucleus. Here we investigated the regulation of molecules involved in glycogen degradation/synthesis in axotomized facial nuclei in rats. Immunoblotting revealed that the amounts of glycogen phosphorylase in the contralateral and ipsilateral nuclei were unchanged for the first 14 days, whereas the amount of glycogen synthase in the axotomized facial nuclei was significantly decreased from days 7-14 post-insult. A quantitative analysis estimated that the glycogen synthase levels in the transected nucleus were reduced to approx. 50% at 14 days post-injury. An immunohistochemical study showed that the injured motoneurons had decreased expressions of glycogen synthase proteins. The glycogen synthase levels in the axotomized facial nucleus had returned to control levels by 5 weeks post-insult, as had the cholinergic markers. The immunohistochemical study also revealed the recovery of glycogen synthase levels at the later stage. The glycogen phosphorylase levels in the injured nucleus were not significantly changed during weeks 3-5 post-insult. Taken together, these results demonstrated that the injured facial motoneurons transiently reduced glycogen synthase levels at around 1-2 weeks post-insult, but restored the levels at 4-5 weeks post-insult. PMID:25152465

  8. Weakened rate-dependent depression of Hoffmann's reflex and increased motoneuron hyperactivity after motor cortical infarction in mice

    PubMed Central

    Lee, S; Toda, T; Kiyama, H; Yamashita, T

    2014-01-01

    Abnormal reflexes associated with spasticity are considered a major determinant of motor impairments occurring after stroke; however, the mechanisms underlying post-stroke spasticity remain unclear. This may be because of the lack of suitable rodent models for studying spasticity after cortical injuries. Thus, the purpose of the present study was to establish an appropriate post-stroke spasticity mouse model. We induced photothrombotic injury in the rostral and caudal forelimb motor areas of mice and used the rate-dependent depression (RDD) of Hoffmann's reflex (H-reflex) as an indicator of spastic symptoms. To detect motoneuron excitability, we examined c-fos mRNA levels and c-Fos immunoreactivity in affected motoneurons using quantitative real-time reverse transcription PCR and immunohistochemical analysis, respectively. To confirm the validity of our model, we confirmed the effect of the anti-spasticity drug baclofen on H-reflex RDDs 1 week post stroke. We found that 3 days after stroke, the RDD was significantly weakened in the affected muscles of stroke mice compared with sham-operated mice, and this was observed for 8 weeks. The c-fos mRNA levels in affected motoneurons were significantly increased in stroke mice compared with sham-operated mice. Immunohistochemical analysis revealed a significant increase in the number of c-Fos-positive motoneurons in stroke mice compared with sham-operated mice at 1, 2, 4, and 8 weeks after stroke; however, the number of c-Fos-positive motoneurons on both sides of the brain gradually decreased over time. Baclofen treatment resulted in recovery of the weakened RDD at 1 week post stroke. Our findings suggest that this is a viable animal model of post-stroke spasticity. PMID:24434515

  9. Weakened rate-dependent depression of Hoffmann's reflex and increased motoneuron hyperactivity after motor cortical infarction in mice.

    PubMed

    Lee, S; Toda, T; Kiyama, H; Yamashita, T

    2014-01-01

    Abnormal reflexes associated with spasticity are considered a major determinant of motor impairments occurring after stroke; however, the mechanisms underlying post-stroke spasticity remain unclear. This may be because of the lack of suitable rodent models for studying spasticity after cortical injuries. Thus, the purpose of the present study was to establish an appropriate post-stroke spasticity mouse model. We induced photothrombotic injury in the rostral and caudal forelimb motor areas of mice and used the rate-dependent depression (RDD) of Hoffmann's reflex (H-reflex) as an indicator of spastic symptoms. To detect motoneuron excitability, we examined c-fos mRNA levels and c-Fos immunoreactivity in affected motoneurons using quantitative real-time reverse transcription PCR and immunohistochemical analysis, respectively. To confirm the validity of our model, we confirmed the effect of the anti-spasticity drug baclofen on H-reflex RDDs 1 week post stroke. We found that 3 days after stroke, the RDD was significantly weakened in the affected muscles of stroke mice compared with sham-operated mice, and this was observed for 8 weeks. The c-fos mRNA levels in affected motoneurons were significantly increased in stroke mice compared with sham-operated mice. Immunohistochemical analysis revealed a significant increase in the number of c-Fos-positive motoneurons in stroke mice compared with sham-operated mice at 1, 2, 4, and 8 weeks after stroke; however, the number of c-Fos-positive motoneurons on both sides of the brain gradually decreased over time. Baclofen treatment resulted in recovery of the weakened RDD at 1 week post stroke. Our findings suggest that this is a viable animal model of post-stroke spasticity. PMID:24434515

  10. Testing the evolutionary conservation of vocal motoneurons in vertebrates.

    PubMed

    Albersheim-Carter, Jacob; Blubaum, Aleksandar; Ballagh, Irene H; Missaghi, Kianoush; Siuda, Edward R; McMurray, George; Bass, Andrew H; Dubuc, Réjean; Kelley, Darcy B; Schmidt, Marc F; Wilson, Richard J A; Gray, Paul A

    2016-04-01

    Medullary motoneurons drive vocalization in many vertebrate lineages including fish, amphibians, birds, and mammals. The developmental history of vocal motoneuron populations in each of these lineages remains largely unknown. The highly conserved transcription factor Paired-like Homeobox 2b (Phox2b) is presumed to be expressed in all vertebrate hindbrain branchial motoneurons, including laryngeal motoneurons essential for vocalization in humans. We used immunohistochemistry and in situ hybridization to examine Phox2b protein and mRNA expression in caudal hindbrain and rostral spinal cord motoneuron populations in seven species across five chordate classes. Phox2b was present in motoneurons dedicated to sound production in mice and frogs (bullfrog, African clawed frog), but not those in bird (zebra finch) or bony fish (midshipman, channel catfish). Overall, the pattern of caudal medullary motoneuron Phox2b expression was conserved across vertebrates and similar to expression in sea lamprey. These observations suggest that motoneurons dedicated to sound production in vertebrates are not derived from a single developmentally or evolutionarily conserved progenitor pool. PMID:26160673

  11. Necdin Protects Embryonic Motoneurons from Programmed Cell Death

    PubMed Central

    Aebischer, Julianne; Sturny, Rachel; Andrieu, David; Rieusset, Anne; Schaller, Fabienne; Geib, Sandrine; Raoul, Cédric; Muscatelli, Françoise

    2011-01-01

    NECDIN belongs to the type II Melanoma Associated Antigen Gene Expression gene family and is located in the Prader-Willi Syndrome (PWS) critical region. Necdin-deficient mice develop symptoms of PWS, including a sensory and motor deficit. However, the mechanisms underlying the motor deficit remain elusive. Here, we show that the genetic ablation of Necdin, whose expression is restricted to post-mitotic neurons in the spinal cord during development, leads to a loss of 31% of specified motoneurons. The increased neuronal loss occurs during the period of naturally-occurring cell death and is not confined to specific pools of motoneurons. To better understand the role of Necdin during the period of programmed cell death of motoneurons we used embryonic spinal cord explants and primary motoneuron cultures from Necdin-deficient mice. Interestingly, while Necdin-deficient motoneurons present the same survival response to neurotrophic factors, we demonstrate that deletion of Necdin leads to an increased susceptibility of motoneurons to neurotrophic factor deprivation. We show that by neutralizing TNFα this increased susceptibility of Necdin-deficient motoneurons to trophic factor deprivation can be reduced to the normal level. We propose that Necdin is implicated through the TNF-receptor 1 pathway in the developmental death of motoneurons. PMID:21912643

  12. Simulated recruitment of medial rectus motoneurons by abducens internuclear neurons: synaptic specificity vs. intrinsic motoneuron properties.

    PubMed

    Dean, P

    1997-09-01

    Ocular motoneuron firing rate is linearly related to conjugate eye position with slope K above recruitment threshold theta. Within the population of ocular motoneurons K increases as theta increases. These differences in firing rate between motoneurons might be determined either by the intrinsic properties of the motoneurons, or by differences in synaptic input to them, or by a combination of the two. This question was investigated by simulating the input signal to medial rectus motoneurons (MR-MNs) from internuclear neurons of the abducens nucleus (INNs). INNs were represented as input nodes in a two-layer neural net, each with weighted connections to every output node representing an MR-MN. Individual simulated MR-MNs were assigned parameters corresponding to an intrinsic current threshold I(R) and an intrinsic frequency-current (f-I) slope gamma. Their firing rates were calculated from these parameters, together with the effective synaptic current produced by their synaptically weighted INN inputs, with the use of assumptions employed in computer simulations of spinal motoneuron pools. The experimentally observed firing rates of MR-MNs served as training data for the net. The following two training conditions were used: 1) synaptic weights were fixed and the intrinsic parameters of the MR-MNs were allowed to vary, corresponding to the situation in which each MR-MN receives a common synaptic drive and 2) intrinsic MR-MN properties were fixed and synaptic weights were allowed to vary. In each case, the varying quantities were trained with a form of gradient descent error reduction. The simulations revealed the following three problems with the common-drive model: 1) the recruitment of INNs produced nonlinear responses in MR-MNs with low thetas; 2) the range of I(R)s required to reproduce the observed range of theta were generally larger than those measured experimentally for cat ocular motoneurons; and 3) the intrinsic f-I slope gamma increased with I

  13. Voltage-dependent amplification of synaptic inputs in respiratory motoneurones.

    PubMed

    Enríquez Denton, M; Wienecke, J; Zhang, M; Hultborn, H; Kirkwood, P A

    2012-07-01

    The role of persistent inward currents (PICs) in cat respiratory motoneurones (phrenic inspiratory and thoracic expiratory) was investigated by studying the voltage-dependent amplification of central respiratory drive potentials (CRDPs), recorded intracellularly, with action potentials blocked with the local anaesthetic derivative, QX-314. Decerebrate unanaesthetized or barbiturate-anaesthetized preparations were used. In expiratory motoneurones, plateau potentials were observed in the decerebrates, but not under anaesthesia. For phrenic motoneurones, no plateau potentials were observed in either state (except in one motoneurone after the abolition of the respiratory drive by means of a medullary lesion), but all motoneurones showed voltage-dependent amplification of the CRDPs, over a wide range of membrane potentials, too wide to result mainly from PIC activation. The measurements of the amplification were restricted to the phase of excitation, thus excluding the inhibitory phase. Amplification was found to be greatest for the smallest CRDPs in the lowest resistance motoneurones and was reduced or abolished following intracellular injection of the NMDA channel blocker, MK-801. Plateau potentials were readily evoked in non-phrenic cervical motoneurones in the same (decerebrate) preparations. We conclude that the voltage-dependent amplification of synaptic excitation in phrenic motoneurones is mainly the result of NMDA channel modulation rather than the activation of Ca2+ channel mediated PICs, despite phrenic motoneurones being strongly immunohistochemically labelled for CaV1.3 channels. The differential PIC activation in different motoneurones, all of which are CaV1.3 positive, leads us to postulate that the descending modulation of PICs is more selective than has hitherto been believed. PMID:22495582

  14. Use of laser microdissection in the investigation of facial motoneuron and neuropil molecular phenotypes after peripheral axotomy

    PubMed Central

    Mesnard, Nichole A.; Alexander, Thomas D.; Sanders, Virginia M.; Jones, Kathryn J.

    2010-01-01

    The mechanism underlying axotomy-induced motoneuron loss is not fully understood, but appears to involve molecular changes within the injured motoneuron and the surrounding local microenvironment (neuropil). The mouse facial nucleus consists of six subnuclei which respond differentially to facial nerve transection at the stylomastoid foramen. The ventromedial (VM) subnucleus maintains virtually full facial motoneuron (FMN) survival following axotomy, whereas the ventrolateral (VL) subnucleus results in significant FMN loss with the same nerve injury. We hypothesized that distinct molecular phenotypes of FMN existed within the two subregions, one responsible for maintaining cell survival and the other promoting cell death. In this study, we used laser microdissection to isolate VM and VL facial subnuclear regions for molecular characterization. We discovered that, regardless of neuronal fate after injury, FMN in either subnuclear region respond vigorously to injury with a characteristic “regenerative” profile and additionally, the surviving VL FMN appear to compensate for the significant FMN loss. In contrast, significant differences in the expression of pro-inflammatory cytokine mRNA in the surrounding neuropil response were found between the two subnuclear regions of the facial nucleus that support a causative role for glial and/or immune-derived molecules in directing the contrasting responses of the FMN to axonal transection. PMID:20570589

  15. Electrotonic characteristics of alpha motoneurones of varying size

    PubMed Central

    Burke, R. E.; ten Bruggencate, G.

    1971-01-01

    1. The neuronal membrane responses to long constant current pulses (essentially current steps) have been studied in cat triceps surae motoneurones identified as to the type of muscle fibres, fast twitch (type F) or slow twitch (type S), innervated by the cell being studied. For each motoneurone the membrane time constant, τM, and input resistance, RN, were determined from the response to a current step. In addition, shorter time constants (`equalizing time constants') resulting from current spread into the dendrites were estimated by graphical analysis. 2. The electrotonic length of the combined motoneurone soma and dendritic tree was estimated from the current step data using the neuronal equivalent cylinder model formulated by Rall (Rall, 1969). The mean electrotonic length of the motoneurone equivalent cylinder was approximately 1·5 in both type F and type S motoneurones. The mean membrane time constant of type F cells was 5·6 msec and that of type S motoneurones was 6·7 msec. This difference in mean τM values was of border line statistical significance. 3. The results indicate that the electrotonic length of the combined dendritic trees of both large type F and small type S motoneurones is essentially the same. The implication of this conclusion for interpretation of previous analyses of the monosynaptic EPSP is discussed. PMID:5545177

  16. The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF-α toxicity involves membrane melatonin receptors

    PubMed Central

    Das, Arabinda; McDowell, Misty; Pava, Matthew J; Smith, Joshua A.; Reiter, Russel J.; Woodward, John J.; Varma, Abhay K.; Ray, Swapan K.; Banik, Naren L.

    2009-01-01

    Loss of motoneurons may underlie some of the deficits in motor function associated with CNS injuries and diseases. We tested whether melatonin, a potent antioxidant and free radical scavenger, would prevent motoneuron apoptosis following exposure to toxins and whether this neuroprotection is mediated by melatonin receptors. Exposure of VSC4.1 motoneurons to either 50 μM H2O2, 25 μM glutamate (LGA), or 50 ng/ml tumor necrosis factor-alpha (TNF-α) for 24 h caused significant increases in apoptosis, as determined by Wright staining and ApopTag assay. Analyses of mRNA and proteins showed increased expression and activities of stress kinases and cysteine proteases and loss of mitochondrial membrane potential during apoptosis. These insults also caused increases in intracellular free [Ca2+] and activities of calpain and caspases. Cells exposed to stress stimuli for 15 min were then treated with 200 nM melatonin. Post-treatment of cells with melatonin attenuated production of reactive oxygen species (ROS) and phosphorylation of p38, MAPK, and JNK1, prevented cell death, and maintained whole-cell membrane potential, indicating functional neuroprotection. Melatonin receptors (MT1 and MT2) were upregulated following treatment with melatonin. To confirm the involvement of MT1 and MT2 in providing neuroprotection, cells were post-treated (20 min) with 10 μM luzindole (melatonin receptor antagonist). Luzindole significantly attenuated melatonin-induced neuroprotection, suggesting that melatonin worked, at least in part, via its receptors to prevent VSC4.1 motoneuron apoptosis. Results suggest that neuroprotection rendered by melatonin to motoneurons is receptor mediated and melatonin may be an effective neuroprotective agent to attenuate motoneuron death in CNS injuries and diseases. PMID:20082663

  17. Characteristics and organization of discharge properties in rat hindlimb motoneurons.

    PubMed

    Turkin, Vladimir V; O'Neill, Derek; Jung, Ranu; Iarkov, Alexandre; Hamm, Thomas M

    2010-09-01

    The discharge properties of hindlimb motoneurons in ketamine-xylazine anesthetized rats were measured to assess contributions of persistent intrinsic currents to these characteristics and to determine their distribution in motoneuron pools. Most motoneurons (30/37) responded to ramp current injections with adapting patterns of discharge and the frequency-current (f-I) relations of nearly all motoneurons included a steep subprimary range of discharge. Despite the prevalence of adapting f-I relations, responses included indications that persistent inward currents (PICs) were activated, including increased membrane noise and prepotentials before discharge, as well as counterclockwise hysteresis and secondary ranges in f-I relations. Examination of spike thresholds and afterhyperpolarization (AHP) trajectories during repetitive discharge revealed systematic changes in threshold and trajectory within the subprimary, primary, and secondary f-I ranges. These changes in the primary and secondary ranges were qualitatively similar to those described previously for cat motoneurons. Within the subprimary range, AHP trajectories often included shallow approaches to threshold following recruitment and slope of the AHP ramp consistently increased until the subprimary range was reached. We suggest that PICs activated near recruitment contributed to these slope changes and formation of the subprimary range. Discharge characteristics were strongly correlated with motoneuron size, using input conductance as an indicator of size. Discharge adaptation, recruitment current, and frequency increased with input conductance, whereas both subprimary and primary f-I gains decreased. These results are discussed with respect to potential mechanisms and their functional implications. PMID:20592119

  18. Aging of motoneurons and synaptic processes in the cat.

    PubMed

    Chase, M H; Morales, F R; Boxer, P A; Fung, S J

    1985-11-01

    The aging of spinal cord alpha motoneurons was explored in old cats with intracellular recording techniques to determine the basic membrane properties of these neurons and their monosynaptic response following activation of group Ia afferent fibers. The conduction velocity of the motoneurons' axons decreased in old animals (14 to 15 years of age) compared with adult controls (1 to 3 years of age). The input resistance of the motoneurons increased in the old cats; no change occurred in the resting membrane potential or spike amplitude. There was a reduction in the delay between the initial segment and the somadendritic components of the antidromic spike. The half-width duration of the monosynaptic EPSP in the old cats increased, but its amplitude did not change. These data indicate that a host of different membrane properties of spinal cord motoneurons and their Ia-monosynaptic input are affected by the aging process. Analysis of the results suggests that the degradation of neuronal processes occurs in all motoneurons rather than preferentially affecting a specific population of motoneurons. PMID:2996926

  19. Developing electrical properties of postnatal mouse lumbar motoneurons

    PubMed Central

    Durand, Jacques; Filipchuk, Anton; Pambo-Pambo, Arnaud; Amendola, Julien; Borisovna Kulagina, Iryna; Guéritaud, Jean-Patrick

    2015-01-01

    We studied the rapid changes in electrical properties of lumbar motoneurons between postnatal days 3 and 9 just before mice weight-bear and walk. The input conductance and rheobase significantly increased up to P8. A negative correlation exists between the input resistance (Rin) and rheobase. Both parameters are significantly correlated with the total dendritic surface area of motoneurons, the largest motoneurons having the lowest Rin and the highest rheobase. We classified the motoneurons into three groups according to their discharge firing patterns during current pulse injection (transient, delayed onset, sustained). The delayed onset firing type has the highest rheobase and the fastest action potential (AP) whereas the transient firing group has the lowest rheobase and the less mature AP. We found 32 and 10% of motoneurons with a transient firing at P3–P5 and P8, respectively. About 20% of motoneurons with delayed onset firing were detected at P8. At P9, all motoneurons exhibit a sustained firing. We defined five groups of motoneurons according to their discharge firing patterns in response to ascending and descending current ramps. In addition to the four classical types, we defined a fifth type called transient for the quasi-absence of discharge during the descending phase of the ramp. This transient type represents about 40% between P3–P5 and tends to disappear with age. Types 1 and 2 (linear and clockwise hysteresis) are the most preponderant at P6–P7. Types 3 and 4 (prolonged sustained and counter clockwise hysteresis) emerge at P8–P9. The emergence of types 3 and 4 probably depends on the maturation of L type calcium channels in the dendrites of motoneurons. No correlation was found between groups defined by step or triangular ramp of currents with the exception of transient firing patterns. Our data support the idea that a switch in the electrical properties of lumbar motoneurons might exist in the second postnatal week of life in mice. PMID

  20. Lectin-based Isolation and Culture of Mouse Embryonic Motoneurons

    PubMed Central

    Conrad, Rebecca; Jablonka, Sibylle; Sczepan, Teresa; Sendtner, Michael; Wiese, Stefan; Klausmeyer, Alice

    2011-01-01

    Spinal motoneurons develop towards postmitotic stages through early embryonic nervous system development and subsequently grow out dendrites and axons. Neuroepithelial cells of the neural tube that express Nkx6.1 are the unique precursor cells for spinal motoneurons1. Though postmitotic motoneurons move towards their final position and organize themselves into columns along the spinal tract2,3. More than 90% of all these differentiated and positioned motoneurons express the transcription factors Islet 1/2. They innervate the muscles of the limbs as well as those of the body and the inner organs. Among others, motoneurons typically express the high affinity receptors for brain derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3), the tropomyosin-related kinase B and C (TrkB, TrkC). They do not express the tropomyosin-related kinase A (TrkA)4. Beside the two high affinity receptors, motoneurons do express the low affinity neurotrophin receptor p75NTR. The p75NTR can bind all neurotrophins with similar but lower affinity to all neurotrophins than the high affinity receptors would bind the mature neurotrophins. Within the embryonic spinal cord, the p75NTR is exclusively expressed by the spinal motoneurons5. This has been used to develop motoneuron isolation techniques to purify the cells from the vast majority of surrounding cells6. Isolating motoneurons with the help of specific antibodies (panning) against the extracellular domains of p75NTR has turned out to be an expensive method as the amount of antibody used for a single experiment is high due to the size of the plate used for panning. A much more economical alternative is the use of lectin. Lectin has been shown to specifically bind to p75NTR as well7. The following method describes an alternative technique using wheat germ agglutinin for a preplating procedure instead of the p75NTR antibody. The lectin is an extremely inexpensive alternative to the p75NTR antibody and the purification grades using

  1. Behaviour of the motoneurone pool in a fatiguing submaximal contraction

    PubMed Central

    McNeil, Chris J; Giesebrecht, Sabine; Gandevia, Simon C; Taylor, Janet L

    2011-01-01

    Abstract During fatigue caused by a sustained maximal voluntary contraction (MVC), motoneurones become markedly less responsive when tested during the silent period following transcranial magnetic stimulation (TMS). To determine whether this reduction depends on the repetitive activation of the motoneurones, responses to TMS (motor evoked potentials, MEPs) and to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were tested during a sustained submaximal contraction at a constant level of electromyographic activity (EMG). In such a contraction, some motoneurones are repetitively activated whereas others are not active. On four visits, eight subjects performed a 10 min maintained-EMG elbow flexor contraction of 25% maximum. Test stimuli were delivered with and without conditioning by TMS given 100 ms prior. Test responses were MEPs or CMEPs (two visits each, small responses evoked by weak stimuli on one visit and large responses on the other). During the sustained contraction, unconditioned CMEPs decreased ∼20% whereas conditioned CMEPs decreased ∼75 and 30% with weak and strong stimuli, respectively. Conditioned MEPs were reduced to the same extent as CMEPs of the same size. The data reveal a novel decrease in motoneurone excitability during a submaximal contraction if EMG is maintained. Further, the much greater reduction of conditioned than unconditioned CMEPs shows the critical influence of voluntary drive on motoneurone responsiveness. Strong test stimuli attenuate the reduction of conditioned CMEPs which indicates that low-threshold motoneurones active in the contraction are most affected. The equivalent reduction of conditioned MEPs and CMEPs suggests that, similar to findings with a sustained MVC, impaired motoneurone responsiveness rather than intracortical inhibition is responsible for the fatigue-related impairment of the MEP during a sustained submaximal contraction. PMID:21606110

  2. Cat hindlimb motoneurons during locomotion. III. Functional segregation in sartorius.

    PubMed

    Hoffer, J A; Loeb, G E; Sugano, N; Marks, W B; O'Donovan, M J; Pratt, C A

    1987-02-01

    Cat sartorius has two distinct anatomical portions, anterior (SA-a) and medial (SA-m). SA-a acts to extend the knee and also to flex the hip. SA-m acts to flex both the knee and the hip. The objective of this study was to investigate how a "single motoneuron pool" is used to control at least three separate functions mediated by the two anatomical portions of one muscle. Discharge patterns of single motoneurons projecting to the sartorius muscle were recorded using floating microelectrodes implanted in the L5 ventral root of cats. The electromyographic activity generated by the anterior and medial portions of sartorius was recorded with chronically implanted electrodes. The muscle portion innervated by each motoneuron was determined by spike-triggered averaging of the EMGs during walking on a motorized treadmill. During normal locomotion, SA-a exhibited two bursts of EMG activity per step cycle, one during the stance phase and one during the late swing phase. In contrast, every recorded motoneuron projecting to SA-a discharged a single burst of action potentials per step cycle. Some SA-a motoneurons discharged only during the stance phase, whereas other motoneurons discharged only during the late swing phase. In all cases, the instantaneous frequencygram of the motoneuron was well fit by the rectified smoothed EMG envelope generated by SA-a during the appropriate phase of the step cycle. During normal locomotion, SA-m exhibited a single burst of EMG activity per step cycle, during the swing phase. The temporal characteristics of the EMG bursts recorded from SA-m differed from the swing-phase EMG bursts generated by SA-a.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3559692

  3. Behaviour of the motoneurone pool in a fatiguing submaximal contraction.

    PubMed

    McNeil, Chris J; Giesebrecht, Sabine; Gandevia, Simon C; Taylor, Janet L

    2011-07-15

    During fatigue caused by a sustained maximal voluntary contraction (MVC), motoneurones become markedly less responsive when tested during the silent period following transcranial magnetic stimulation (TMS). To determine whether this reduction depends on the repetitive activation of the motoneurones, responses to TMS (motor evoked potentials, MEPs) and to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were tested during a sustained submaximal contraction at a constant level of electromyographic activity (EMG). In such a contraction, some motoneurones are repetitively activated whereas others are not active. On four visits, eight subjects performed a 10 min maintained-EMG elbow flexor contraction of 25% maximum. Test stimuli were delivered with and without conditioning by TMS given 100 ms prior. Test responses were MEPs or CMEPs (two visits each, small responses evoked by weak stimuli on one visit and large responses on the other). During the sustained contraction, unconditioned CMEPs decreased ∼20% whereas conditioned CMEPs decreased ∼75 and 30% with weak and strong stimuli, respectively. Conditioned MEPs were reduced to the same extent as CMEPs of the same size. The data reveal a novel decrease in motoneurone excitability during a submaximal contraction if EMG is maintained. Further, the much greater reduction of conditioned than unconditioned CMEPs shows the critical influence of voluntary drive on motoneurone responsiveness. Strong test stimuli attenuate the reduction of conditioned CMEPs which indicates that low-threshold motoneurones active in the contraction are most affected. The equivalent reduction of conditioned MEPs and CMEPs suggests that, similar to findings with a sustained MVC, impaired motoneurone responsiveness rather than intracortical inhibition is responsible for the fatigue-related impairment of the MEP during a sustained submaximal contraction. PMID:21606110

  4. Intrinsic excitability differs between murine hypoglossal and spinal motoneurons.

    PubMed

    Tadros, M A; Fuglevand, A J; Brichta, A M; Callister, R J

    2016-05-01

    Motoneurons differ in the behaviors they control and their vulnerability to disease and aging. For example, brain stem motoneurons such as hypoglossal motoneurons (HMs) are involved in licking, suckling, swallowing, respiration, and vocalization. In contrast, spinal motoneurons (SMs) innervating the limbs are involved in postural and locomotor tasks requiring higher loads and lower movement velocities. Surprisingly, the properties of these two motoneuron pools have not been directly compared, even though studies on HMs predominate in the literature compared with SMs, especially for adult animals. Here we used whole cell patch-clamp recording to compare the electrophysiological properties of HMs and SMs in age-matched neonatal mice (P7-P10). Passive membrane properties were remarkably similar in HMs and SMs, and afterhyperpolarization properties did not differ markedly between the two populations. HMs had narrower action potentials (APs) and a faster upstroke on their APs compared with SMs. Furthermore, HMs discharged APs at higher frequencies in response to both step and ramp current injection than SMs. Therefore, while HMs and SMs have similar passive properties, they differ in their response to similar levels of depolarizing current. This suggests that each population possesses differing suites of ion channels that allow them to discharge at rates matched to the different mechanical properties of the muscle fibers that drive their distinct motor functions. PMID:26936988

  5. A medullary inhibitory region for trigeminal motoneurons in the cat.

    PubMed

    Castillo, P; Pedroarena, C; Chase, M H; Morales, F R

    1991-05-24

    The present report describes the effects on trigeminal motoneurons of stimulation of a circumscribed site within the parvocellular region of the medullary reticular formation. This medullary site was selected because anatomical studies have shown that premotor interneurons project from this site to the trigeminal motorpool. Electrical stimulation of this site induced IPSPs (PcRF-IPSPs) in jaw-closer motoneurons. A population of these IPSPs, recorded contralateral to the site of stimulation, exhibited latencies shorter than 1.5 ms (mean 1.16 +/- 0.08 SD). Their mean amplitude was 1.72 mV +/- 1.13 SD and their mean duration was 3.52 ms +/- 2.15 SD. We believe that these PcRF-IPSPs arose as the result of activation of a monosynaptic pathway. A comparable inhibitory input from this site to ipsilateral jaw-closer motoneurons and to both contra and ipsilateral digastric motoneurons was also observed. We therefore conclude that this medullary PcRF site contains premotor interneurons that are capable of postsynaptically inhibiting motoneurons that innervate antagonistic jaw muscles. PMID:1884229

  6. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation

    PubMed Central

    Kariya, Shingo; Obis, Teresa; Garone, Caterina; Akay, Turgay; Sera, Fusako; Iwata, Shinichi; Homma, Shunichi; Monani, Umrao R.

    2014-01-01

    Spinal muscular atrophy is a common motor neuron disease caused by low survival motoneuron (SMN), a key protein in the proper splicing of genes. Restoring the protein is therefore a promising therapeutic strategy. Implementation of this strategy, however, depends on defining the temporal requirements for SMN. Here, we used controlled knockdown of SMN in transgenic mice to determine the precise postnatal stage requirements for this protein. Reducing SMN in neonatal mice resulted in a classic SMA-like phenotype. Unexpectedly, depletion of SMN in adults had relatively little effect. Insensitivity to low SMN emerged abruptly at postnatal day 17, which coincided with establishment of the fully mature neuromuscular junction (NMJ). Mature animals depleted of SMN eventually exhibited evidence of selective neuromuscular pathology that was made worse by traumatic injury. The ability to regenerate the mature NMJ in aged or injured SMN-depleted mice was grossly impaired, a likely consequence of the inability to meet the surge in demand for motoneuronal SMN that was seen in controls. Our results demonstrate that relative maturity of the NMJ determines the temporal requirement for the SMN protein. These observations suggest that the use of potent but potentially deleterious SMN-enhancing agents could be tapered in human patients once the neuromuscular system matures and reintroduced as needed to enhance SMN for remodeling aged or injured NMJs. PMID:24463453

  7. The distribution of motoneurones supplying chick hind limb muscles.

    PubMed Central

    Landmesser, L

    1978-01-01

    1. The motor nuclei supplying many of the hind limb muscles were localized in late chick embryos (stage 36-37; 10-11 days) by utilizing the technique of retrograde transport of horseradish peroxidase. 2. Each nucleus was found to be localized in a characteristic position in both the rostro-caudal and transverse plane of the spinal cord with only slight individual variation. 3. Each motor nucleus consisted of an elongate, coherent cluster of labelled cells, with few cells occurring outside the cluster. Thus, there did not appear to be extensive overlap of nuclei nor extensive intermingling of motoneurones projecting to different muscles. 4. The position of a motor nucleus in the transverse plane was not correlated with whether its muscle was used as an extensor or flexor; nor were adjacent nuclei necessarily co-activated during normal unrestrained walking movements as deduced from e.m.g. recordings. The position of a motor nucleus also was not correlated in a topographical manner with the adult position in the limb of the muscle to which it projected. 5. Further, while no correlation was found between the rostrocaudal position of a motor nucleus and the embryonic muscle mass from which its muscle was derived, such a relationship existed for the medio-lateral position; all muscles arising from the dorsal muscle mass, regardless of their function or adult position, were innervated by laterally situated motoneurones, all muscles arising from the ventral muscle mass by medially situated motoneurones. 6. It is concluded that motoneurone position is most closely correlated with ontogenetic events presumaeriphery. It can also be inferred that the central connexions onto motoneurones, responsible for their proper activation, cannot be achieved by a simple mechanism based largely on the position of the motoneurone soma. Images Text-fig. 6 Plate 1 PMID:731549

  8. Down-Regulation of KCC2 Expression and Phosphorylation in Motoneurons, and Increases the Number of in Primary Afferent Projections to Motoneurons in Mice with Post-Stroke Spasticity

    PubMed Central

    Toda, Takuya; Ishida, Kazuto; Kiyama, Hiroshi; Yamashita, Toshihide; Lee, Sachiko

    2014-01-01

    Spasticity obstructs motor function recovery post-stroke, and has been reported to occur in spinal cord injury and electrophysiological studies. The purpose of the present study was to assess spinal cord circuit spasticity in post-stroke mice. At 3, 7, 21, and 42 d after photothrombotic ischemic cortical injury in C57BL/6J mice, we observed decreased rate-dependent depression (RDD) of the Hoffmann reflex (H reflex) in the affected forelimb of mice compared with the limbs of sham mice and the non-affected forelimb. This finding suggests a hyper-excitable stretch reflex in the affected forelimb. We then performed immunohistochemical and western blot analyses to examine the expression of the potassium-chloride cotransporter 2 (KCC2) and phosphorylation of the KCC2 serine residue, 940 (S940), since this is the main chloride extruder that affects neuronal excitability. We also performed immunohistochemical analyses on the number of vesicular glutamate transporter 1 (vGluT1)-positive boutons to count the number of Ia afferent fibers that connect to motoneurons. Western bolts revealed that, compared with sham mice, experimental mice had significantly reduced KCC2 expression at 7 d post-stroke, and dephosphorylated S940 at 3 and 7 d post-stroke in motoneuron plasma membranes. We also observed a lower density of KCC2-positive areas in the plasma membrane of motoneurons at 3 and 7 d post-stroke. However, western blot and immunohistochemical analyses revealed that there were no differences between groups 21 and 42 d post-stroke, respectively. In addition, at 7 and 42 d post-stroke, experimental mice exhibited a significant increase in vGluT1 boutons compared with sham mice. Our findings suggest that both the down-regulation of KCC2 and increases in Ia afferent fibers are involved in post-stroke spasticity. PMID:25546454

  9. Hypoxic response of hypoglossal motoneurones in the in vivo cat.

    PubMed Central

    Pierrefiche, O; Bischoff, A M; Richter, D W; Spyer, K M

    1997-01-01

    1. In current and voltage clamp, the effects of hypoxia were studied on resting and synaptic properties of hypoglossal motoneurones in barbiturate-anaesthetized adult cats. 2. Twenty-nine hypoglossal motoneurones with a mean membrane potential of -55 mV responded rapidly to acute hypoxia with a persistent membrane depolarization of about +17 mV. This depolarization correlated with the development of a persistent inward current of 0.3 nA at holding potentials close to resting membrane potential. 3. Superior laryngeal nerve (SLN) stimulation-evoked EPSPs were reduced in amplitude by, on average, 46% while IPSP amplitude was reduced by 31% SLN stimulation-evoked EPSCs were reduced by 50-70%. 4. Extracellular application of adenosine (10 mM) hyperpolarized hypoglossal motoneurones by, on average, 5.6 mV, from a control value of -62 mV. SLN stimulation-evoked EPSPs decreased by 18% and IPSPs decreased by 46% during adenosine application. 5. Extracellular application of the KATP channel blocker glibenclamide led to a blockade of a persistent outward current and a significant increase of SLN stimulation-evoked EPSCs. 6. We conclude that hypoglossal motoneurones have a very low tolerance to hypoxia. They appear to be under metabolic stress even in normoxia and their capacity to activate protective potassium currents is limited when compared with other brainstem neurones. This may help to explain the rapid disturbance of hypoglossal function during energy depletion. PMID:9457652

  10. Modulation of human motoneuron activity by a mental arithmetic task.

    PubMed

    Bensoussan, Laurent; Duclos, Yann; Rossi-Durand, Christiane

    2012-10-01

    This study aimed to determine whether the performance of a mental task affects motoneuron activity. To this end, the tonic discharge pattern of wrist extensor motor units was analyzed in healthy subjects while they were required to maintain a steady wrist extension force and to concurrently perform a mental arithmetic (MA) task. A shortening of the mean inter-spike interval (ISI) and a decrease in ISI variability occurred when MA task was superimposed to the motor task. Aloud and silent MA affected equally the rate and variability of motoneuron discharge. Increases in surface EMG activity and force level were consistent with the modulation of the motor unit discharge rate. Trial-by-trial analysis of the characteristics of motor unit firing revealed that performing MA increases activation of wrist extensor SMU. It is suggested that increase in muscle spindle afferent activity, resulting from fusimotor drive activation by MA, may have contributed to the increase in synaptic inputs to motoneurons during the mental task performance, likely together with enhancement in the descending drive. The finding that a mental task affects motoneuron activity could have consequences in assessment of motor disabilities and in rehabilitation in motor pathologies. PMID:23159444

  11. Central Pupillary Light Reflex Circuits in the Cat: II. Morphology, Ultrastructure and Inputs of Preganglionic Motoneurons

    PubMed Central

    Sun, Wensi; May, Paul J.

    2014-01-01

    Preganglionic motoneurons supplying the ciliary ganglion control lens accommodation and pupil diameter. In cats, these motoneurons make up the preganglionic Edinger-Westphal population, which lies rostral, dorsal and ventral to the oculomotor nucleus. A recent cat study suggested that caudal motoneurons control the lens and rostral motoneurons control the pupil. This led us to examine the morphology, ultrastructure and pretectal inputs of these populations. Preganglionic motoneurons retrogradely labeled by introducing tracer into the cat ciliary ganglion generally fell into two morphologic categories. Fusiform neurons were located rostrally, in the anteromedian nucleus and between the oculomotor nuclei. Multipolar neurons were found caudally, dorsal and ventral to the oculomotor nucleus. The dendrites of preganglionic motoneurons within the anteromedian nucleus crossed the midline, providing a possible basis for consensual responses. Ultrastructurally, several different classes of synaptic profiles contact preganglionic motoneurons, suggesting their activity may be modified by a variety of inputs. Furthermore, there were differences between the synaptic populations contacting the rostral and caudal populations, supporting the contention that these populations display functional differences. Anterogradely labeled pretectal terminals were observed in close association with labeled preganglionic motoneurons, particularly in the rostral population. Ultrastructural analysis revealed that these terminals, packed with clear, spherical vesicles, made asymmetric synaptic contacts onto motoneurons in the rostral population indicating these cells serve the pupillary light reflex. Thus, the preganglionic motoneurons found in the cat display morphologic, ultrastructural and connectional differences suggesting that this rostral preganglionic population is specialized for pupil control, while more caudal elements control the lens. PMID:24706263

  12. Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

    PubMed Central

    Leroy, Félix; Lamotte d'Incamps, Boris; Imhoff-Manuel, Rebecca D; Zytnicki, Daniel

    2014-01-01

    In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration. DOI: http://dx.doi.org/10.7554/eLife.04046.001 PMID:25313866

  13. A repertoire of rhythmic bursting produced by hypoglossal motoneurons in physiological and pathological conditions

    PubMed Central

    Cifra, Alessandra; Nani, Francesca; Sharifullina, Elina; Nistri, Andrea

    2009-01-01

    The brainstem nucleus hypoglossus contains motoneurons that provide the exclusive motor nerve supply to the tongue. In addition to voluntary tongue movements, tongue muscles rhythmically contract during a wide range of physiological activities, such as respiration, swallowing, chewing and sucking. Hypoglossal motoneurons are destroyed early in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease often associated with a deficit in the transport system of the neurotransmitter glutamate. The present study shows how periodic electrical discharges of motoneurons are mainly produced by a neuronal network that drives them into bursting mode via glutamatergic excitatory synapses. Burst activity is, however, modulated by the intrinsic properties of motoneurons that collectively synchronize their discharges via gap junctions to create ‘group bursters’. When glial uptake of glutamate is blocked, a distinct form of pathological bursting spontaneously emerges and leads to motoneuron death. Conversely, H2O2-induced oxidative stress strongly increases motoneuron excitability without eliciting bursting. Riluzole (the only drug currently licensed for the treatment of ALS) suppresses bursting of hypoglossal motoneurons caused by blockage of glutamate uptake and limits motoneuron death. These findings highlight how different patterns of electrical oscillations of brainstem motoneurons underpin not only certain physiological activities, but also motoneuron death induced by glutamate transporter impairment. PMID:19651651

  14. Central pupillary light reflex circuits in the cat: II. Morphology, ultrastructure, and inputs of preganglionic motoneurons.

    PubMed

    Sun, Wensi; May, Paul J

    2014-12-15

    Preganglionic motoneurons supplying the ciliary ganglion control lens accommodation and pupil diameter. In cats, these motoneurons make up the preganglionic Edinger-Westphal population, which lies rostral, dorsal, and ventral to the oculomotor nucleus. A recent cat study suggested that caudal motoneurons control the lens and rostral motoneurons control the pupil. This led us to examine the morphology, ultrastructure, and pretectal inputs of these populations. Preganglionic motoneurons retrogradely labeled by introducing tracer into the cat ciliary ganglion generally fell into two morphologic categories. Fusiform neurons were located rostrally, in the anteromedian nucleus and between the oculomotor nuclei. Multipolar neurons were found caudally, dorsal and ventral to the oculomotor nucleus. The dendrites of preganglionic motoneurons within the anteromedian nucleus crossed the midline, providing a possible basis for consensual responses. Ultrastructurally, several different classes of synaptic profiles contact preganglionic motoneurons, suggesting that their activity may be modified by a variety of inputs. Furthermore, there were differences in the synaptic populations contacting the rostral vs. caudal populations, supporting the contention that these populations display functional differences. Anterogradely labeled pretectal terminals were observed in close association with labeled preganglionic motoneurons, particularly in the rostral population. Ultrastructural analysis revealed that these terminals, packed with clear, spherical vesicles, made asymmetric synaptic contacts onto motoneurons in the rostral population, indicating that these cells serve the pupillary light reflex. Thus, the preganglionic motoneurons found in the cat display morphologic, ultrastructural, and connectional differences suggesting that this rostral preganglionic population is specialized for pupil control, whereas more caudal elements control the lens. PMID:24706263

  15. Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

    PubMed Central

    Leroy, Félix; Lamotte d'Incamps, Boris; Imhoff-Manuel, Rebecca D; Zytnicki, Daniel

    2014-01-01

    In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration. DOI: http://dx.doi.org/10.7554/eLife.04046.001

  16. Succinate dehydrogenase activity and soma size of motoneurons innervating different portions of the rat tibialis anterior

    NASA Technical Reports Server (NTRS)

    Ishihara, A.; Roy, R. R.; Edgerton, V. R.

    1995-01-01

    The spatial distribution, soma size and oxidative enzyme activity of gamma and alpha motoneurons innervating muscle fibres in the deep (away from the surface of the muscle) and superficial (close to the surface of the muscle) portions of the tibialis anterior in normal rats were determined. The deep portion had a higher percentage of high oxidative fibres than the superficial portion of the muscle. Motoneurons were labelled by retrograde neuronal transport of fluorescent tracers: Fast Blue and Nuclear Yellow were injected into the deep portion and Nuclear Yellow into the superficial portion of the muscle. Therefore, motoneurons innervating the deep portion were identified by both a blue fluorescent cytoplasm and a golden-yellow fluorescent nucleus, while motoneurons innervating the superficial portion were identified by only a golden-yellow fluorescent nucleus. After staining for succinate dehydrogenase activity on the same section used for the identification of the motoneurons, soma size and succinate dehydrogenase activity of the motoneurons were measured. The gamma and alpha motoneurons innervating both the deep and superficial portions were located primarily at L4 and were intermingled within the same region of the dorsolateral portion of the ventral horn in the spinal cord. Mean soma size was similar for either gamma or alpha motoneurons in the two portions of the muscle. The alpha motoneurons innervating the superficial portion had a lower mean succinate dehydrogenase activity than those innervating the deep portion of the muscle. An inverse relationship between soma size and succinate dehydrogenase activity of alpha, but not gamma, motoneurons innervating both the deep and superficial portions was observed. Based on three-dimensional reconstructions within the spinal cord, there were no apparent differences in the spatial distribution of the motoneurons, either gamma or alpha, associated with the deep and superficial compartments of the muscle. The data

  17. c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling

    PubMed Central

    Fontana, Xavier; Hristova, Mariya; Da Costa, Clive; Patodia, Smriti; Thei, Laura; Makwana, Milan; Spencer-Dene, Bradley; Latouche, Morwena; Mirsky, Rhona; Jessen, Kristjan R.; Klein, Rüdiger

    2012-01-01

    The AP-1 transcription factor c-Jun is a master regulator of the axonal response in neurons. c-Jun also functions as a negative regulator of myelination in Schwann cells (SCs) and is strongly reactivated in SCs upon axonal injury. We demonstrate here that, after injury, the absence of c-Jun specifically in SCs caused impaired axonal regeneration and severely increased neuronal cell death. c-Jun deficiency resulted in decreased expression of several neurotrophic factors, and GDNF and Artemin, both of which encode ligands for the Ret receptor tyrosine kinase, were identified as novel direct c-Jun target genes. Genetic inactivation of Ret specifically in neurons resulted in regeneration defects without affecting motoneuron survival and, conversely, administration of recombinant GDNF and Artemin protein substantially ameliorated impaired regeneration caused by c-Jun deficiency. These results reveal an unexpected function for c-Jun in SCs in response to axonal injury, and identify paracrine Ret signaling as an important mediator of c-Jun function in SCs during regeneration. PMID:22753894

  18. Transmitter inputs to different motoneuron subgroups in the oculomotor and trochlear nucleus in monkey

    PubMed Central

    Zeeh, Christina; Mustari, Michael J.; Hess, Bernhard J. M.; Horn, Anja K. E.

    2015-01-01

    In all vertebrates the eyes are moved by six pairs of extraocular muscles enabling horizontal, vertical and rotatory movements. Recent work showed that each extraocular muscle is controlled by two motoneuronal groups: (1) Motoneurons of singly-innervated muscle fibers (SIF) that lie within the boundaries of motonuclei mediating a fast muscle contraction; and (2) motoneurons of multiply-innervated muscle fibers (MIF) in the periphery of motonuclei mediating a tonic muscle contraction. Currently only limited data about the transmitter inputs to the SIF and MIF motoneurons are available. Here we performed a quantitative study on the transmitter inputs to SIF and MIF motoneurons of individual muscles in the oculomotor and trochlear nucleus in monkey. Pre-labeled motoneurons were immunostained for GABA, glutamate decarboxylase, GABA-A receptor, glycine transporter 2, glycine receptor 1, and vesicular glutamate transporters 1 and 2. The main findings were: (1) the inhibitory control of SIF motoneurons for horizontal and vertical eye movements differs. Unlike in previous primate studies a considerable GABAergic input was found to all SIF motoneuronal groups, whereas a glycinergic input was confined to motoneurons of the medial rectus (MR) muscle mediating horizontal eye movements and to those of the levator palpebrae (LP) muscle elevating the upper eyelid. Whereas SIF and MIF motoneurons of individual eye muscles do not differ numerically in their GABAergic, glycinergic and vGlut2 input, vGlut1 containing terminals densely covered the supraoculomotor area (SOA) targeting MR MIF motoneurons. It is reasonable to assume that the vGlut1 input affects the near response system in the SOA, which houses the preganglionic neurons mediating pupillary constriction and accommodation and the MR MIF motoneurones involved in vergence. PMID:26257611

  19. Transmitter inputs to different motoneuron subgroups in the oculomotor and trochlear nucleus in monkey.

    PubMed

    Zeeh, Christina; Mustari, Michael J; Hess, Bernhard J M; Horn, Anja K E

    2015-01-01

    In all vertebrates the eyes are moved by six pairs of extraocular muscles enabling horizontal, vertical and rotatory movements. Recent work showed that each extraocular muscle is controlled by two motoneuronal groups: (1) Motoneurons of singly-innervated muscle fibers (SIF) that lie within the boundaries of motonuclei mediating a fast muscle contraction; and (2) motoneurons of multiply-innervated muscle fibers (MIF) in the periphery of motonuclei mediating a tonic muscle contraction. Currently only limited data about the transmitter inputs to the SIF and MIF motoneurons are available. Here we performed a quantitative study on the transmitter inputs to SIF and MIF motoneurons of individual muscles in the oculomotor and trochlear nucleus in monkey. Pre-labeled motoneurons were immunostained for GABA, glutamate decarboxylase, GABA-A receptor, glycine transporter 2, glycine receptor 1, and vesicular glutamate transporters 1 and 2. The main findings were: (1) the inhibitory control of SIF motoneurons for horizontal and vertical eye movements differs. Unlike in previous primate studies a considerable GABAergic input was found to all SIF motoneuronal groups, whereas a glycinergic input was confined to motoneurons of the medial rectus (MR) muscle mediating horizontal eye movements and to those of the levator palpebrae (LP) muscle elevating the upper eyelid. Whereas SIF and MIF motoneurons of individual eye muscles do not differ numerically in their GABAergic, glycinergic and vGlut2 input, vGlut1 containing terminals densely covered the supraoculomotor area (SOA) targeting MR MIF motoneurons. It is reasonable to assume that the vGlut1 input affects the near response system in the SOA, which houses the preganglionic neurons mediating pupillary constriction and accommodation and the MR MIF motoneurones involved in vergence. PMID:26257611

  20. Inhibition of Sirt1 promotes neural progenitors toward motoneuron differentiation from human embryonic stem cells

    SciTech Connect

    Zhang, Yun; Wang, Jing; Chen, Guian; Fan, Dongsheng; Deng, Min

    2011-01-14

    Research highlights: {yields} Nicotinamide inhibit Sirt1. {yields} MASH1 and Ngn2 activation. {yields} Increase the expression of HB9. {yields} Motoneurons formation increases significantly. -- Abstract: Several protocols direct human embryonic stem cells (hESCs) toward differentiation into functional motoneurons, but the efficiency of motoneuron generation varies based on the human ESC line used. We aimed to develop a novel protocol to increase the formation of motoneurons from human ESCs. In this study, we tested a nuclear histone deacetylase protein, Sirt1, to promote neural precursor cell (NPC) development during differentiation of human ESCs into motoneurons. A specific inhibitor of Sirt1, nicotinamide, dramatically increased motoneuron formation. We found that about 60% of the cells from the total NPCs expressed HB9 and {beta}III-tubulin, commonly used motoneuronal markers found in neurons derived from ESCs following nicotinamide treatment. Motoneurons derived from ESC expressed choline acetyltransferase (ChAT), a positive marker of mature motoneuron. Moreover, we also examined the transcript levels of Mash1, Ngn2, and HB9 mRNA in the differentiated NPCs treated with the Sirt1 activator resveratrol (50 {mu}M) or inhibitor nicotinamide (100 {mu}M). The levels of Mash1, Ngn2, and HB9 mRNA were significantly increased after nicotinamide treatment compared with control groups, which used the traditional protocol. These results suggested that increasing Mash1 and Ngn2 levels by inhibiting Sirt1 could elevate HB9 expression, which promotes motoneuron differentiation. This study provides an alternative method for the production of transplantable motoneurons, a key requirement in the development of hESC-based cell therapy in motoneuron disease.

  1. The control of sets of motoneurones by local interneurones in the locust.

    PubMed Central

    Burrows, M

    1980-01-01

    1. A motoneurone innervating a muscle in a hind leg of a locust is controlled in a graded manner by many non-spiking, local interneurones. There is overlap and fractionation of control between these interneurones. Some interneurones depolarize the motoneurone over part of its range, others hyperpolarize it, whilst some do both. 2. The interneurones organize the small number of motoneurones that innervate one muscle into overlapping sets of various sizes. A motoneurone can therefore be activated individually or in particular combinations with its fellow motoneurones. 3. The motoneurones innervating two muscles of a joint are also organized into overlapping sets by many local interneurones. This permits the motoneurones to the two muscles to be activated reciprocally, together, or independently. 4. One interneurone can elicit a co-ordinated movement of one, two or even three joints in a hind leg that are components of the normal behaviour of the locust. 5. A single interneurone acting alone does not usually elicit the maximum output from one motoneurone, nor a complete piece of behaviour. A stronger contraction of a muscle and a more complete movement results from the action of groups of interneurones. 6. It is suggested that local interneurones, exerting graded control over motoneurones are a major element in the organization of motor patterns in the locust. PMID:7359394

  2. Neuroprotective effects of testosterone on dendritic morphology following partial motoneuron depletion: Efficacy in female rats

    PubMed Central

    Wilson, Randall E.; Coons, Kellie D.; Sengelaub, Dale R.

    2009-01-01

    Motoneuron loss is a significant medical problem, capable of causing severe movement disorders and even death. We have previously demonstrated that partial depletion of motoneurons induces dendritic atrophy in remaining motoneurons, with a concomitant reduction in motor activation. Treatment of male rats with testosterone attenuates the regressive changes following partial motoneuron depletion. To test whether testosterone has similar effects in females, we examined potential neuroprotective effects in motoneurons innervating muscles of the quadriceps of female rats. Motoneurons were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, some saporin-injected rats were given implants containing testosterone or left untreated. Four weeks later, surviving motoneurons were labeled with cholera toxin-conjugated HRP, and dendritic arbors were reconstructed in 3 dimensions. Compared to normal females, partial motoneuron depletion resulted in decreased dendritic length in remaining quadriceps motoneurons, and this atrophy was greatly attenuated by testosterone treatment. These findings suggest that testosterone has neuroprotective effects on morphology in both males and females, further supporting a role for testosterone as a neurotherapeutic agent in the injured nervous system. PMID:19735695

  3. State-dependent phenomena in cat masseter motoneurons.

    PubMed

    Kohlmeier, K A; López-Rodríguez, F; Liu, R H; Morales, F R; Chase, M H

    1996-05-25

    In the present study we explored the mechanisms of carbachol-induced muscle atonia in the alpha-chloralose-anesthetized animal. We compared our findings to those that have been previously obtained in unanesthetized cats during muscle atonia occurring during natural active sleep. Accordingly, in cats anesthetized with alpha-chloralose, intracellular records were obtained from masseter motoneurons before and after carbachol-induced motor atonia. Following the induction of atonia, the membrane potential activity was dominated by high-frequency, discrete, hyperpolarizing potentials. These hyperpolarizing potentials were reversed in polarity by the intracellular injection of chloride ions and abolished by the application of strychnine. These findings indicate that they were inhibitory postsynaptic potentials (IPSPs) mediated by glycine. These IPSPs appeared exclusively during muscle atonia. In addition, masseter motoneurons were significantly hyperpolarized and their rheobase increased. There was a decrease in input resistance and membrane time constant. In the alpha-chloralose-anesthetized preparation, stimulation of the nucleus pontis oralis (NPO) induced IPSPs in masseter motoneurons following, but never prior to, the pontine injection of carbachol. Thus, this is the first demonstration that "reticular response-reversal' may be elicited in an anesthetized preparation. Another state-dependent phenomenon of active sleep, the occurrence of IPSPs in motoneurons that are temporally correlated with ponto-geniculo-occipital (PGO) waves, was also observed in this preparation only after carbachol administration. Based on the data in this report, we conclude that the inhibitory system that mediates atonia during the state of active sleep can be activated in an animal that is anesthetized with alpha-chloralose. Specifically, the neuronal groups that generate spontaneous IPSPs, those that mediate the phenomenon of reticular response-reversal, and those involved in the generation

  4. Changes in the electrophysiological properties of cat spinal motoneurons following the intramuscular injection of adriamycin compared with changes in the properties of motoneurons in aged cats.

    PubMed

    Liu, R H; Yamuy, J; Xi, M C; Morales, F R; Chase, M H

    1995-11-01

    1. This study was undertaken to investigate the effects of adriamycin (ADM, Doxorubicin) on the basic electrophysiological properties of spinal cord motoneurons in the adult cat. ADM was injected into the biceps, gastrocnemius, semitendinosus, and semimembranosus muscles of the left hindlimb (1.2 mg per muscle). Intracellular recordings from motoneurons innervating these muscles were carried out 12, 20, or 40 days after ADM administration and from corresponding motoneurons in untreated control cats. 2. Twelve days after ADM injection, motoneurons innervating ADM-treated muscles (ADM MNs) exhibited statistically significant increases in input resistance, membrane time constant, and amplitude of the action potential's afterhyperpolarization (AHP). In addition, there was a statistically significant decrease in rheobase and in the delay between the action potential of the initial segment (IS) and that of the somadendritic (SD) portion of the motoneuron (IS-SD delay). There were no significant changes in the resting membrane potential, threshold depolarization, action potential amplitude, or axonal conduction velocity. 3. The changes in electrical properties of motoneurons at 20 and 40 days after ADM injection were qualitatively similar to those observed at 12 days. However, at 40 days after ADM injection there was a statistically significant decrease in the axonal conduction velocity of the ADM MNs. 4. The normal correlations that are present between the AHP duration and electrical properties of the control motoneurons were observed in the ADM MNs, e.g., AHP duration was positively correlated with the input resistance and time constant and negatively correlated with the axonal conduction velocity. The correlation coefficients, however, were reduced in comparison with the control data. 5. This study demonstrates that ADM exerts significant effects on the electrical properties of motoneurons when injected into their target muscles. The majority of the changes in

  5. Transcriptional enhancement of Smn levels in motoneurons is crucial for proper axon morphology in zebrafish.

    PubMed

    Spiró, Zoltán; Koh, Angela; Tay, Shermaine; See, Kelvin; Winkler, Christoph

    2016-01-01

    An unresolved mystery in the field of spinal muscular atrophy (SMA) is why a reduction of the ubiquitously expressed Smn protein causes defects mostly in motoneurons. We addressed the possibility that this restricted vulnerability stems from elevated Smn expression in motoneurons. To explore this, we established an ex vivo zebrafish culture system of GFP-marked motoneurons to quantitatively measure Smn protein and smn mRNA levels as well as promoter activity in motoneurons versus other cell types. Importantly, we uncovered that Smn levels are elevated in motoneurons by means of transcriptional activation. In addition, we identified the ETS family transcription factor Etv5b to be responsible for increased smn transcription in motoneurons. Moreover, we established that the additional supply of Smn protein in motoneurons is necessary for proper axonogenesis in a cell-autonomous manner. These findings demonstrate the reliance of motoneurons on more Smn, thereby adding a novel piece of evidence for their increased vulnerability under SMA conditions. PMID:27273160

  6. Early electrophysiological abnormalities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis.

    PubMed

    Bories, Cyril; Amendola, Julien; Lamotte d'Incamps, Boris; Durand, Jacques

    2007-01-01

    Amyotrophic lateral sclerosis is a lethal, adult-onset disease characterized by progressive degeneration of motoneurons. Recent data have suggested that the disease could be linked to abnormal development of the motor nervous system. Therefore, we investigated the electrical properties of lumbar motoneurons in an in-vitro neonatal spinal cord preparation isolated from SOD1(G85R) mice, which is a transgenic model of amyotrophic lateral sclerosis. The study was performed on young animals at the beginning of their second week, between postnatal days 6 and 10. Measurements of resting membrane potential and action potential characteristics of motoneurons were similar in wild-type and SOD1(G85R) mice. However, the input resistance of motoneurons from transgenic mice was significantly lower than that of wild-type animals, whereas their membrane capacitance was increased, strongly suggesting larger SOD1(G85R) motoneurons. Furthermore, the slope of the frequency-intensity curve was steeper in motoneurons from wild-type pups. Interestingly, the input resistance as well as the slope of the frequency-intensity curves of other spinal neurons did not show such differences. Finally, the amplitude of dorsal root-evoked potentials following high-intensity stimulation was significantly smaller in SOD1(G85R) motoneurons. The superoxide dismutase 1 mutation thus induces specific alterations of the functional properties of motoneurons early in development. PMID:17284186

  7. Transcriptional enhancement of Smn levels in motoneurons is crucial for proper axon morphology in zebrafish

    PubMed Central

    Spiró, Zoltán; Koh, Angela; Tay, Shermaine; See, Kelvin; Winkler, Christoph

    2016-01-01

    An unresolved mystery in the field of spinal muscular atrophy (SMA) is why a reduction of the ubiquitously expressed Smn protein causes defects mostly in motoneurons. We addressed the possibility that this restricted vulnerability stems from elevated Smn expression in motoneurons. To explore this, we established an ex vivo zebrafish culture system of GFP-marked motoneurons to quantitatively measure Smn protein and smn mRNA levels as well as promoter activity in motoneurons versus other cell types. Importantly, we uncovered that Smn levels are elevated in motoneurons by means of transcriptional activation. In addition, we identified the ETS family transcription factor Etv5b to be responsible for increased smn transcription in motoneurons. Moreover, we established that the additional supply of Smn protein in motoneurons is necessary for proper axonogenesis in a cell-autonomous manner. These findings demonstrate the reliance of motoneurons on more Smn, thereby adding a novel piece of evidence for their increased vulnerability under SMA conditions. PMID:27273160

  8. State-dependent control of lumbar motoneurons by the hypocretinergic system.

    PubMed

    Yamuy, Jack; Fung, Simon J; Xi, Mingchu; Chase, Michael H

    2010-02-01

    Neurons in the lateral hypothalamus (LH) that synthesize hypocretins (Hcrt-1 and Hcrt-2) are active during wakefulness and excite lumbar motoneurons. Because hypocretinergic cells also discharge during phasic periods of rapid eye movement (REM) sleep, we sought to examine their action on the activity of motoneurons during this state. Accordingly, cat lumbar motoneurons were intracellularly recorded, under alpha-chloralose anesthesia, prior to (control) and during the carbachol-induced REM sleep-like atonia (REMc). During control conditions, LH stimulation induced excitatory postsynaptic potentials (composite EPSP) in motoneurons. In contrast, during REMc, identical LH stimulation induced inhibitory PSPs in motoneurons. We then tested the effects of LH stimulation on motoneuron responses following the stimulation of the nucleus reticularis gigantocellularis (NRGc) which is part of a brainstem-spinal cord system that controls motoneuron excitability in a state-dependent manner. LH stimulation facilitated NRGc stimulation-induced composite EPSP during control conditions whereas it enhanced NRGc stimulation-induced IPSPs during REMc. These intriguing data indicate that the LH exerts a state-dependent control of motor activity. As a first step to understand these results, we examined whether hypocretinergic synaptic mechanisms in the spinal cord were state dependent. We found that the juxtacellular application of Hcrt-1 induced motoneuron excitation during control conditions whereas motoneuron inhibition was enhanced during REMc. These data indicate that the hypocretinergic system acts on motoneurons in a state-dependent manner via spinal synaptic mechanisms. Thus, deficits in Hcrt-1 may cause the coexistence of incongruous motor signs in cataplectic patients, such as motor suppression during wakefulness and movement disorders during REM sleep. PMID:19962375

  9. Opiate-Induced Suppression of Rat Hypoglossal Motoneuron Activity and Its Reversal by Ampakine Therapy

    PubMed Central

    Lorier, Amanda R.; Funk, Gregory D.; Greer, John J.

    2010-01-01

    Background Hypoglossal (XII) motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of μ-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s). We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity. Methodology/Principal Findings A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the μ-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717) alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons. Conclusions/Significance The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract μ-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron

  10. Effects of background noise on the response of rat and cat motoneurones to excitatory current transients.

    PubMed Central

    Poliakov, A V; Powers, R K; Sawczuk, A; Binder, M D

    1996-01-01

    1. We studied the responses of rat hypoglossal motoneurones to excitatory current transients (ECTs) using a brainstem slice preparation. Steady, repetitive discharge at rates of 12-25 impulses s-1 was elicited from the motoneurones by injecting long (40 s) steps of constant current. Poisson trains of the ECTs were superimposed on these steps. The effects of additional synaptic noise was simulated by adding a zero-mean random process to the stimuli. 2. We measured the effects of the ECTs on motoneurone discharge probability by compiling peristimulus time histograms (PSTHs) between the times of occurrence of the ECTs and the motoneurone spikes. The ECTs produced modulation of motoneurone discharge similar to that produced by excitatory postsynaptic currents. 3. The addition of noise altered the pattern of the motoneurone response to the current transients: both the amplitude and the area of the PSTH peaks decreased as the power of the superimposed noise was increased. Noise tended to reduce the efficacy of the ECTs, particularly when the motoneurones were firing at lower frequencies. Although noise also increased the firing frequency of the motoneurones slightly, the effects of noise on ECT efficacy did not simply result from noise-induced changes in mean firing rate. 4. A modified version of the experimental protocol was performed in lumbar motoneurones of intact, pentobarbitone-anaesthetized cats. These recordings yielded results similar to those obtained in rat hypoglossal motoneurones in vitro. 5. Our results suggest that the presence of concurrent synaptic inputs reduces the efficacy of any one input. The implications of this change in efficacy and the possible underlying mechanisms are discussed. PMID:8866358

  11. Zebrafish Mnx proteins specify one motoneuron subtype and suppress acquisition of interneuron characteristics

    PubMed Central

    2012-01-01

    Background Precise matching between motoneuron subtypes and the muscles they innervate is a prerequisite for normal behavior. Motoneuron subtype identity is specified by the combination of transcription factors expressed by the cell during its differentiation. Here we investigate the roles of Mnx family transcription factors in specifying the subtypes of individually identified zebrafish primary motoneurons. Results Zebrafish has three Mnx family members. We show that each of them has a distinct and temporally dynamic expression pattern in each primary motoneuron subtype. We also show that two Mnx family members are expressed in identified VeLD interneurons derived from the same progenitor domain that generates primary motoneurons. Surprisingly, we found that Mnx proteins appear unnecessary for differentiation of VeLD interneurons or the CaP motoneuron subtype. Mnx proteins are, however, required for differentiation of the MiP motoneuron subtype. We previously showed that MiPs require two temporally-distinct phases of Islet1 expression for normal development. Here we show that in the absence of Mnx proteins, the later phase of Islet1 expression is initiated but not sustained, and MiPs become hybrids that co-express morphological and molecular features of motoneurons and V2a interneurons. Unexpectedly, these hybrid MiPs often extend CaP-like axons, and some MiPs appear to be entirely transformed to a CaP morphology. Conclusions Our results suggest that Mnx proteins promote MiP subtype identity by suppressing both interneuron development and CaP axon pathfinding. This is, to our knowledge, the first report of transcription factors that act to distinguish CaP and MiP subtype identities. Our results also suggest that MiP motoneurons are more similar to V2 interneurons than are CaP motoneurons. PMID:23122226

  12. Persistent currents and discharge patterns in rat hindlimb motoneurons.

    PubMed

    Hamm, Thomas M; Turkin, Vladimir V; Bandekar, Neha K; O'Neill, Derek; Jung, Ranu

    2010-09-01

    We report here the first direct measurements of persistent inward currents (PICs) in rat hindlimb motoneurons, obtained from ketamine-xylazine anesthetized rats during slow voltage ramps performed by single-electrode somatic voltage clamp. Most motoneurons expressed PICs and current-voltage (I-V) relations often contained a negative-slope region (NSR; 13/19 cells). PICs activated at -52.7 ± 3.89 mV, 9 mV negative to spike threshold. NSR onset was -44.2 ± 4.1 mV. PIC amplitudes were assessed by maximum inward currents measured relative to extrapolated leak current and to NSR-onset current. PIC conductance at potentials just positive to activation was assessed by the relative change in slope conductance (g(in)/g(leak)). PIC amplitudes varied widely; some exceeded 5 and 10 nA relative to current at NSR onset or leak current, respectively. PIC amplitudes did not vary significantly with input conductance, but PIC amplitudes normalized by recruitment current decreased with increasing input conductance. Similarly, g(in)/g(leak) decreased with increasing input conductance. Currents near resting potential on descending limbs of I-V relations were often outward, relative to ascending-limb currents. This residual outward current was correlated with increases in leak conductance on the descending limb and with input conductance. Excluding responses with accommodation, residual outward currents matched differences between recruitment and derecruitment currents, suggesting a role for residual outward current in frequency adaptation. Comparison of potentials for PIC activation and NSR onset with interspike trajectories during discharge demonstrated correspondence between PIC activation and frequency-current (f-I) range boundaries. Contributions of persistent inward and outward currents to motoneuron discharge characteristics are discussed. PMID:20592117

  13. Adaptation of cat motoneurons to sustained and intermittent extracellular activation.

    PubMed Central

    Spielmann, J M; Laouris, Y; Nordstrom, M A; Robinson, G A; Reinking, R M; Stuart, D G

    1993-01-01

    1. The main purpose of this study was to quantify the adaptation of spinal motoneurons to sustained and intermittent activation, using an extracellular route of stimulating current application to single test cells, in contrast to an intracellular route, as has been used previously. In addition, associations were tested between firing rate properties of the tested cells and other type (size)-related properties of these cells and their motor units. 2. Motoneurons supplying the medial gastrocnemius muscle of the deeply anaesthetized cat were stimulated for 240 s with microelectrodes which passed sustained extracellular current at 1.25 times the threshold for repetitive firing. Many cells were also tested following a rest period with intermittent 1 s current pulses (duration 600 ms) at the same relative stimulus strength. Cell discharge was assessed from the EMG of the motor unit innervated by the test neuron. The motoneurons and their motor units were assigned to four categories (i.e. types FF, FR, S and F; where F = FF + FR) based on conventional criteria. In all, twenty F (16 FF, 4 FR) and fourteen S cells were studied with sustained stimulation. Thirty of these cells (17 F, 13 S) and an additional two cells (1 F, 1 S) were studied with intermittent stimulation. 3. The mean threshold current required for sustained firing for a period of > or = 2 s was not significantly different for F and S cells. However, most of the other measured parameters of motoneuron firing differed significantly for these two cell groups. For example, at 1.25 times the threshold current for repetitive firing, the mean firing duration in response to 240 s of sustained activation was 123 +/- 88 s (+/- S.D.) for F cells vs. 233 +/- 19 s for S cells. These values were significantly longer than those from a comparable, previously reported study that employed intracellular stimulation. With intermittent stimulation, the firing durations of F and S cells were not significantly different from each

  14. Extensor motoneurone properties are altered immediately before and during fictive locomotion in the adult decerebrate rat

    PubMed Central

    MacDonell, C W; Power, K E; Chopek, J W; Gardiner, K R; Gardiner, P F

    2015-01-01

    Key points This is the first report, in adult decerebrate rats, to examine intracellular hindlimb motoneurone properties during quiescence, fictive locomotion and a tonic period immediately before fictive locomotion that is characterized by increased peripheral nerve activity. It is shown for the first time during fictive locomotion that motoneurones become more responsive in the tonic period, suggesting that the motoneurone pool becomes primed before patterned motor output commences. Spike frequency adaptation exists in quiescence and during fictive locomotion during constant excitation with injected current but not during centrally driven fictive locomotion. Motoneurones within the extensor motor pool show changes in excitability even when they are not directly involved in locomotion. The data show increased responsiveness of motoneurones during locomotion via a lowered threshold for spike initiation and decreased rheobase. Abstract This study examined motoneurone properties during fictive locomotion in the adult rat for the first time. Fictive locomotion was induced via electrical stimulation of the mesencephalic locomotor region in decerebrate adult rats under neuromuscular blockade to compare basic and rhythmic motoneurone properties in antidromically identified extensor motoneurones during: (1) quiescence, before and after fictive locomotion; (2) the ‘tonic’ period immediately preceding locomotor-like activity, whereby the amplitude of peripheral flexor (peroneal) and extensor (tibial) nerves are increased but alternation has not yet occurred; and (3) locomotor-like episodes. Locomotion was identified by alternating flexor–extensor nerve activity, where the motoneurone either produced membrane oscillations consistent with a locomotor drive potential (LDP) or did not display membrane oscillation during alternating nerve activity. Cells producing LDPs were referred to as such, while those that did not were referred to as ‘idle’ motoneurones. LDP and

  15. Synaptic control of hindlimb motoneurones during three forms of the fictive scratch reflex in the turtle.

    PubMed Central

    Robertson, G A; Stein, P S

    1988-01-01

    1. The turtle spinal cord produces three forms of the fictive scratch reflex in response to tactile stimulation of sites on the body surface. Common to all three forms is the rhythmic alternation of activity between hip protractor and hip retractor motoneurones. Hip protractor motoneurone activity is monitored via nerves innervating the hip protractor muscle puboischiofemoralis internus pars anteroventralis (VP-HP). Hip retractor activity is monitored via nerves innervating several monoarticular hip retractor muscles, one hip adductor muscle, and several biarticular hip retractor-knee flexor muscles (HR-KF). Each form is characterized by the timing of activity of motoneurones innervating femorotibialis (FT-KE), a monoarticular knee extensor muscle, within this alternating cycle (Robertson, Mortin, Keifer & Stein, 1985). In the present study, intracellular recordings revealed a corresponding regulation of synaptic drive to knee extensor motoneurones with respect to the synaptic drive to the motoneurones innervating antagonist muscles of the hip. These patterns of synaptic activation give rise to the distinct motor pattern underlying each form of the scratch reflex. 2. VP-HP, HR-KF and FT-KE motoneurones all exhibited phasic depolarizing and hyperpolarizing changes in membrane voltage during the production of the rhythmic motor patterns underlying each stratch form. Membrane depolarization is caused by synaptic excitation (EPSPs) and gives rise to motoneurone discharge. Hyperpolarization is primarily the result of postsynaptic inhibition (IPSPs) mediated by an increased conductance of chloride ions (Cl-) and ensures motor pool quiescence during antagonist activation. 3. VP-HP motoneurones depolarized during activation of the VP-HP motor pool and hyperpolarized during activation of the HR-KF motor pool. HR-KF motoneurones depolarized during activation of the HR-KF motor pool and hyperpolarized during activation of the VP-HP motor pool. In many cases, the amplitude of

  16. Axotomized neonatal motoneurons overexpressing the bcl2 proto-oncogene retain functional electrophysiological properties.

    PubMed Central

    Alberi, S; Raggenbass, M; de Bilbao, F; Dubois-Dauphin, M

    1996-01-01

    Bcl2 overexpression prevents axotomy-induced neuronal death of neonatal facial motoneurons, as defined by morphological criteria. However, the functional properties of these surviving lesioned transgenic neurons are unknown. Using transgenic mice overexpressing the protein Bcl2, we have investigated the bioelectrical properties of transgenic facial motoneurons from 7 to 20 days after neonatal unilateral axotomy using brain-stem slices and whole cell patch-clamp recording. Nonaxotomized facial motoneurons from wild-type and transgenic mice had similar properties; they had an input resistance of 38 +/- 6 M omega and fired repetitively after injection of positive current pulses. When cells were voltage-clamped at or near their resting membrane potential, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartic acid (NMDA), or vasopressin generated sustained inward currents. In transgenic axotomized mice, facial motoneurons could be found located ipsilaterally to the lesion; they had an input resistance of 150 +/- 30 M omega, indicating that they were smaller in size, fired repetitively, and were also responsive to AMPA, NMDA, and vasopressin. Morphological measurements achieved 1 week after the lesion have shown that application of brain-derived neurotrophic factor prevented the reduction in size of axotomized transgenic motoneurons. These data indicate that Bcl2 not only prevents morphological apoptotic death of axotomized neonatal transgenic motoneurons but also permits motoneurons to conserve functional electrophysiological properties. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:8633001

  17. Postnatal electrical and morphological abnormalities in lumbar motoneurons from transgenic mouse models of amyotrophic lateral sclerosis.

    PubMed

    Amendola, J; Gueritaud, J P; Lamotte d'Incamps, B; Bories, C; Liabeuf, S; Allene, C; Pambo-Pambo, A; Durand, J

    2007-11-01

    Antidromically identified lumbar motoneurons intracellularly recorded in the entire brainstem/spinal cord preparation isolated from SOD1(G85R) postnatal mice (P3-P10) were labelled with neurobiotin and fully reconstructed in 3D from serial sections in order to analyse their morphology. This staining procedure revealed differences between WT and SOD1(G85R) dendritic trees for most metric and topologic parameters analyzed. A highly complex morphology of SOD1(G85R) motoneurons dendrites (increased number of branching points and terminations) was found and the dendritic trees were longer compared to the WT motoneurons. These morphological changes observed in P8-P9 motoneurons mice occurred concomitantly with a decrease in the input resistance and gain. During electrophysiological recordings, four patterns of discharge were observed in response to ramp stimulations, that were equally distributed in WT and SOD1(G85R) motoneurons. In slice preparation, whole cell patch-clamp recordings made from developing motoneurons in SOD1(G85R) and double transgenic SOD1(G93A)/Hb9-eGFP mice showed that Riluzole, a blocker of persistent inward sodium conductance, altered the repetitive firing in a similar way for the 2 strains. These results show that the SOD1 mutations linked to familial ALS alter the development of the electrical and morphological properties of lumbar motoneurons. PMID:18075124

  18. Absence of synergy for monosynaptic Group I inputs between abdominal and internal intercostal motoneurons

    PubMed Central

    Ford, T. W.; Meehan, C. F.

    2014-01-01

    Internal intercostal and abdominal motoneurons are strongly coactivated during expiration. We investigated whether that synergy was paralleled by synergistic Group I reflex excitation. Intracellular recordings were made from motoneurons of the internal intercostal nerve of T8 in anesthetized cats, and the specificity of the monosynaptic connections from afferents in each of the two main branches of this nerve was investigated. Motoneurons were shown by antidromic excitation to innervate three muscle groups: external abdominal oblique [EO; innervated by the lateral branch (Lat)], the region of the internal intercostal muscle proximal to the branch point (IIm), and muscles innervated from the distal remainder (Dist). Strong specificity was observed, only 2 of 54 motoneurons showing excitatory postsynaptic potentials (EPSPs) from both Lat and Dist. No EO motoneurons showed an EPSP from Dist, and no IIm motoneurons showed one from Lat. Expiratory Dist motoneurons fell into two groups. Those with Dist EPSPs and none from Lat (group A) were assumed to innervate distal internal intercostal muscle. Those with Lat EPSPs (group B) were assumed to innervate abdominal muscle (transversus abdominis or rectus abdominis). Inspiratory Dist motoneurons (assumed to innervate interchondral muscle) showed Dist EPSPs. Stimulation of dorsal ramus nerves gave EPSPs in 12 instances, 9 being in group B Dist motoneurons. The complete absence of heteronymous monosynaptic Group I reflex excitation between muscles that are synergistically activated in expiration leads us to conclude that such connections from muscle spindle afferents of the thoracic nerves have little role in controlling expiratory movements but, where present, support other motor acts. PMID:24920027

  19. Neuroprotective effects of NGF, BDNF, NT-3 and GDNF on axotomized extraocular motoneurons in neonatal rats.

    PubMed

    Morcuende, S; Muñoz-Hernández, R; Benítez-Temiño, B; Pastor, A M; de la Cruz, R R

    2013-10-10

    Neurotrophic factors delivered from target muscles are essential for motoneuronal survival, mainly during development and early postnatal maturation. It has been shown that the disconnection between motoneurons and their innervated muscle by means of axotomy produces a vast neuronal death in neonatal animals. In the present work, we have evaluated the effects of different neurotrophic factors on motoneuronal survival after neonatal axotomy, using as a model the motoneurons innervating the extraocular eye muscles. With this purpose, neonatal rats were monocularly enucleated at the day of birth (postnatal day 0) and different neurotrophic treatments (NGF, BDNF, NT-3, GDNF and the mixture of BDNF+GDNF) were applied intraorbitally by means of a Gelfoam implant (a single dose of 5 μg of each factor). We first demonstrated that extraocular eye muscles of neonatal rats expressed these neurotrophic factors and therefore constituted a natural source of retrograde delivery for their innervating motoneurons. By histological and immunocytochemical methods we determined that all treatments significantly rescued extraocular motoneurons from axotomy-induced cell death. For the dose used, NGF and GDNF were the most potent survival factors for these motoneurons, followed by BDNF and lastly by NT-3. The simultaneous administration of BDNF and GDNF did not increase the survival-promoting effects above those obtained by GDNF alone. Interestingly, the rescue effects of all neurotrophic treatments persisted even 30 days after lesion. The administration of these neurotrophic factors, with the exception of NT-3, also prevented the loss of the cholinergic phenotype observed by 10 days after axotomy. At the dosage applied, NGF and GDNF were revealed again as the most effective neuroprotective agents against the axotomy-induced decrease in ChAT. Two remarkable findings highlighted in the present work that contrasted with other motoneuronal types after neonatal axotomy: first, the extremely

  20. Resistance of extraocular motoneuron terminals to effects of amyotrophic lateral sclerosis sera

    NASA Technical Reports Server (NTRS)

    Mosier, D. R.; Siklos, L.; Appel, S. H.

    2000-01-01

    In sporadic ALS (s-ALS), axon terminals contain increased intracellular calcium. Passively transferred sera from patients with s-ALS increase intracellular calcium in spinal motoneuron terminals in vivo and enhance spontaneous transmitter release, a calcium-dependent process. In this study, passive transfer of s-ALS sera increased spontaneous release from spinal but not extraocular motoneuron terminals, suggesting that the resistance to physiologic abnormalities induced by s-ALS sera in mice parallels the resistance of extraocular motoneurons to dysfunction and degeneration in ALS.

  1. The parallel growth of motoneuron axons with the dorsal aorta depends on Vegfc/Vegfr3 signaling in zebrafish

    PubMed Central

    Kwon, Hyouk-Bum; Fukuhara, Shigetomo; Asakawa, Kazuhide; Ando, Koji; Kashiwada, Takeru; Kawakami, Koichi; Hibi, Masahiko; Kwon, Young-Guen; Kim, Kyu-Won; Alitalo, Kari; Mochizuki, Naoki

    2013-01-01

    Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in motoneurons resulted in enhanced axon growth of motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary motoneurons. PMID:24046321

  2. Inhibition of motoneurons during the cutaneous silent period in the spinal cord of the turtle.

    PubMed

    Guzulaitis, Robertas; Hounsgaard, Jorn; Alaburda, Aidas

    2012-07-01

    The transient suppression of motor activity in the spinal cord after a cutaneous stimulus is termed the cutaneous silent period (CSP). It is not known if CSP is due to suppression of the premotor network or direct inhibition of motoneurons. This issue was examined by intracellular recordings from motoneurons in the isolated carapace-spinal cord preparation from adult turtles during rhythmic scratch-like reflex. Electrical stimulation of cutaneous nerves induced CSP-like suppression of motor nerve firing during rhythmic network activity. The stimulus that generated the CSP-like suppression of motor activity evokes a polysynaptic compound synaptic potential in motoneurons and suppressed their firing. This compound synaptic potential was hyperpolarizing near threshold for action potentials and was associated with a substantial increase in conductance during the CSP in the motor pool. These results show that direct postsynaptic inhibition of motoneurons contributes to the CSP. PMID:22580573

  3. Naturally occurring somatic motoneuron death in a teleost angelfish, Pterophyllum scalare.

    PubMed

    Sakamoto, H; Yoshida, M; Uematsu, K

    1999-05-28

    Naturally occurring somatic motoneuron death in a teleost angelfish, Pterophyllum scalare, was investigated histochemically and electron microscopically. The number of motor axons in the ventral root, which corresponds to the motoneuron number in spinal hemisegment, was rapidly increased beyond the adult value within 3 days after hatching, and then decreased to reach the adult value within a few weeks. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) histochemistry, which detects fragmented nuclear DNA characteristic to apoptotic cells, showed that the apoptotic cells are located in the motor column of the cord in the larvae at specific developmental stages. Electron microscopic observations of the spinal cells further confirmed the motoneuron apoptosis. The present data suggest that the massive death of somatic motoneurons at certain ontogenic stages which has been known to occur in higher vertebrates also takes place in fish. PMID:10400233

  4. Effect of quercetine on survival and morphological properties of cultured embryonic rat spinal motoneurones.

    PubMed

    Ternaux, Jean-Pierre; Portalier, Paule

    2002-10-25

    Quercetine a flavonoid compound present in many plants and in the extract of Ginkgo biloba was shown to enhance the survival of purified rat spinal embryonic motoneurones, sampled at day embryonic 15 and maintained in culture for several days. Survival of embryonic spinal motoneurones is dose dependent and concentrations of quercetine ranging from 1 to 10 microM increase by 25% the number of living motoneurones in the culture. Excepted a slight significant decrease in the number of branches at day 3 and a small reduction of total neuritic length, no drastic changes in the motoneurones morphologies were observed in presence of quercetine. Results are discussed in term of neuronal protective effect of quercetine. PMID:12377378

  5. Altered calcium homeostasis in spinal motoneurons but not in oculomotor neurons of SOD-1 knockout mice.

    PubMed

    Siklós, L; Engelhardt, J I; Reaume, A G; Scott, R W; Adalbert, R; Obál, I; Appel, S H

    2000-05-01

    SOD-1-deficient mice demonstrate no loss of motoneurons but are still vulnerable to axotomy and ischemic insults. To investigate possible reasons for vulnerability of motoneuron populations, we studied changes in ultrastructural calcium distribution during maturation in spinal- and oculomotor neurons in SOD-1(-/-) mice. Between 3 and 11 months the cytoplasmic component of the intracellular calcium changed at a lower rate in spinal motoneurons and motor axon terminals in the interosseus muscle of SOD-1(-/-) animals compared to wild-type controls. No such dissimilarities were noted in the oculomotor system, or in mitochondrial calcium contents of either cell type. These data suggest that the lack of SOD-1 may be associated with vulnerability to insult by depletion of non-mitochondrial calcium stores selectively in motoneurons lacking parvalbumin and/or calbindin D28K. PMID:10805095

  6. RNA content in spinal cord motoneurons during hypokinesia

    NASA Technical Reports Server (NTRS)

    Gorbunova, A. V.

    1980-01-01

    The effect of a diminished motor activity of rats upon the ribonucleic and (RNA) content in a single isolated motoneuron of frontal of their spinal cord was studied. Within a 1 to 30 day exposure of rats to the hypokinetic conditions, RNA content was found to decrease on the 1st, 3rd, and 5th day and to return to the initial level by the 7th day. No changes in RNA content were observed during the subsequent stages of the xperiments. The volume of the nerve cells declined on the 3rd and 5th day, whereas RNA concentration reduced on the 1st, 3rd, 5th, and 30th day.

  7. Influence of asphyxia upon the responses of spinal motoneurons.

    PubMed

    LLOYD, D P C

    1953-05-01

    Observations have been made upon asphyxial and postasphyxial changes in the electrical responses of motoneurons to antidromic stimulation. Analysis has been aided by the use of a simple method for locating conduction blocks in the circumstances of volume conduction. Asphyxiation has been produced by suspending artificial ventilation. Regular practice has been to restore ventilation immediately after complete conduction block is established. This has permitted study of the postasphyxial state, but not of the effects of prolonged asphyxiation with the latter of which this paper is not concerned. With asphyxiation produced in the manner outlined a latent period of approximately 1 minute precedes the onset of asphyxial change. The initial change, to judge by the work of others (6, 7), is beginning central depolarization. At the same time there is a severe loss of somatic after-potential (Fig. 1). Through this loss the dendrites acquire the ability to carry two volleys in rapid succession (Fig. 13). These changes appear to reach completion within approximately 30 seconds. There follows a period of convulsive activity during which reciprocal amplitude changes in the response of axons and dendrites prove that a fluctuation in somatic responsivity is taking place (Fig. 11). Intermittent impulse discharge in ventral roots is seen (Fig. 1). Conduction block may be developing slowly throughout the period of convulsive activity (Fig. 11). Frequently there is a rather definite instant at which convulsive activity ceases and a rapid development of block begins. Usually the recorded amplitude of the dendritic response then increases to a peak (the preterminal increment) before final disappearance (Figs. 9 to 11, 13 to 15). A variety of reasons has been advanced to show that this preterminal increment represents not increased response, but rather a developing block (Figs. 11 to 13). When fully established, asphyxial block is located at the junction of the initial and myelinated

  8. Marked and variable inhibition by chemical fixation of cytochrome oxidase and succinate dehydrogenase in single motoneurons

    NASA Technical Reports Server (NTRS)

    Chalmers, G. R.; Edgerton, V. R.

    1989-01-01

    The effect of tissue fixation on succinate dehydrogenase and cytochrome oxidase activity in single motoneurons of the rat was demonstrated using a computer image processing system. Inhibition of enzyme activity by chemical fixation was variable, with some motoneurons being affected more than others. It was concluded that quantification of enzymatic activity in chemically fixed tissue provides an imprecise estimate of enzyme activities found in fresh-frozen tissues.

  9. Motoneuron axon pathfinding errors in zebrafish: Differential effects related to concentration and timing of nicotine exposure

    SciTech Connect

    Menelaou, Evdokia; Paul, Latoya T.; Perera, Surangi N.; Svoboda, Kurt R.

    2015-04-01

    Nicotine exposure during embryonic stages of development can affect many neurodevelopmental processes. In the developing zebrafish, exposure to nicotine was reported to cause axonal pathfinding errors in the later born secondary motoneurons (SMNs). These alterations in SMN axon morphology coincided with muscle degeneration at high nicotine concentrations (15–30 μM). Previous work showed that the paralytic mutant zebrafish known as sofa potato exhibited nicotine-induced effects onto SMN axons at these high concentrations but in the absence of any muscle deficits, indicating that pathfinding errors could occur independent of muscle effects. In this study, we used varying concentrations of nicotine at different developmental windows of exposure to specifically isolate its effects onto subpopulations of motoneuron axons. We found that nicotine exposure can affect SMN axon morphology in a dose-dependent manner. At low concentrations of nicotine, SMN axons exhibited pathfinding errors, in the absence of any nicotine-induced muscle abnormalities. Moreover, the nicotine exposure paradigms used affected the 3 subpopulations of SMN axons differently, but the dorsal projecting SMN axons were primarily affected. We then identified morphologically distinct pathfinding errors that best described the nicotine-induced effects on dorsal projecting SMN axons. To test whether SMN pathfinding was potentially influenced by alterations in the early born primary motoneuron (PMN), we performed dual labeling studies, where both PMN and SMN axons were simultaneously labeled with antibodies. We show that only a subset of the SMN axon pathfinding errors coincided with abnormal PMN axonal targeting in nicotine-exposed zebrafish. We conclude that nicotine exposure can exert differential effects depending on the levels of nicotine and developmental exposure window. - Highlights: • Embryonic nicotine exposure can specifically affect secondary motoneuron axons in a dose-dependent manner.

  10. Extensor motoneurone properties are altered immediately before and during fictive locomotion in the adult decerebrate rat.

    PubMed

    MacDonell, C W; Power, K E; Chopek, J W; Gardiner, K R; Gardiner, P F

    2015-05-15

    This study examined motoneurone properties during fictive locomotion in the adult rat for the first time. Fictive locomotion was induced via electrical stimulation of the mesencephalic locomotor region in decerebrate adult rats under neuromuscular blockade to compare basic and rhythmic motoneurone properties in antidromically identified extensor motoneurones during: (1) quiescence, before and after fictive locomotion; (2) the 'tonic' period immediately preceding locomotor-like activity, whereby the amplitude of peripheral flexor (peroneal) and extensor (tibial) nerves are increased but alternation has not yet occurred; and (3) locomotor-like episodes. Locomotion was identified by alternating flexor-extensor nerve activity, where the motoneurone either produced membrane oscillations consistent with a locomotor drive potential (LDP) or did not display membrane oscillation during alternating nerve activity. Cells producing LDPs were referred to as such, while those that did not were referred to as 'idle' motoneurones. LDP and idle motoneurones during locomotion had hyperpolarized spike threshold (Vth ; LDP: 3.8 mV; idle: 5.8 mV), decreased rheobase and an increased discharge rate (LDP: 64%; idle: 41%) during triangular ramp current injection even though the frequency-current slope was reduced by 70% and 55%, respectively. Modulation began in the tonic period immediately preceding locomotion, with a hyperpolarized Vth and reduced rheobase. Spike frequency adaptation did not occur in spiking LDPs or firing generated from sinusoidal current injection, but occurred during a sustained current pulse during locomotion. Input conductance showed no change. Results suggest motoneurone modulation occurs across the pool and is not restricted to motoneurones engaged in locomotion. PMID:25809835

  11. Nitrergic innervation of trigeminal and hypoglossal motoneurons in the cat.

    PubMed

    Pose, Ines; Fung, Simon; Sampogna, Sharon; Chase, Michael H; Morales, Francisco R

    2005-04-11

    The present study was undertaken to determine the location of trigeminal and hypoglossal premotor neurons that express neuronal nitric oxide synthase (nNOS) in the cat. Cholera toxin subunit b (CTb) was injected into the trigeminal (mV) or the hypoglossal (mXII) motor nuclei in order to label the corresponding premotor neurons. CTb immunocytochemistry was combined with NADPH-d histochemistry or nNOS immunocytochemistry to identify premotor nitrergic (NADPH-d(+)/CTb(+) or nNOS(+)/ CTb(+) double-labeled) neurons. Premotor trigeminal as well as premotor hypoglossal neurons were located in the ventro-medial medullary reticular formation in a region corresponding to the nucleus magnocellularis (Mc) and the ventral aspect of the nucleus reticularis gigantocellularis (NRGc). Following the injection of CTb into the mV, this region was found to contain a total of 60 +/- 15 double-labeled neurons on the ipsilateral side and 33 +/- 14 on the contralateral side. CTb injections into the mXII resulted in 40 +/- 17 double-labeled neurons in this region on the ipsilateral side and 16 +/- 5 on the contralateral side. Thus, we conclude that premotor trigeminal and premotor hypoglossal nitrergic cells coexist in the same medullary region. They are colocalized with a larger population of nitrergic cells (7200 +/- 23). Premotor neurons in other locations did not express nNOS. The present data demonstrate that a population of neurons within the Mc and the NRGc are the source of the nitrergic innervation of trigeminal and hypoglossal motoneurons. Based on the characteristics of nitric oxide actions and its diffusibility, we postulate that these neurons may serve to synchronize the activity of mV and mXII motoneurons. PMID:15804497

  12. Reversal of the late phase of spike frequency adaptation in cat spinal motoneurons during fictive locomotion.

    PubMed

    Brownstone, Robert M; Krawitz, Sherry; Jordan, Larry M

    2011-03-01

    In spinal motoneurons, late spike frequency adaptation (SFA) is defined as the slowing of the firing rate over tens of seconds and can be seen during sustained or intermittent current injection. Although the function of late SFA is not known, it may result in a decrease in force production over time, or muscle fatigue. Because locomotion can persist for long periods of time without fatigue, late SFA was studied using intracellular recordings from adult cat motoneurons during fictive locomotion. Of eight lumbar motoneurons studied, all showed late adaptation during control conditions, but none demonstrated late adaptation during locomotor activity. The most consistent properties that correlated with the presence or absence of late SFA were those related to availability of fast, inactivating sodium channels, particularly action potential rate of rise. Evidence of the reversal of late SFA during locomotion was present for several minutes following locomotor trials, consistent with the suggestion that SFA is modulated through slow metabotropic pathways. The abolition of late adaptation in spinal motoneurons during fictive locomotion is an example of a state-dependent change in the "intrinsic" properties of mammalian motoneurons. This change contributes to increased excitability of motoneurons during locomotion and results in robust firing during sustained locomotion. PMID:21177992

  13. Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability.

    PubMed

    Fritz, Elsa; Izaurieta, Pamela; Weiss, Alexandra; Mir, Franco R; Rojas, Patricio; Gonzalez, David; Rojas, Fabiola; Brown, Robert H; Madrid, Rodolfo; van Zundert, Brigitte

    2013-06-01

    Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motoneurons starting in adulthood. Recent studies using cell or animal models document that astrocytes expressing disease-causing mutations of human superoxide dismutase 1 (hSOD1) contribute to the pathogenesis of ALS by releasing a neurotoxic factor(s). Neither the mechanism by which this neurotoxic factor induces motoneuron death nor its cellular site of action has been elucidated. Here we show that acute exposure of primary wild-type spinal cord cultures to conditioned medium derived from astrocytes expressing mutant SOD1 (ACM-hSOD1(G93A)) increases persistent sodium inward currents (PC(Na)), repetitive firing, and intracellular calcium transients, leading to specific motoneuron death days later. In contrast to TTX, which paradoxically increased twofold the amplitude of calcium transients and killed motoneurons, reduction of hyperexcitability by other specific (mexiletine) and nonspecific (spermidine and riluzole) blockers of voltage-sensitive sodium (Na(v)) channels restored basal calcium transients and prevented motoneuron death induced by ACM-hSOD1(G93A). These findings suggest that riluzole, the only FDA-approved drug with known benefits for ALS patients, acts by inhibiting hyperexcitability. Together, our data document that a critical element mediating the non-cell-autonomous toxicity of ACM-hSOD1(G93A) on motoneurons is increased excitability, an observation with direct implications for therapy of ALS. PMID:23486205

  14. Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability

    PubMed Central

    Fritz, Elsa; Izaurieta, Pamela; Weiss, Alexandra; Mir, Franco R.; Rojas, Patricio; Gonzalez, David; Rojas, Fabiola; Brown, Robert H.; Madrid, Rodolfo

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motoneurons starting in adulthood. Recent studies using cell or animal models document that astrocytes expressing disease-causing mutations of human superoxide dismutase 1 (hSOD1) contribute to the pathogenesis of ALS by releasing a neurotoxic factor(s). Neither the mechanism by which this neurotoxic factor induces motoneuron death nor its cellular site of action has been elucidated. Here we show that acute exposure of primary wild-type spinal cord cultures to conditioned medium derived from astrocytes expressing mutant SOD1 (ACM-hSOD1G93A) increases persistent sodium inward currents (PCNa), repetitive firing, and intracellular calcium transients, leading to specific motoneuron death days later. In contrast to TTX, which paradoxically increased twofold the amplitude of calcium transients and killed motoneurons, reduction of hyperexcitability by other specific (mexiletine) and nonspecific (spermidine and riluzole) blockers of voltage-sensitive sodium (Nav) channels restored basal calcium transients and prevented motoneuron death induced by ACM-hSOD1G93A. These findings suggest that riluzole, the only FDA-approved drug with known benefits for ALS patients, acts by inhibiting hyperexcitability. Together, our data document that a critical element mediating the non-cell-autonomous toxicity of ACM-hSOD1G93A on motoneurons is increased excitability, an observation with direct implications for therapy of ALS. PMID:23486205

  15. Tonic inhibition and ponto-geniculo-occipital-related activities shape abducens motoneuron discharge during REM sleep

    PubMed Central

    Escudero, Miguel; Márquez-Ruiz, Javier

    2008-01-01

    Eye movements, ponto-geniculo-occipital (PGO) waves, muscular atonia and desynchronized cortical activity are the main characteristics of rapid eye movement (REM) sleep. Although eye movements designate this phase, little is known about the activity of the oculomotor system during REM sleep. In this work, we recorded binocular eye movements by the scleral search-coil technique and the activity of identified abducens (ABD) motoneurons along the sleep–wake cycle in behaving cats. The activity of ABD motoneurons during REM sleep was characterized by a tonic decrease of their mean firing rate throughout this period, and short bursts and pauses coinciding with the occurrence of PGO waves. We demonstrate that the decrease in the mean firing discharge was due to an active inhibition of ABD motoneurons, and that the occurrence of primary and secondary PGO waves induced a pattern of simultaneous but opposed phasic activation and inhibition on each ABD nucleus. With regard to eye movements, during REM sleep ABD motoneurons failed to codify eye position as during alertness, but continued to codify eye velocity. The pattern of tonic inhibition and the phasic activations and inhibitions shown by ABD motoneurons coincide with those reported in other non-oculomotor motoneurons, indicating that the oculomotor system – contrary to what has been accepted until now – is not different from other motor systems during REM sleep, and that all motor systems are receiving similar command signals during this period. PMID:18499728

  16. Drive latencies in hypoglossal motoneurons indicate developmental change in the brainstem respiratory network

    NASA Astrophysics Data System (ADS)

    Fietkiewicz, Christopher; Loparo, Kenneth A.; Wilson, Christopher G.

    2011-10-01

    The respiratory rhythm originates and diverges from the brainstem to drive thousands of motoneurons that are responsible for control of the diaphragm, intercostals and upper airway. These motoneurons are known to have a wide range of phase relationships, even within a single motoneuron pool. The proposed source of this rhythm, the preBötzinger complex (preBötC), responds to an array of developmental changes in the first days post-birth, specifically at postnatal day 3 (P3). We hypothesize that such developmental changes in the preBötC have a direct effect on motoneuron phase relationships and should be detectable around age P3. To test our hypothesis, we obtained single- and dual-voltage-clamp recordings of hypoglossal motoneurons in an in vitro slice preparation. We introduce a novel approach to analyzing the phase relationships between motoneurons by using cross-correlation analysis to determine the drive latencies. This analysis reveals that the distribution of drive latencies undergoes a significant change at or before age P3. We use a computational model of the in vitro slice to demonstrate the observed phase differences and hypothesize that network heterogeneity alone may not be sufficient to explain them. Through simulations, we show the effects on the preBötC of different network characteristics such as clustering and common inputs.

  17. Time course of human motoneuron recovery after sustained low-level voluntary activity.

    PubMed

    Héroux, Martin E; Butler, Annie A; Gandevia, Simon C; Taylor, Janet L; Butler, Jane E

    2016-02-01

    Motoneurons often fire repetitively and for long periods. In sustained voluntary contractions the excitability of motoneurons declines. We provide the first detailed description of the time course of human motoneuron recovery after sustained activity at a constant discharge rate. We recorded the discharge of single motor units (MUs, n = 30) with intramuscular wire electrodes inserted in triceps brachii during weak isometric contractions. Subjects (n = 15) discharged single MUs at a constant frequency (∼10 Hz) with visual feedback for prolonged durations (3-7 min) until rectified surface electromyogram (sEMG) of triceps brachii increased by ∼100%. After a rest of 1-2, 15, 30, 60, 120, or 240 s, subjects briefly resumed the contraction with the target MU at the same discharge rate. Each MU was tested with three to four rest periods. The magnitude of sEMG was increased when contractions were resumed, and the target motoneuron discharged at the test frequency following rest intervals of 2-60 s (P = 0.001-0.038). The increased sEMG indicates that greater excitatory drive was needed to discharge the motoneuron at the test rate. The increase in EMG recovered exponentially with a time constant of 28 s but did not return to baseline even after a rest period of ∼240 s. Thus the decline in motoneuron excitability from a weak contraction takes several minutes to recover fully. PMID:26609117

  18. Improved regeneration after femoral nerve injury in mice lacking functional T- and B-lymphocytes.

    PubMed

    Mehanna, Ali; Szpotowicz, Emanuela; Schachner, Melitta; Jakovcevski, Igor

    2014-11-01

    The immune system plays important functional roles in regeneration after injury to the mammalian central and peripheral nervous systems. After damage to the peripheral nerve several types of immune cells, invade the nerve within hours after the injury. To gain insights into the contribution of T- and B-lymphocytes to recovery from injury we used the mouse femoral nerve injury paradigm. RAG2-/- mice lacking mature T- and B-lymphocytes due to deletion of the recombination activating gene 2 were subjected to resection and surgical reconstruction of the femoral nerve, with the wild-type mice of the same inbred genetic background serving as controls. According to single frame motion analyses, RAG2-/- mice showed better motor recovery in comparison to control mice at four and eight weeks after injury. Retrograde tracing of regrown/sprouted axons of spinal motoneurons showed increased numbers of correctly projecting motoneurons in the lumbar spinal cord of RAG2-/- mice compared with controls. Whereas there was no difference in the motoneuron soma size between genotypes, RAG2-/- mice displayed fewer cholinergic and inhibitory synaptic terminals around somata of spinal motoneurons both prior to and after injury, compared with wild-type mice. Extent of myelination of regrown axons in the motor branch of the femoral nerve measured as g-ratio was more extensive in RAG2-/- than in control mice eight weeks after injury. We conclude that activated T- and B-lymphocytes restrict motor recovery after femoral nerve injury, associated with the increased survival of motoneurons and improved remyelination. PMID:24967682

  19. Synaptic Connectivity between Renshaw Cells and Motoneurons in the Recurrent Inhibitory Circuit of the Spinal Cord

    PubMed Central

    Moore, Niall J.; Bhumbra, Gardave S.; Foster, Joshua D.

    2015-01-01

    Renshaw cells represent a fundamental component of one of the first discovered neuronal circuits, but their function in motor control has not been established. They are the only central neurons that receive collateral projections from motor outputs, yet the efficacy of the excitatory synapses from single and converging motoneurons remains unknown. Here we present the results of dual whole-cell recordings from identified, synaptically connected Renshaw cell-motoneuron pairs in the mouse lumbar spinal cord. The responses from single Renshaw cells demonstrate that motoneuron synapses elicit large excitatory conductances with few or no failures. We show that the strong excitatory input from motoneurons results from a high probability of neurotransmitter release onto multiple postsynaptic contacts. Dual current-clamp recordings confirm that single motoneuron inputs were sufficient to depolarize the Renshaw cell beyond threshold for firing. Reciprocal connectivity was observed in approximately one-third of the paired recordings tested. Ventral root stimulation was used to evoke currents from Renshaw cells or motoneurons to characterize responses of single neurons to the activation of their corresponding presynaptic cell populations. Excitatory or inhibitory synaptic inputs in the recurrent inhibitory loop induced substantial effects on the excitability of respective postsynaptic cells. Quantal analysis estimates showed a large number of converging inputs from presynaptic motoneuron and Renshaw cell populations. The combination of considerable synaptic efficacy and extensive connectivity within the recurrent circuitry indicates a role of Renshaw cells in modulating motor outputs that may be considerably more important than has been previously supposed. SIGNIFICANCE STATEMENT We have recently shown that Renshaw cells mediate powerful shunt inhibition on motoneuron excitability. Here we complete a quantitative description of the recurrent circuit using recordings of

  20. Changes in electrophysiological properties of cat hypoglossal motoneurons during carbachol-induced motor inhibition.

    PubMed

    Fung, S J; Yamuy, J; Xi, M C; Engelhardt, J K; Morales, F R; Chase, M H

    2000-12-01

    The control of hypoglossal motoneurons during sleep is important from a basic science perspective as well as to understand the bases for pharyngeal occlusion which results in the obstructive sleep apnea syndrome. In the present work, we used intracellular recording techniques to determine changes in membrane properties in adult cats in which atonia was produced by the injection of carbachol into the pontine tegmentum (AS-carbachol). During AS-carbachol, 86% of the recorded hypoglossal motoneurons were found to be postsynaptically inhibited on the basis of analyses of their electrical properties; the electrical properties of the remaining 14% were similar to motoneurons recorded during control conditions. Those cells that exhibited changes in their electrical properties during AS-carbachol also displayed large-amplitude inhibitory synaptic potentials. Following sciatic nerve stimulation, hypoglossal motoneurons which responded with a depolarizing potential during control conditions exhibited a hyperpolarizing potential during AS-carbachol. Both spontaneous and evoked inhibitory potentials recorded during AS-carbachol were comparable to those that have been previously observed in trigeminal and spinal cord motoneurons under similar experimental conditions as well as during naturally occurring active sleep. Calculations based on modeling the changes that we found in input resistance and membrane time constant with a three-compartment neuron model suggest that shunts are present in all three compartments of the hypoglossal motoneuron model. Taken together, these data indicate that postsynaptic inhibitory drives are widely distributed on the soma-dendritic tree of hypoglossal motoneurons during AS-carbachol. These postsynaptic inhibitory actions are likely to be involved in the pathophysiology of obstructive sleep apnea. PMID:11102580

  1. Glutamate uptake block triggers deadly rhythmic bursting of neonatal rat hypoglossal motoneurons

    PubMed Central

    Sharifullina, Elina; Nistri, Andrea

    2006-01-01

    In the brain the extracellular concentration of glutamate is controlled by glial transporters that restrict the neurotransmitter action to synaptic sites and avoid excitotoxicity. Impaired transport of glutamate occurs in many cases of amyotrophic lateral sclerosis, a devastating motoneuron disease. Motoneurons of the brainstem nucleus hypoglossus are among the most vulnerable, giving early symptoms like slurred speech and dysphagia. However, the direct consequences of extracellular glutamate build-up, due to uptake block, on synaptic transmission and survival of hypoglossal motoneurons remain unclear and have been studied using the neonatal rat brainstem slice preparation as a model. Patch clamp recording from hypoglossal motoneurons showed that, in about one-third of these cells, inhibition of glutamate transport with the selective blocker dl-threo-β-benzyloxyaspartate (TBOA; 50 μ m) unexpectedly led to the emergence of rhythmic bursting consisting of inward currents of long duration with superimposed fast oscillations and synaptic events. Synaptic inhibition block facilitated bursting. Bursts had a reversal potential near 0 mV, and were blocked by tetrodotoxin, the gap junction blocker carbenoxolone, or antagonists of AMPA, NMDA or mGluR1 glutamate receptors. Intracellular Ca2+ imaging showed bursts as synchronous discharges among motoneurons. Synergy of activation of distinct classes of glutamate receptor plus gap junctions were therefore essential for bursting. Ablating the lateral reticular formation preserved bursting, suggesting independence from propagated network activity within the brainstem. TBOA significantly increased the number of dead motoneurons, an effect prevented by the same agents that suppressed bursting. Bursting thus represents a novel hallmark of motoneuron dysfunction triggered by glutamate uptake block. PMID:16455692

  2. Basic electrophysiological properties of spinal cord motoneurons during old age in the cat.

    PubMed

    Morales, F R; Boxer, P A; Fung, S J; Chase, M H

    1987-07-01

    1. The electrophysiological properties of alpha-motoneurons in old cats (14-15 yr) were compared with those of adult cats (1-3 yr). These properties were measured utilizing intracellular recording and stimulating techniques. 2. Unaltered in the old cat motoneurons were the membrane potential, action potential amplitude, and slopes of the initial segment (IS) and soma dendritic (SD) spikes, as well as the duration and amplitude of the action potential's afterhyperpolarization. 3. In contrast, the following changes in the electrophysiological properties of lumbar motoneurons were found in the old cats: a decrease in axonal conduction velocity, a shortening of the IS-SD delay, an increase in input resistance, and a decrease in rheobase. 4. In spite of these considerable changes in motoneuron properties in the old cat, normal correlations between different electrophysiological properties were maintained. The following key relationships, among others, were the same in adult and old cat motoneurons: membrane potential polarization versus action potential amplitude, duration of the afterhyperpolarization versus motor axon conduction velocity, and rheobase versus input conductance. 5. A review of the existing literature reveals that neither chronic spinal cord section nor deafferentation (13, 21) in adult animals produce the changes observed in old cats. Thus we consider it unlikely that a loss of synaptic contacts was responsible for the modifications in electrophysiological properties observed in old cat motoneurons. 6. We conclude that during old age there are significant changes in the soma-dendritic portion of cat motoneurons, as indicated by the modifications found in input resistance, rheobase, and IS-SD delay, as well as significant changes in their axons, as indicated by a decrease in conduction velocity. PMID:3612223

  3. Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection.

    PubMed

    Erceg, Slaven; Ronaghi, Mohammad; Oria, Marc; Roselló, Mireia García; Aragó, Maria Amparo Pérez; Lopez, Maria Gomez; Radojevic, Ivana; Moreno-Manzano, Victoria; Rodríguez-Jiménez, Francisco-Javier; Bhattacharya, Shom Shanker; Cordoba, Juan; Stojkovic, Miodrag

    2010-09-01

    Human embryonic stem cells (hESC) hold great promise for the treatment of patients with many neurodegenerative diseases particularly those arising from cell loss or neural dysfunction including spinal cord injury. This study evaluates the therapeutic effects of transplanted hESC-derived oligodendrocyte progenitors (OPC) and/or motoneuron progenitors (MP) on axonal remyelination and functional recovery of adult rats after complete spinal cord transection. OPC and/or MP were grafted into the site of injury in the acute phase. Based on Basso-Beattie-Bresnahan scores recovery of locomotor function was significantly enhanced in rats treated with OPC and/or MP when compared with control animals. When transplanted into the spinal cord immediately after complete transection, OPC and MP survived, migrated, and differentiated into mature oligodendrocytes and neurons showing in vivo electrophysiological activity. Taken together, these results indicate that OPC and MP derived from hESC could be a useful therapeutic strategy to repair injured spinal cord. PMID:20665739

  4. Transplanted Oligodendrocytes and Motoneuron Progenitors Generated from Human Embryonic Stem Cells Promote Locomotor Recovery After Spinal Cord Transection

    PubMed Central

    Erceg, Slaven; Ronaghi, Mohammad; Oria, Marc; García Roselló, Mireia; Aragó, Maria Amparo Pérez; Lopez, Maria Gomez; Radojevic, Ivana; Moreno-Manzano, Victoria; Rodríguez-Jiménez, Francisco-Javier; Shanker Bhattacharya, Shom; Cordoba, Juan; Stojkovic, Miodrag

    2010-01-01

    Human embryonic stem cells (hESC) hold great promise for the treatment of patients with many neurodegenerative diseases particularly those arising from cell loss or neural dysfunction including spinal cord injury. This study evaluates the therapeutic effects of transplanted hESC-derived oligodendrocyte progenitors (OPC) and/or motoneuron progenitors (MP) on axonal remyelination and functional recovery of adult rats after complete spinal cord transection. OPC and/or MP were grafted into the site of injury in the acute phase. Based on Basso-Beattie-Bresnahan scores recovery of locomotor function was significantly enhanced in rats treated with OPC and/or MP when compared with control animals. When transplanted into the spinal cord immediately after complete transection, OPC and MP survived, migrated, and differentiated into mature oligodendrocytes and neurons showing in vivo electrophysiological activity. Taken together, these results indicate that OPC and MP derived from hESC could be a useful therapeutic strategy to repair injured spinal cord. Stem Cells 2010; 28:1541–1549. PMID:20665739

  5. Dependence of phrenic motoneurone output on the oscillatory component of arterial blood gas composition.

    PubMed Central

    Cross, B A; Grant, B J; Guz, A; Jones, P W; Semple, S J; Stidwill, R P

    1979-01-01

    1. The hypothesis that respiratory oscillations of arterial blood gas composition influence ventilation has been examined. 2. Phrenic motoneurone output recorded in the C5 root of the left phrenic nerve and the respiratory oscillations of arterial pH in the right common carotid artery were measured in vagotomized anaesthetized dogs which had been paralysed and artificially ventilated. 3. The effect of a change in tidal volume for one or two breaths on phrenic motoneurone output was measured with the inspiratory pump set at a constant frequency similar to, and in phase with, the animal's own respiratory frequency. A reduction of tidal volume to zero or an increase by 30% led to a corresponding change of mean carotid artery pH level. The changes of carotid artery pH resulted in a change of phrenic motoneurone output, predominantly of expiratory time (Te) but to a lesser extent of inspiratory time (T1) and also peak amplitude of 'integrated' phrenic motoneurone output (Phr). Denervation of the carotid bifurcation blocked this response. 4. The onset of movement of the inspiratory pump was triggered by the onset of phrenic motoneurone output. When a time delay was interposed between them, the phase relationship between respiratory oscillations of arterial pH and phrenic motoneurone output altered. The dominant effect was to alter Te; smaller and less consistent changes of Phr and T1 were observed. 5. When the inspiratory pump was maintained at a constant frequency but independent of and slightly different from the animal's own respiratory frequency (as judged by phrenic motoneurone output), the phase relationship between phrenic motoneurone output and the respiratory oscillations of pH changed breath by breath over a sequence of 100-200 breaths, without change of the mean level of arterial blood gas composition. Te varied by up to 30% about its mean value depending on the phase relationship. Ti and Phr were also dependent on the phase relationship but varied to a lesser

  6. How shunting inhibition affects the discharge of lumbar motoneurones: a dynamic clamp study in anaesthetized cats

    PubMed Central

    Brizzi, L; Meunier, C; Zytnicki, D; Donnet, M; Hansel, D; d'Incamps, B Lamotte; van Vreeswijk, C

    2004-01-01

    In the present work, dynamic clamp was used to inject a current that mimicked tonic synaptic activity in the soma of cat lumbar motoneurones with a microelectrode. The reversal potential of this current could be set at the resting potential so as to prevent membrane depolarization or hyperpolarization. The only effect of the dynamic clamp was then to elicit a constant and calibrated increase of the motoneurone input conductance. The effect of the resulting shunt was investigated on repetitive discharges elicited by current pulses. Shunting inhibition reduced very substantially the firing frequency in the primary range without changing the slope of the current–frequency curves. The shift of the I–f curve was proportional to the conductance increase imposed by the dynamic clamp and depended on an intrinsic property of the motoneurone that we called the shunt potential. The shunt potential ranged between 11 and 37 mV above the resting potential, indicating that the sensitivity of motoneurones to shunting inhibition was quite variable. The shunt potential was always near or above the action potential voltage threshold. A theoretical model allowed us to interpret these experimental results. The shunt potential was shown to be a weighted time average of membrane voltage. The weighting factor is the phase response function of the neurone that peaks at the end of the interspike interval. The shunt potential indicates whether mixed synaptic inputs have an excitatory or inhibitory effect on the ongoing discharge of the motoneurone. PMID:15169842

  7. The tight relationship between asymmetric signaling and locational excitability in motoneuron dendrites

    PubMed Central

    Kim, Hojeong; Heckman, C J

    2015-01-01

    Spinal motoneurons possess large, highly branching dendritic structures that contain thousands of synaptic contacts and various voltage-gated ion channels (VGICs). Research has indicated that dendritic arborization and cable properties provide the basis for foundational dendritic processing, which is characterized by direction-dependent signal propagation and location-dependent channel activation in dendritic arbors. Due to these arbors' complex structure, signals attenuate differentially depending on whether propagation occurs from the soma to the dendrite or in the opposite direction. In addition, current thresholds for the activation of dendritic ion channels differ depending on the location of these channels within dendrites. However, whether and how these foundational properties for dendritic signaling and excitability are related in motoneurons remains unclear. Based on our analyses of anatomically reconstructed motoneurons and novel reduced models, we propose that 1) directional signal propagation is similar across spinal motoneurons, regardless of cell type-specific structures; 2) reduced models that retain dendritic signaling asymmetry can accurately replicate anatomical dendritic excitability in both passive and active modes; and 3) asymmetric signal propagation and locational dendritic excitability are closely related, irrespective of motoneurons' arbor structures. PMID:27066175

  8. Alpha-7 and alpha-4 nicotinic receptor subunit immunoreactivity in genioglossus muscle motoneurons.

    PubMed

    Dehkordi, Ozra; Millis, Richard M; Dennis, Gary C; Coleman, Bernell R; Johnson, Sheree M; Changizi, Loubat; Ovid Trouth, C

    2005-02-15

    In the present study, immunohistochemistry combined with retrograde labeling techniques were used to determine if hypoglossal motoneurons (HMNs), retrogradely labeled after cholera toxin B subunit (CTB) injection to the genioglossus muscle in rats, show immunoreactivity for alpha-7 and alpha-4 subunits of nicotinic acetylcholine receptors (nAChRs). CTB-positive HMNs projecting to the genioglossus muscle were consistently labeled throughout the rostrocaudal extent of the hypoglossal nuclei with the greatest labeling at and caudal to area postrema. Alpha-7 subunit immunoreactivity was found in 39.44+/-5.10% of 870 CTB-labeled motoneurons and the alpha-4 subunit in 51.01+/-3.71% of 983 CTB-positive neurons. Rostrally, the number of genioglossal motoneurons demonstrating immunoreactivity for the alpha-7 subunit was 45.85+/-10.04% compared to 34.96+/-5.11% at and caudal to area postrema (P>0.1). The number of genioglossal motoneurons that showed immunoreactivity for the alpha-4 subunit was 55.03+/-4.83% at and caudal to area postrema compared to 42.98+/-3.90% in rostral areas (P=0.074). These results demonstrate that nAChR immunoreactivity is present in genioglossal motoneurons and suggest a role for alpha-7 and alpha-4 subunits containing nAChRs in the regulation of upper airway patency. PMID:15705531

  9. Uncoupling nicotine mediated motoneuron axonal pathfinding errors and muscle degeneration in zebrafish

    SciTech Connect

    Welsh, Lillian; Tanguay, Robert L.; Svoboda, Kurt R.

    2009-05-15

    Zebrafish embryos offer a unique opportunity to investigate the mechanisms by which nicotine exposure impacts early vertebrate development. Embryos exposed to nicotine become functionally paralyzed by 42 hpf suggesting that the neuromuscular system is compromised in exposed embryos. We previously demonstrated that secondary spinal motoneurons in nicotine-exposed embryos were delayed in development and that their axons made pathfinding errors (Svoboda, K.R., Vijayaraghaven, S., Tanguay, R.L., 2002. Nicotinic receptors mediate changes in spinal motoneuron development and axonal pathfinding in embryonic zebrafish exposed to nicotine. J. Neurosci. 22, 10731-10741). In that study, we did not consider the potential role that altered skeletal muscle development caused by nicotine exposure could play in contributing to the errors in spinal motoneuron axon pathfinding. In this study, we show that an alteration in skeletal muscle development occurs in tandem with alterations in spinal motoneuron development upon exposure to nicotine. The alteration in the muscle involves the binding of nicotine to the muscle-specific AChRs. The nicotine-induced alteration in muscle development does not occur in the zebrafish mutant (sofa potato, [sop]), which lacks muscle-specific AChRs. Even though muscle development is unaffected by nicotine exposure in sop mutants, motoneuron axonal pathfinding errors still occur in these mutants, indicating a direct effect of nicotine exposure on nervous system development.

  10. The use of dendrograms to describe the electrical activity of motoneurons underlying behaviors in leeches

    PubMed Central

    Juárez-Hernández, León J.; Bisson, Giacomo; Torre, Vincent

    2013-01-01

    The present manuscript aims at identifying patterns of electrical activity recorded from neurons of the leech nervous system, characterizing specific behaviors. When leeches are at rest, the electrical activity of neurons and motoneurons is poorly correlated. When leeches move their head and/or tail, in contrast, action potential (AP) firing becomes highly correlated. When the head or tail suckers detach, specific patterns of electrical activity are detected. During elongation and contraction the electrical activity of motoneurons in the Medial Anterior and Dorsal Posterior nerves increase, respectively, and several motoneurons are activated both during elongation and contraction. During crawling, swimming, and pseudo-swimming patterns of electrical activity are better described by the dendrograms of cross-correlations of motoneurons pairs. Dendrograms obtained from different animals exhibiting the same behavior are similar and by averaging these dendrograms we obtained a template underlying a given behavior. By using this template, the corresponding behavior is reliably identified from the recorded electrical activity. The analysis of dendrograms during different leech behavior reveals the fine orchestration of motoneurons firing specific to each stereotyped behavior. Therefore, dendrograms capture the subtle changes in the correlation pattern of neuronal networks when they become involved in different tasks or functions. PMID:24098274

  11. The tight relationship between asymmetric signaling and locational excitability in motoneuron dendrites.

    PubMed

    Kim, Hojeong; Heckman, C J

    2015-01-01

    Spinal motoneurons possess large, highly branching dendritic structures that contain thousands of synaptic contacts and various voltage-gated ion channels (VGICs). Research has indicated that dendritic arborization and cable properties provide the basis for foundational dendritic processing, which is characterized by direction-dependent signal propagation and location-dependent channel activation in dendritic arbors. Due to these arbors' complex structure, signals attenuate differentially depending on whether propagation occurs from the soma to the dendrite or in the opposite direction. In addition, current thresholds for the activation of dendritic ion channels differ depending on the location of these channels within dendrites. However, whether and how these foundational properties for dendritic signaling and excitability are related in motoneurons remains unclear. Based on our analyses of anatomically reconstructed motoneurons and novel reduced models, we propose that 1) directional signal propagation is similar across spinal motoneurons, regardless of cell type-specific structures; 2) reduced models that retain dendritic signaling asymmetry can accurately replicate anatomical dendritic excitability in both passive and active modes; and 3) asymmetric signal propagation and locational dendritic excitability are closely related, irrespective of motoneurons' arbor structures. PMID:27066175

  12. Motoneuron differentiation of induced pluripotent stem cells from SOD1G93A mice.

    PubMed

    Yao, Xiao-Li; Ye, Cheng-Hui; Liu, Qiang; Wan, Jian-bo; Zhen, Jun; Xiang, Andy Peng; Li, Wei-Qiang; Wang, Yitao; Su, Huangxing; Lu, Xi-Lin

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder mainly affecting motor neurons. Mutations in superoxide dismutase-1 (SOD-1) account for about 20% of familial ALS patients. A robust supply of motoneurons carrying the mutated gene would help understand the causes of motoneuron death and develop new therapeutics for the disease. Here, we established induced pluripotent stem (iPS) cell lines from SOD1G93A mice and compared their potency in motoneuron generation with normal iPS cells and mouse embryonic stem cells (E14). Our results showed that iPS cells derived from SOD1G93A mice possessed the similar potency in neuronal differentiation to normal iPS cells and E14 cells and can be efficiently driven to motoneuron-like phenotype. These cells exhibited typical neuronal morphology, expressed key motoneuron markers, including ChAT and HB9, and generated repetitive trains of action potentials. Furthermore, these neurons highly expressed human SOD-1 and exhibited shorter neurites compared to controls. The present study provides evidence that ALS-iPS cells can be used as disease models in high-throughput screening and mechanistic studies due to their ability to efficiently differentiate into specific neuronal subtypes. PMID:23724084

  13. Anesthetic isoflurane attenuates activated microglial cytokine-induced VSC4.1 motoneuronal apoptosis

    PubMed Central

    Yang, Shuangmei; Liu, Jun; Zhang, Xiaoran; Tian, Jianmin; Zuo, Zhichao; Liu, Jingjing; Yue, Xiuqin

    2016-01-01

    Isoflurane (ISO) exhibits neuroprotective effects against inflammation and apoptosis. However, the role of ISO in motoneuronal apoptosis induced by activated microglia remains poorly studied. We investigated the protective effects of ISO on the apoptosis of ventral spinal cord 4.1 (VSC4.1) motoneurons induced by lipopolysaccharide (LPS)-activated BV-2 microglia. Results indicated that ISO inhibited NF-κB activation and pro-inflammatory cytokine release in LPS-treated BV-2 microglia. Conditioned medium (CM) from activated BV-2 cells treated by ISO directly prevented VSC4.1 motoneurons from LPS-CM-induced neuronal apoptosis, as determined by the following: reductions in caspase-8, caspase-9, and caspase-3 activities; downregulation of pro-apoptotic procaspase-8, cleaved (cl)-caspase-8, procaspase-9, cl-caspase-9, caspase-3, cl-caspase-3, Bid, Bax, and cytochrome c expression; and upregulation of anti-apoptotic Bcl-2 expression in LPS-CM-cultured VSC4.1 motoneurons. Findings demonstrated that ISO inhibits BV-2 microglia activation and alleviates VSC4.1 motoneuronal apoptosis induced by microglial activation. These effects suggest that ISO can be used as an alternative agent for reducing neuronal apoptosis. PMID:27186270

  14. Adenosine-mediated modulation of ventral horn interneurons and spinal motoneurons in neonatal mice.

    PubMed

    Witts, Emily C; Nascimento, Filipe; Miles, Gareth B

    2015-10-01

    Neuromodulation allows neural networks to adapt to varying environmental and biomechanical demands. Purinergic signaling is known to be an important modulatory system in many parts of the CNS, including motor control circuitry. We have recently shown that adenosine modulates the output of mammalian spinal locomotor control circuitry (Witts EC, Panetta KM, Miles GB. J Neurophysiol 107: 1925-1934, 2012). Here we investigated the cellular mechanisms underlying this adenosine-mediated modulation. Whole cell patch-clamp recordings were performed on ventral horn interneurons and motoneurons within in vitro mouse spinal cord slice preparations. We found that adenosine hyperpolarized interneurons and reduced the frequency and amplitude of synaptic inputs to interneurons. Both effects were blocked by the A1-type adenosine receptor antagonist DPCPX. Analysis of miniature postsynaptic currents recorded from interneurons revealed that adenosine reduced their frequency but not amplitude, suggesting that adenosine acts on presynaptic receptors to modulate synaptic transmission. In contrast to interneurons, recordings from motoneurons revealed an adenosine-mediated depolarization. The frequency and amplitude of synaptic inputs to motoneurons were again reduced by adenosine, but we saw no effect on miniature postsynaptic currents. Again these effects on motoneurons were blocked by DPCPX. Taken together, these results demonstrate differential effects of adenosine, acting via A1 receptors, in the mouse spinal cord. Adenosine has a general inhibitory action on ventral horn interneurons while potentially maintaining motoneuron excitability. This may allow for adaptation of the locomotor pattern generated by interneuronal networks while helping to ensure the maintenance of overall motor output. PMID:26311185

  15. Distinct Roles of Muscle and Motoneuron LRP4 in Neuromuscular Junction Formation

    PubMed Central

    Wu, Haitao; Lu, Yisheng; Shen, Chengyong; Patel, Neil; Gan, Lin; Xiong, Wen C.; Mei, Lin

    2012-01-01

    SUMMARY Neuromuscular junction (NMJ) formation requires precise interaction between motoneurons and muscle fibers. LRP4 is a receptor of agrin that is thought to act incis to stimulate MuSK in muscle fibers for postsynaptic differentiation. Here we dissected the roles of LRP4 in muscle fibers and motoneurons in NMJ formation by cell-specific mutation. Studies of muscle-specific mutants suggest that LRP4 is involved in deciding where to form AChR clusters in muscle fibers, postsynaptic differentiation, and axon terminal development. LRP4 in HEK293 cells increased synapsin or SV2 puncta in contacting axons of co-cultured neurons, suggesting a synaptogenic function. Analysis of LRP4 muscle and motoneuron double mutants and mechanistic studies suggest that NMJ formation may also be regulated by LRP4 in motoneurons, which could serve as agrin’s receptor in trans to induce AChR clusters. These observations uncovered distinct roles of LRP4 in motoneurons and muscles in NMJ development. PMID:22794264

  16. Distinct roles of muscle and motoneuron LRP4 in neuromuscular junction formation.

    PubMed

    Wu, Haitao; Lu, Yisheng; Shen, Chengyong; Patel, Neil; Gan, Lin; Xiong, Wen C; Mei, Lin

    2012-07-12

    Neuromuscular junction (NMJ) formation requires precise interaction between motoneurons and muscle fibers. LRP4 is a receptor of agrin that is thought to act in cis to stimulate MuSK in muscle fibers for postsynaptic differentiation. Here we dissected the roles of LRP4 in muscle fibers and motoneurons in NMJ formation by cell-specific mutation. Studies of muscle-specific mutants suggest that LRP4 is involved in deciding where to form AChR clusters in muscle fibers, postsynaptic differentiation, and axon terminal development. LRP4 in HEK293 cells increased synapsin or SV2 puncta in contacting axons of cocultured neurons, suggesting a synaptogenic function. Analysis of LRP4 muscle and motoneuron double mutants and mechanistic studies suggest that NMJ formation may also be regulated by LRP4 in motoneurons, which could serve as agrin's receptor in trans to induce AChR clusters. These observations uncovered distinct roles of LRP4 in motoneurons and muscles in NMJ development. PMID:22794264

  17. Multifunctional laryngeal motoneurons: an intracellular study in the cat.

    PubMed

    Shiba, K; Satoh, I; Kobayashi, N; Hayashi, F

    1999-04-01

    We studied the patterns of membrane potential changes in laryngeal motoneurons (LMs) during vocalization, coughing, swallowing, sneezing, and the aspiration reflex in decerebrate paralyzed cats. LMs, identified by antidromic activation from the recurrent laryngeal nerve, were expiratory (ELMs) or inspiratory (ILMs) cells that depolarized during their respective phases in eupnea. During vocalization, most ELMs depolarized and most ILMs hyperpolarized. Some ILMs depolarized slightly during vocalization. During coughing, ELMs depolarized abruptly at the transition from the inspiratory to the expiratory phase. In one-third of ELMs, this depolarization persisted throughout the abdominal burst. In the remainder ("type A"), it was interrupted by a transient repolarization. ILMs exhibited a membrane potential trajectory opposite to that of type A ELMs during coughing. During swallowing, the membrane potential of ELMs decreased transiently at the onset of the hypoglossal burst and then depolarized strongly during the burst. ILMs hyperpolarized sharply at the onset of the burst and depolarized as hypoglossal activity ceased. During sneezing, ELMs and ILMs exhibited membrane potential changes similar to those of type A ELMs and ILMs during coughing. During the aspiration reflex, ELMs and ILMs exhibited bell-shaped hyperpolarization and depolarization trajectories, respectively. We conclude that central drives to LMs, consisting of complex combinations of excitation and inhibition, vary during vocalization and upper airway defensive reflexes. This study provides data for analysis of the neuronal networks that produce these various behaviors and analysis of network reorganization caused by changes in dynamic connections between the respiratory and nonrespiratory neuronal networks. PMID:10087084

  18. Mild Hyperbaric Oxygen Improves Decreased Oxidative Capacity of Spinal Motoneurons Innervating the Soleus Muscle of Rats with Type 2 Diabetes.

    PubMed

    Takemura, Ai; Ishihara, Akihiko

    2016-09-01

    Rats with type 2 diabetes exhibit decreased oxidative capacity, such as reduced oxidative enzyme activity, low-intensity staining for oxidative enzymes in fibers, and no high-oxidative type IIA fibers, in the skeletal muscle, especially in the soleus muscle. In contrast, there are no data available concerning the oxidative capacity of spinal motoneurons innervating skeletal muscle of rats with type 2 diabetes. This study examined the oxidative capacity of motoneurons innervating the soleus muscle of non-obese rats with type 2 diabetes. In addition, this study examined the effects of mild hyperbaric oxygen at 1.25 atmospheres absolute with 36 % oxygen for 10 weeks on the oxidative capacity of motoneurons innervating the soleus muscle because mild hyperbaric oxygen improves the decreased oxidative capacity of the soleus muscle in non-obese rats with type 2 diabetes. Spinal motoneurons innervating the soleus muscle were identified using nuclear yellow, a retrograde fluorescent neuronal tracer. Thereafter, the cell body sizes and succinate dehydrogenase activity of identified motoneurons were analyzed. Decreased succinate dehydrogenase activity of small-sized alpha motoneurons innervating the soleus muscle was observed in rats with type 2 diabetes. The decreased succinate dehydrogenase activity of these motoneurons was improved by mild hyperbaric oxygen. Therefore, we concluded that rats with type 2 diabetes have decreased oxidative capacity in motoneurons innervating the soleus muscle and this decreased oxidative capacity is improved by mild hyperbaric oxygen. PMID:27220333

  19. Hox transcription factors influence motoneuron identity through the integrated actions of both homeodomain and non-homeodomain regions

    PubMed Central

    Misra, Mala; Sours, Emily; Lance-Jones, Cynthia

    2012-01-01

    Background Hox transcription factors play a critical role in the specification of motoneuron subtypes within the spinal cord. Our previous work showed that two orthologous members of this family, Hoxd10 and Hoxd11, exert opposing effects on motoneuron development in the lumbosacral (LS) spinal cord of the embryonic chick: Hoxd10 promotes the development of lateral motoneuron subtypes that project to dorsal limb muscles, while Hoxd11 represses the development of lateral subtypes in favor of medial subtypes that innervate ventral limb muscles and axial muscles. The striking degree of homology between the DNA-binding homeodomains of Hoxd10 and Hoxd11 suggested that non-homeodomain regions mediate their divergent effects. In the present study, we investigate the relative contributions of homeodomain and non-homeodomain regions of Hoxd10 and Hoxd11 to motoneuron specification. Results Using in ovo electroporation to express chimeric and mutant constructs in LS motoneurons, we find that both the homeodomain and non-homeodomain regions of Hoxd10 are necessary to specify lateral motoneurons. In contrast, non-homeodomain regions of Hoxd11 are sufficient to repress lateral motoneuron fates in favor of medial fates. Conclusions Together, our data demonstrate that even closely related Hox orthologues rely on distinct combinations of homeodomain-dependent and -independent mechanisms to specify motoneuron identity. PMID:22411553

  20. Motoneurons, DUM cells, and sensory neurons in an insect thoracic ganglion: a tracing study in the stick insect Carausius morosus.

    PubMed

    Goldammer, Jens; Büschges, Ansgar; Schmidt, Joachim

    2012-02-01

    Anatomical features of leg motoneurons, dorsal unpaired median (DUM) cells, and sensory neurons in stick insect mesothoracic ganglia were examined using fluorescent dye backfills of lateral nerves. Structures were analyzed in whole-mounts of ganglia and transverse sections. Numbers of motoneurons and details of their structure by far exceed previously published data. The general neuroanatomical layout of motoneurons matches the general orthopteran pattern. Cell bodies of excitatory motoneurons form clusters in the lateral cortex, dendrites branch mainly in the dorsal neuropil. We identified nine DUM cells, six of which have axons in nerve nl5. Most sensory fibers terminate in the ventral association center (VAC). Twenty-three small cell bodies located close to the soma of the fast extensor tibiae motoneuron likely belong to strand receptors. Labeled structures are compared with previously published data from stick insects and other orthopterous insects. PMID:21618233

  1. Neuroplasticity and Repair in Rodent Neurotoxic Models of Spinal Motoneuron Disease

    PubMed Central

    Gulino, Rosario

    2016-01-01

    Retrogradely transported toxins are widely used to set up protocols for selective lesioning of the nervous system. These methods could be collectively named “molecular neurosurgery” because they are able to destroy specific types of neurons by using targeted neurotoxins. Lectins such as ricin, volkensin, or modeccin and neuropeptide- or antibody-conjugated saporin represent the most effective toxins used for neuronal lesioning. Some of these specific neurotoxins could be used to induce selective depletion of spinal motoneurons. In this review, we extensively describe two rodent models of motoneuron degeneration induced by volkensin or cholera toxin-B saporin. In particular, we focus on the possible experimental use of these models to mimic neurodegenerative diseases, to dissect the molecular mechanisms of neuroplastic changes underlying the spontaneous functional recovery after motoneuron death, and finally to test different strategies of neural repair. The potential clinical applications of these approaches are also discussed. PMID:26862439

  2. Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease

    PubMed Central

    Selvaraj, Bhuvaneish Thangaraj; Frank, Nicolas; Bender, Florian L.P.; Asan, Esther

    2012-01-01

    Axonal maintenance, plasticity, and regeneration are influenced by signals from neighboring cells, in particular Schwann cells of the peripheral nervous system. Schwann cells produce neurotrophic factors, but the mechanisms by which ciliary neurotrophic factor (CNTF) and other neurotrophic molecules modify the axonal cytoskeleton are not well understood. In this paper, we show that activated signal transducer and activator of transcription-3 (STAT3), an intracellular mediator of the effects of CNTF and other neurotrophic cytokines, acts locally in axons of motoneurons to modify the tubulin cytoskeleton. Specifically, we show that activated STAT3 interacted with stathmin and inhibited its microtubule-destabilizing activity. Thus, ectopic CNTF-mediated activation of STAT3 restored axon elongation and maintenance in motoneurons from progressive motor neuronopathy mutant mice, a mouse model of motoneuron disease. This mechanism could also be relevant for other neurodegenerative diseases and provide a target for new therapies for axonal degeneration. PMID:23109669

  3. Non-Cell-Autonomous Regulation of Retrograde Motoneuronal Axonal Transport in an SBMA Mouse Model.

    PubMed

    Halievski, Katherine; Kemp, Michael Q; Breedlove, S Marc; Miller, Kyle E; Jordan, Cynthia L

    2016-01-01

    Defects in axonal transport are seen in motoneuronal diseases, but how that impairment comes about is not well understood. In spinal bulbar muscular atrophy (SBMA), a disorder linked to a CAG/polyglutamine repeat expansion in the androgen receptor (AR) gene, the disease-causing AR disrupts axonal transport by acting in both a cell-autonomous fashion in the motoneurons themselves, and in a non-cell-autonomous fashion in muscle. The non-cell-autonomous mechanism is suggested by data from a unique "myogenic" transgenic (TG) mouse model in which an AR transgene expressed exclusively in skeletal muscle fibers triggers an androgen-dependent SBMA phenotype, including defects in retrograde transport. However, motoneurons in this TG model retain the endogenous AR gene, leaving open the possibility that impairments in transport in this model also depend on ARs in the motoneurons themselves. To test whether non-cell-autonomous mechanisms alone can perturb retrograde transport, we generated male TG mice in which the endogenous AR allele has the testicular feminization mutation (Tfm) and, consequently, is nonfunctional. Males carrying the Tfm allele alone show no deficits in motor function or axonal transport, with or without testosterone treatment. However, when Tfm males carrying the myogenic transgene (Tfm/TG) are treated with testosterone, they develop impaired motor function and defects in retrograde transport, having fewer retrogradely labeled motoneurons and deficits in endosomal flux based on time-lapse video microscopy of living axons. These findings demonstrate that non-cell-autonomous disease mechanisms originating in muscle are sufficient to induce defects in retrograde transport in motoneurons. PMID:27517091

  4. Non-Cell-Autonomous Regulation of Retrograde Motoneuronal Axonal Transport in an SBMA Mouse Model

    PubMed Central

    Halievski, Katherine; Kemp, Michael Q.; Breedlove, S. Marc; Miller, Kyle E.

    2016-01-01

    Abstract Defects in axonal transport are seen in motoneuronal diseases, but how that impairment comes about is not well understood. In spinal bulbar muscular atrophy (SBMA), a disorder linked to a CAG/polyglutamine repeat expansion in the androgen receptor (AR) gene, the disease-causing AR disrupts axonal transport by acting in both a cell-autonomous fashion in the motoneurons themselves, and in a non-cell-autonomous fashion in muscle. The non-cell-autonomous mechanism is suggested by data from a unique “myogenic” transgenic (TG) mouse model in which an AR transgene expressed exclusively in skeletal muscle fibers triggers an androgen-dependent SBMA phenotype, including defects in retrograde transport. However, motoneurons in this TG model retain the endogenous AR gene, leaving open the possibility that impairments in transport in this model also depend on ARs in the motoneurons themselves. To test whether non-cell-autonomous mechanisms alone can perturb retrograde transport, we generated male TG mice in which the endogenous AR allele has the testicular feminization mutation (Tfm) and, consequently, is nonfunctional. Males carrying the Tfm allele alone show no deficits in motor function or axonal transport, with or without testosterone treatment. However, when Tfm males carrying the myogenic transgene (Tfm/TG) are treated with testosterone, they develop impaired motor function and defects in retrograde transport, having fewer retrogradely labeled motoneurons and deficits in endosomal flux based on time-lapse video microscopy of living axons. These findings demonstrate that non-cell-autonomous disease mechanisms originating in muscle are sufficient to induce defects in retrograde transport in motoneurons. PMID:27517091

  5. Calcium dynamics and buffering in motoneurones of the mouse spinal cord.

    PubMed

    Palecek, J; Lips, M B; Keller, B U

    1999-10-15

    1. A quantitative analysis of endogenous calcium homeostasis was performed on 65 motoneurones in slices of the lumbar spinal cord from 2- to 8-day-old mice by simultaneous patch-clamp and microfluorometric calcium measurements. 2. Somatic calcium concentrations were monitored with a temporal resolution in the millisecond time domain. Measurements were performed by using a monochromator for excitation and a photomultiplier detection system. 3. Somatic calcium signalling was investigated during defined voltage-clamp protocols. Calcium responses were observed for membrane depolarizations positive to -50 mV. A linear relation between depolarization time and free calcium concentrations ([Ca2+]i) indicated that voltage-dependent calcium influx dominated the response. 4. Endogenous calcium homeostasis was quantified by using the 'added buffer' approach. In the presence of fura-2 and mag-fura-5, calcium transients decayed according to a monoexponential function. Decay-time constants showed a linear dependence on dye concentration and the extrapolated constant in the absence of indicator dye was 371 +/- 120 ms (n = 13 cells, 21 C). 5. For moderate elevations (< 1 microM), recovery kinetics of depolarization-induced calcium transients were characterized by a calcium-independent, 'effective' extrusion rate gamma = 140 +/- 47 s-1 (n = 13 cells, 21 C). 6. The endogenous calcium binding ratio for fixed buffers in spinal motoneurones was kappaB' = 50 +/- 17 (n = 13 cells), indicating that less than 2 % of cytosolic calcium ions contributed to [Ca2+]i. 7. Endogenous binding ratios in spinal motoneurones were small compared to those found in hippocampal or cerebellar Purkinje neurones. From a functional perspective, they provided motoneurones with rapid dynamics of cytosolic [Ca2+]i for a given set of influx, extrusion and uptake mechanisms. 8. With respect to pathophysiological conditions, our measurements are in agreement with a model where the selective vulnerability of spinal

  6. Tremor in Parkinson's disease patients can be induced by uncontrolled activation and uninhibited synchronization of alpha2-motoneuron firing to which alpha1-motoneuron firing synchronizes.

    PubMed

    Schalow, Giselher

    2005-12-01

    With the surface electromyography (sEMG) and the single nerve-fibre action potential recording method a mechanism is measured how rhythmic muscle contraction and tremor in Parkinson's disease patients is generated. With sEMG it could be shown that the tremor started when alpha2-motor units (FR-type) spontaneously began to fire synchronizedly oscillatory. Two possibilities of alpha2-motor unit synchronization were observed. In one case one alpha2-motor unit started to fire oscillatory and other alpha2-motor units started to fire oscillatory in synchronization with the first alpha2-motor unit. In a second case several alpha2-motor units fired oscillatory, but not in a synchronized manner. With the synchronization of the oscillatory firing alpha2-motor units again synchronizedly oscillatory firing of several alpha2-motor units appeared. When later on, several additional alpha1-motor units (FF-type) started to fire and in synchrony with the synchronizedly oscillatory firing alpha2-motor units (FR-type), rhythmic muscle contraction and tremor were observed. Visible muscle contraction and tremor stopped, when the alpha1-motor units stopped firing, which could a.o. be achieved by the patient concentrating on the tremor. The single nerve-fibre action potential recording method showed that alpha1 and alpha2-motoneurons in the cauda equine nerve roots fired oscillatory, that they could synchronize their firing and that these oscillatory firing motoneurons could build up an external loop to the periphery in the way that gamma-motoneurons and muscle spindle afferents were included in the rhythmic coordinated firing But the synchronization of oscillatory firing was only transient and the building up of an external loop to the periphery only occurred in non-Parkinson patients upon strong repetitive reflex stimulation. It is therefore concluded that in patients with Parkinson's disease there is firstly a lack of inhibition, so that motoneurons can start to fire oscillatory upon

  7. Mechanisms of spinal motoneurons survival in rats under simulated hypogravity on earth

    NASA Astrophysics Data System (ADS)

    Islamov, R. R.; Mishagina, E. A.; Tyapkina, O. V.; Shajmardanova, G. F.; Eremeev, A. A.; Kozlovskaya, I. B.; Nikolskij, E. E.; Grigorjev, A. I.

    2011-05-01

    It was previously shown that different cell types in vivo and in vitro may die via apoptosis under weightlessness conditions in space as well as in simulated hypogravity on the Earth. We assessed survivability of spinal motoneurons of rats after 35-day antiorthostatic hind limb suspension. Following weight bearing, unloading the total protein content in lumbar spinal cord is dropped by 21%. The electrophysiological studies of m. gastrocnemius revealed an elevated motoneurons' reflex excitability and conduction disturbances in the sciatic nerve axons. The number of myelinated fibers in the ventral root of experimental animals was insignificantly increased by 35-day of antiorthostatic hind limb suspension, although the retrograde axonal transport was significantly decreased during the first week of simulated hypogravity. The results of the immunohistochemical assay with antibodies against proapoptotic protein caspase 9 and cytotoxicity marker neuron specific nitric oxide synthase (nNOS) and the TUNEL staining did not reveal any signs of apoptosis in motoneurons of suspended and control animals. To examine the possible adaptation mechanisms activated in motoneurons in response to simulated hypogravity we investigated immunoexpression of Hsp25 and Hsp70 in lumbar spinal cord of the rats after 35-day antiorthostatic hind limb suspension. Comparative analysis of the immunohistochemical reaction with anti-Hsp25 antibodies revealed differential staining of motoneurons in intact and experimental animals. The density of immunoprecipitate with anti-Hsp25 antibodies was substantially higher in motoneurons of the 35-day suspended than control rats and the more intensive precipitate in this reaction was observed in motoneuron neuritis. Quantitative analysis of Hsp25 expression demonstrated an increase in the Hsp25 level by 95% in experimental rats compared to the control. The immunoexpression of Hsp70 found no qualitative and quantitative differences in control and experimental

  8. Cat hindlimb motoneurons during locomotion. I. Destination, axonal conduction velocity, and recruitment threshold.

    PubMed

    Hoffer, J A; Loeb, G E; Marks, W B; O'Donovan, M J; Pratt, C A; Sugano, N

    1987-02-01

    Fine flexible wire microelectrodes chronically implanted in the fifth lumbar ventral root (L5 VR) of 17 cats rendered stable records of the natural discharge patterns of 164 individual axons during locomotion on a treadmill. Fifty-one out of 164 axons were identified as motoneurons projecting to the anterior thigh muscle group. For these axons, the centrifugal propagation of action potentials was demonstrated by the technique of spike-triggered averaging using signals recorded from cuff electrodes implanted around the femoral nerve. The axonal conduction velocity was measured from the femoral nerve cuff records. For 43/51 motoneurons, the corresponding target muscle was identified by spike-triggered averaging of signals recorded from bipolar EMG electrodes implanted in each of the anterior thigh muscles: vastus intermedius, medialis and lateralis, sartorius anterior and medialis, and rectus femoris. For 32/51 motoneurons, the recruitment threshold during locomotion was determined from the mean value of the rectified digitally smoothed EMG of the target muscle measured at the time when the motoneuron fired its first spike for each step. The recruitment threshold of every motoneuron was relatively constant for a given speed of walking, but for some units there were small systematic variations as a function of treadmill speed (range: 0.1-1.3 m/s). Recruitment thresholds were standardized with respect to the mean value of peak EMG activity of the target muscle during 16 s of walking at 0.5 m/s. For 28/51 motoneurons recorded in nine cats, recruitment thresholds (range: 3-93% of peak target muscle EMG) were linearly correlated (r = 0.51, P less than 0.02) to axonal conduction velocities (range: 57-117 m/s). In addition, for seven recorded pairs of motoneurons that projected to the same muscle in the same cat, the recruitment thresholds were ordered by relative conduction velocities. Taken together, these results are consistent with the notion that, in normal cat

  9. TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury.

    PubMed

    Martínez-Gálvez, Gabriel; Zambrano, Juan M; Diaz Soto, Juan C; Zhan, Wen-Zhi; Gransee, Heather M; Sieck, Gary C; Mantilla, Carlos B

    2016-02-01

    Unilateral cervical spinal cord hemisection at C2 (C2SH) interrupts descending bulbospinal inputs to phrenic motoneurons, paralyzing the diaphragm muscle. Recovery after C2SH is enhanced by brain derived neurotrophic factor (BDNF) signaling via the tropomyosin-related kinase subtype B (TrkB) receptor in phrenic motoneurons. The role for gene therapy using adeno-associated virus (AAV)-mediated delivery of TrkB to phrenic motoneurons is not known. The present study determined the therapeutic efficacy of intrapleural delivery of AAV7 encoding for full-length TrkB (AAV-TrkB) to phrenic motoneurons 3 days post-C2SH. Diaphragm EMG was recorded chronically in male rats (n=26) up to 21 days post-C2SH. Absent ipsilateral diaphragm EMG activity was verified 3 days post-C2SH. A greater proportion of animals displayed recovery of ipsilateral diaphragm EMG activity during eupnea by 14 and 21 days post-SH after AAV-TrkB (10/15) compared to AAV-GFP treatment (2/11; p=0.031). Diaphragm EMG amplitude increased over time post-C2SH (p<0.001), and by 14 days post-C2SH, AAV-TrkB treated animals displaying recovery achieved 48% of the pre-injury values compared to 27% in AAV-GFP treated animals. Phrenic motoneuron mRNA expression of glutamatergic AMPA and NMDA receptors revealed a significant, positive correlation (r(2)=0.82), with increased motoneuron NMDA expression evident in animals treated with AAV-TrkB and that displayed recovery after C2SH. Overall, gene therapy using intrapleural delivery of AAV-TrkB to phrenic motoneurons is sufficient to promote recovery of diaphragm activity, adding a novel potential intervention that can be administered after upper cervical spinal cord injury to improve impaired respiratory function. PMID:26607912

  10. Control of hypoglossal motoneurones during naturally occurring sleep and wakefulness in the intact, unanaesthetized cat: a field potential study.

    PubMed

    Fung, Simon J; Chase, Michael H

    2014-08-01

    The present electrophysiological study was designed to determine the discharge threshold of hypoglossal motoneurones during naturally occurring states of sleep and wakefulness in the intact, unanaesthetized cat. The antidromic field potential, which reflects the net level of membrane excitability of motoneurones and therefore their discharge threshold, was recorded in the hypoglossal nucleus following stimulation of the hypoglossal nerve. The amplitude of the antidromic field potential was larger during wakefulness and non-rapid eye movement (NREM) sleep compared with REM sleep. There was no significant difference in the amplitude of the field potential when wakefulness was compared with NREM sleep (P = 0.103, df = 3, t = 2.324). However, there was a 46% reduction in amplitude during REM sleep compared with NREM sleep (P < 0.001, df = 10, t = 6.421) or wakefulness (P < 0.01, df = 4, t = -4.598). These findings indicate that whereas the excitability of motoneurones that comprise the hypoglossal motor pool is relatively constant during wakefulness and NREM sleep, their excitability is significantly reduced during REM sleep. This state-dependent pattern of control of hypoglossal motoneurones during REM sleep is similar to that reported for motoneurones in other motor nuclei at all levels of the neuraxis. The decrease in the evoked response of hypoglossal motoneurones, which reflects a significant increase in the discharge threshold of individual motoneurones, results in atonia of the lingual and related muscles during REM sleep. PMID:24605864

  11. Sensitization of neonatal rat lumbar motoneuron by the inflammatory pain mediator bradykinin

    PubMed Central

    Bouhadfane, Mouloud; Kaszás, Attila; Rózsa, Balázs; Harris-Warrick, Ronald M; Vinay, Laurent; Brocard, Frédéric

    2015-01-01

    Bradykinin (Bk) is a potent inflammatory mediator that causes hyperalgesia. The action of Bk on the sensory system is well documented but its effects on motoneurons, the final pathway of the motor system, are unknown. By a combination of patch-clamp recordings and two-photon calcium imaging, we found that Bk strongly sensitizes spinal motoneurons. Sensitization was characterized by an increased ability to generate self-sustained spiking in response to excitatory inputs. Our pharmacological study described a dual ionic mechanism to sensitize motoneurons, including inhibition of a barium-sensitive resting K+ conductance and activation of a nonselective cationic conductance primarily mediated by Na+. Examination of the upstream signaling pathways provided evidence for postsynaptic activation of B2 receptors, G protein activation of phospholipase C, InsP3 synthesis, and calmodulin activation. This study questions the influence of motoneurons in the assessment of hyperalgesia since the withdrawal motor reflex is commonly used as a surrogate pain model. DOI: http://dx.doi.org/10.7554/eLife.06195.001 PMID:25781633

  12. Functional Expression of T-Type Ca2+ Channels in Spinal Motoneurons of the Adult Turtle

    PubMed Central

    Canto-Bustos, Martha; Loeza-Alcocer, Emanuel; González-Ramírez, Ricardo; Gandini, María A.; Delgado-Lezama, Rodolfo; Felix, Ricardo

    2014-01-01

    Voltage-gated Ca2+ (CaV) channels are transmembrane proteins comprising three subfamilies named CaV1, CaV2 and CaV3. The CaV3 channel subfamily groups the low-voltage activated Ca2+ channels (LVA or T-type) a significant role in regulating neuronal excitability. CaV3 channel activity may lead to the generation of complex patterns of action potential firing such as the postinhibitory rebound (PIR). In the adult spinal cord, these channels have been found in dorsal horn interneurons where they control physiological events near the resting potential and participate in determining excitability. In motoneurons, CaV3 channels have been found during development, but their functional expression has not yet been reported in adult animals. Here, we show evidence for the presence of CaV3 channel-mediated PIR in motoneurons of the adult turtle spinal cord. Our results indicate that Ni2+ and NNC55-0396, two antagonists of CaV3 channel activity, inhibited PIR in the adult turtle spinal cord. Molecular biology and biochemical assays revealed the expression of the CaV3.1 channel isotype and its localization in motoneurons. Together, these results provide evidence for the expression of CaV3.1 channels in the spinal cord of adult animals and show also that these channels may contribute to determine the excitability of motoneurons. PMID:25255145

  13. Extrasynaptic α6 Subunit-Containing GABAA Receptors Modulate Excitability in Turtle Spinal Motoneurons

    PubMed Central

    Andres, Carmen; Aguilar, Justo; González-Ramírez, Ricardo; Elias-Viñas, David; Felix, Ricardo; Delgado-Lezama, Rodolfo

    2014-01-01

    Motoneurons are furnished with a vast repertoire of ionotropic and metabotropic receptors as well as ion channels responsible for maintaining the resting membrane potential and involved in the regulation of the mechanisms underlying its membrane excitability and firing properties. Among them, the GABAA receptors, which respond to GABA binding by allowing the flow of Cl− ions across the membrane, mediate two distinct forms of inhibition in the mature nervous system, phasic and tonic, upon activation of synaptic or extrasynaptic receptors, respectively. In a previous work we showed that furosemide facilitates the monosynaptic reflex without affecting the dorsal root potential. Our data also revealed a tonic inhibition mediated by GABAA receptors activated in motoneurons by ambient GABA. These data suggested that the high affinity GABAA extrasynaptic receptors may have an important role in motor control, though the molecular nature of these receptors was not determined. By combining electrophysiological, immunofluorescence and molecular biology techniques with pharmacological tools here we show that GABAA receptors containing the α6 subunit are expressed in adult turtle spinal motoneurons and can function as extrasynaptic receptors responsible for tonic inhibition. These results expand our understanding of the role of GABAA receptors in motoneuron tonic inhibition. PMID:25531288

  14. Localization of pectoral fin motoneurons (sonic and hovering) in the croaking gourami Trichopsis vittatus.

    PubMed

    Ladich, F; Fine, M L

    1992-01-01

    The pectoral fin of the croaking gourami, Trichopsis vittatus, has become modified as a sound-producing organ and retains its original function in locomotion and hovering. We used retrograde transport of horseradish peroxidase to localize sonic motoneurons in Trichopsis. Betta splendens, a related nonsonic gourami with unspecialized pectoral fins, served as a control. A single injection into Trichopsis epaxial muscle labeled a dorsal motor column of large cells (mean of 16.3 microns) ventrolateral to the central canal. Pectoral motoneurons formed a ventrolateral spinal motor column of smaller neurons (means from 7.7 to 11.9 microns, depending upon fish size), of about 2 mm in rostrocaudal extent, starting in the caudal medulla. Our data suggest that motoneurons for different pectoral muscles are segregated into rostrocaudal pools within the column. Distribution, morphology and size of motoneurons were similar between Trichopsis and Betta, and there was no evidence of a distinct population of neurons which might be specialized exclusively for sound production. These data suggest that a fish can evolve a specialized end organ without major reorganization of the central nervous system. PMID:1537046

  15. Extrasynaptic α6 subunit-containing GABAA receptors modulate excitability in turtle spinal motoneurons.

    PubMed

    Andres, Carmen; Aguilar, Justo; González-Ramírez, Ricardo; Elias-Viñas, David; Felix, Ricardo; Delgado-Lezama, Rodolfo

    2014-01-01

    Motoneurons are furnished with a vast repertoire of ionotropic and metabotropic receptors as well as ion channels responsible for maintaining the resting membrane potential and involved in the regulation of the mechanisms underlying its membrane excitability and firing properties. Among them, the GABAA receptors, which respond to GABA binding by allowing the flow of Cl- ions across the membrane, mediate two distinct forms of inhibition in the mature nervous system, phasic and tonic, upon activation of synaptic or extrasynaptic receptors, respectively. In a previous work we showed that furosemide facilitates the monosynaptic reflex without affecting the dorsal root potential. Our data also revealed a tonic inhibition mediated by GABAA receptors activated in motoneurons by ambient GABA. These data suggested that the high affinity GABAA extrasynaptic receptors may have an important role in motor control, though the molecular nature of these receptors was not determined. By combining electrophysiological, immunofluorescence and molecular biology techniques with pharmacological tools here we show that GABAA receptors containing the α6 subunit are expressed in adult turtle spinal motoneurons and can function as extrasynaptic receptors responsible for tonic inhibition. These results expand our understanding of the role of GABAA receptors in motoneuron tonic inhibition. PMID:25531288

  16. Emerging Roles of Filopodia and Dendritic Spines in Motoneuron Plasticity during Development and Disease

    PubMed Central

    Kanjhan, Refik; Noakes, Peter G.; Bellingham, Mark C.

    2016-01-01

    Motoneurons develop extensive dendritic trees for receiving excitatory and inhibitory synaptic inputs to perform a variety of complex motor tasks. At birth, the somatodendritic domains of mouse hypoglossal and lumbar motoneurons have dense filopodia and spines. Consistent with Vaughn's synaptotropic hypothesis, we propose a developmental unified-hybrid model implicating filopodia in motoneuron spinogenesis/synaptogenesis and dendritic growth and branching critical for circuit formation and synaptic plasticity at embryonic/prenatal/neonatal period. Filopodia density decreases and spine density initially increases until postnatal day 15 (P15) and then decreases by P30. Spine distribution shifts towards the distal dendrites, and spines become shorter (stubby), coinciding with decreases in frequency and increases in amplitude of excitatory postsynaptic currents with maturation. In transgenic mice, either overexpressing the mutated human Cu/Zn-superoxide dismutase (hSOD1G93A) gene or deficient in GABAergic/glycinergic synaptic transmission (gephyrin, GAD-67, or VGAT gene knockout), hypoglossal motoneurons develop excitatory glutamatergic synaptic hyperactivity. Functional synaptic hyperactivity is associated with increased dendritic growth, branching, and increased spine and filopodia density, involving actin-based cytoskeletal and structural remodelling. Energy-dependent ionic pumps that maintain intracellular sodium/calcium homeostasis are chronically challenged by activity and selectively overwhelmed by hyperactivity which eventually causes sustained membrane depolarization leading to excitotoxicity, activating microglia to phagocytose degenerating neurons under neuropathological conditions. PMID:26843990

  17. Electrophysiological properties of laryngeal motoneurones in rats submitted to chronic intermittent hypoxia

    PubMed Central

    Moraes, Davi J A; Machado, Benedito H

    2015-01-01

    To keep an appropriate airflow to and from the lungs under physiological conditions a precise neural co-ordination of the upper airway resistance by laryngeal motoneurones in the nucleus ambiguus is essential. Chronic intermittent hypoxia (CIH), an important component of obstructive sleep apnoea, may alter these fine mechanisms. Here, using nerve and whole cell patch clamp recordings in in situ preparations of rats we investigated the effects of CIH on the respiratory control of the upper airway resistance, on the electrophysiological properties of laryngeal motoneurones in the nucleus ambiguus, and the role of carotid body (CB) afferents to the brainstem on the underlying mechanisms of these effects. CIH rats exhibited longer pre-inspiratory and lower post-inspiratory superior laryngeal nerve activities than control rats. These changes produced exaggerated glottal abduction (before inspiration) and decreased glottal adduction during post-inspiration, indicating a reduction of upper airway resistance during these respiratory phases after CIH. CB denervation abolished these changes produced by CIH. Regarding choline acetyltransferase positive-laryngeal motoneurones, CIH increased the firing frequency of inspiratory and decreased the firing frequency of post-inspiratory laryngeal motoneurones, without changes in their intrinsic electrophysiological properties. These data show that the effects of CIH on the upper airway resistance and laryngeal motoneurones activities are driven by the integrity of CB, which afferents induce changes in the central respiratory generators in the brainstem. These neural changes in the respiratory network seem to be an adaptive process required for an appropriated pulmonary ventilation and control of upper airway resistance under intermittent episodes of hypoxia. Key points The respiratory control of the glottis by laryngeal motoneurones is characterized by inspiratory abduction and post-inspiratory adduction causing decreases and

  18. Possible functions of transmitter-controlled plateau potentials in alpha motoneurones.

    PubMed

    Eken, T; Hultborn, H; Kiehn, O

    1989-01-01

    An increasing number of vertebrate central neurones has been shown to possess complex membrane properties. However, the functional significance of such properties is unclear. The aim of the present paper is to review some old and new findings in this field from this laboratory. First, a bistability in alpha motoneurones in reduced preparations is described. Thereafter we present some new data on a bistable behaviour in motor units in unrestrained intact animals during posture. Finally, the possible role of motoneuronal bistability in locomotion and in spasticity is discussed. Recently a bistable firing behaviour in motoneurones was described in the unanaesthetized decerebrate cat. This behaviour is generated by a plateau potential, which causes long-lasting excitability increase and can be initiated and terminated by short-lasting synaptic excitation and inhibition respectively, and is contingent upon activity in descending noradrenergic and serotonergic systems. In an in vitro preparation of the turtle spinal cord the plateau potential was shown to be serotonin dependent and generated by a voltage-dependent non-inactivating calcium conductance. In order to elucidate possible functional consequences of a bistable firing behaviour in the intact animal, the firing pattern of individual soleus motor units was studied by means of chronic EMG registration in awake unrestrained rats during quiet standing. Implanted electrodes allowed the delivery of excitatory and inhibitory stimulus trains to the motoneurones. It was found that short-lasting synaptic stimulation could induce maintained shifts between two stable levels of motoneurone firing frequencies, as in the decerebrate cat. Spontaneous shifts between the same two levels were also present. It seems most likely that plateau potentials are responsible for this bistable firing property in intact animals. The role of plateau potentials in locomotion is difficult to study. At present there are no clear indications of the

  19. Mechanism and Function of Mixed-Mode Oscillations in Vibrissa Motoneurons

    PubMed Central

    Golomb, David

    2014-01-01

    Vibrissa motoneurons in the facial nucleus innervate the intrinsic and extrinsic muscles that move the whiskers. Their intrinsic properties affect the way they process fast synaptic input from the vIRT and Bötzinger nuclei together with serotonergic neuromodulation. In response to constant current (Iapp) injection, vibrissa motoneurons may respond with mixed mode oscillations (MMOs), in which sub-threshold oscillations (STOs) are intermittently mixed with spikes. This study investigates the mechanisms involved in generating MMOs in vibrissa motoneurons and their function in motor control. It presents a conductance-based model that includes the M-type K+ conductance, gM, the persistent Na+ conductance, gNaP, and the cationic h conductance, gh. For gh = 0 and moderate values of gM and gNaP, the model neuron generates STOs, but not MMOs, in response to Iapp injection. STOs transform abruptly to tonic spiking as the current increases. In addition to STOs, MMOs are generated for gh>0 for larger values of Iapp; the Iapp range in which MMOs appear increases linearly with gh. In the MMOs regime, the firing rate increases with Iapp like a Devil's staircase. Stochastic noise disrupts the temporal structure of the MMOs, but for a moderate noise level, the coefficient of variation (CV) is much less than one and varies non-monotonically with Iapp. Furthermore, the estimated time period between voltage peaks, based on Bernoulli process statistics, is much higher in the MMOs regime than in the tonic regime. These two phenomena do not appear when moderate noise generates MMOs without an intrinsic MMO mechanism. Therefore, and since STOs do not appear in spinal motoneurons, the analysis can be used to differentiate different MMOs mechanisms. MMO firing activity in vibrissa motoneurons suggests a scenario in which moderate periodic inputs from the vIRT and Bötzinger nuclei control whisking frequency, whereas serotonergic neuromodulation controls whisking amplitude. PMID

  20. Cannabinoid agonists rearrange synaptic vesicles at excitatory synapses and depress motoneuron activity in vivo.

    PubMed

    García-Morales, Victoria; Montero, Fernando; Moreno-López, Bernardo

    2015-05-01

    Impairment of motor skills is one of the most common acute adverse effects of cannabis. Related studies have focused mainly on psychomotor alterations, and little is known about the direct impact of cannabinoids (CBs) on motoneuron physiology. As key modulators of synaptic function, CBs regulate multiple neuronal functions and behaviors. Presynaptic CB1 mediates synaptic strength depression by inhibiting neurotransmitter release, via a poorly understood mechanism. The present study examined the effect of CB agonists on excitatory synaptic inputs incoming to hypoglossal motoneurons (HMNs) in vitro and in vivo. The endocannabinoid anandamide (AEA) and the synthetic CB agonist WIN 55,212-2 rapidly and reversibly induced short-term depression (STD) of glutamatergic synapses on motoneurons by a presynaptic mechanism. Presynaptic effects were fully reversed by the CB1-selective antagonist AM281. Electrophysiological and electron microscopy analysis showed that WIN 55,212-2 reduced the number of synaptic vesicles (SVs) docked to active zones in excitatory boutons. Given that AM281 fully abolished depolarization-induced depression of excitation, motoneurons can be feasible sources of CBs, which in turn act as retrograde messengers regulating synaptic function. Finally, microiontophoretic application of the CB agonist O-2545 reversibly depressed, presumably via CB1, glutamatergic inspiratory-related activity of HMNs in vivo. Therefore, evidence support that CBs, via presynaptic CB1, induce excitatory STD by reducing the readily releasable pool of SVs at excitatory synapses, then attenuating motoneuron activity. These outcomes contribute a possible mechanistic basis for cannabis-associated motor performance disturbances such as ataxia, dysarthria and dyscoordination. PMID:25595101

  1. Synergistic but transient rescue effects of BDNF and GDNF on axotomized neonatal motoneurons.

    PubMed

    Vejsada, R; Tseng, J L; Lindsay, R M; Acheson, A; Aebischer, P; Kato, A C

    1998-05-01

    Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), members of distinct families of polypeptide growth factors, have been shown to support motoneurons under various in vitro and in vivo conditions. We used a model of motoneuron cell death induced by sciatic nerve section in newborn rats and compared the efficacy of BDNF and GDNF administered alone or simultaneously in order to determine whether combinations of neurotrophic proteins can produce more potent motoneuron rescue than individual factors. The factors were administered by different methods, including (i) a single dose on to the transected nerve, (ii) continuous delivery from implanted slow-release polymer rods (BDNF) or encapsulated cells (GDNF), and (iii) repeated systemic injections (BDNF). Irrespective of the method of administration, either factor alone produced rescue effects which dramatically declined at two weeks as compared to one week post-lesion. In contrast, this decrease was significantly reduced when BDNF and GDNF were used simultaneously provided that one factor was applied on to the nerve while the other was continuously released from the rods or capsules. Other combinations in which GDNF was replaced by ciliary neurotrophic factor or axokine-1 failed to reproduce such additive activity. Two conclusions can be made from these experiments. First, when BDNF and GDNF are administered simultaneously but by distinct routes of delivery, their survival-promoting effects on the injured developing motoneurons are potentiated; second, even continuous delivery of each of these trophic factors alone cannot completely abrogate the time-dependent decline in rescue effects in this model of motoneuron cell death. PMID:9522368

  2. Eye Movements and Abducens Motoneuron Behavior During Cholinergically Induced REM Sleep

    PubMed Central

    Marquez-Ruiz, Javier; Escudero, Miguel

    2009-01-01

    Study objectives: The injection of cholinergic drugs in the pons has been largely used to induce REM sleep as a useful model to study different processes during this period. In the present study, microinjections of carbachol in the nucleus reticularis pontis oralis (NRPO) were performed to test the hypothesis that eye movements and the behavior of extraocular motoneurons during induced REM sleep do not differ from those during spontaneous REM sleep. Methods: Six female adult cats were prepared for chronic recording of eye movements (by means of the search-coil technique) and electroencephalography, electromyography, ponto-geniculo-occipital (PGO) waves at the lateral geniculate nucleus, and identified abducens motoneuron activities after microinjections of the cholinergic agonist carbachol into the NRPO. Results: Unilateral microinjections (n = 13) of carbachol in the NRPO induced REM sleep-like periods in which the eyes performed a convergence and downward rotation interrupted by phasic complex rapid eye movements associated to PGO waves. During induced-REM sleep abducens motoneurons lost their tonic activity and eye position codification, but continued codifying eye velocity during the burst of eye movements. Conclusion: The present results show that eye movements and the underlying behavior of abducens motoneurons are very similar to those present during natural REM sleep. Thus, microinjection of carbachol seems to activate the structures responsible for the exclusive oculomotor behavior observed during REM sleep, validating this pharmacological model and enabling a more efficient exploration of phasic and tonic phenomena underlying eye movements during REM sleep. Citation: Marquez-Ruiz J; Escudero M. Eye movements and abducens motoneuron behavior during cholinergically induced REM sleep. SLEEP 2009;32(4):471–481. PMID:19413141

  3. Neuronal nitric oxide synthase inhibitor, 7-nitroindazole, delays motor dysfunction and spinal motoneuron degeneration in the wobbler mouse.

    PubMed

    Ikeda, K; Iwasaki, Y; Kinoshita, M

    1998-09-18

    Gene mutations of superoxide dismutase (SOD) have been discovered in familial amyotrophic lateral sclerosis (ALS). Neuronal nitric oxide synthase (NOS), endothelial NOS and 3-nitrotyrosine immunoreactivities are selectively increased in the spinal motoneurons of sporadic ALS. Other study suggests that 3-nitrotyrosine immunoreactivity is enhanced in the spinal motoneurons of sporadic and familial ALS patients. The hypothesis is postulated that increased production of radical species, such as superoxide and peroxynitrite, may cause motoneuron degeneration in ALS. There are increased amounts of nitric oxide and SOD hypoactivities in the brain and spinal cord of wobbler mice. NOS is also induced in the vacuolated spinal motoneurons or axons in this animal. Free radicals might contribute to the pathogenesis of wobbler mouse motoneuron disease. Lecithinized SOD treatment has retarded the progression of this disease. This evidence allowed us to determine whether NOS inhibitors delay progression of wobbler mouse motoneuron disease. After clinical diagnosis at age 3-4 weeks, wobbler mice were injected with intraperitoneal non-selective NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg), two doses of neuronal NOS inhibitor, 7-nitroindazole (5 or 50 mg/kg) or a vehicle solution, daily for 4 weeks in a blind fashion. In comparison with vehicle, 7-nitroindazole-treated mice potentiated grip strength and attenuated deformities in the forelimbs. 7-Nitroindazole treatment increased the biceps muscle weight, reduced denervation muscle atrophy, and suppressed degeneration of spinal motoneurons. To a lesser degree, L-NAME-treated mice displayed slowed progression of disease. The present studies indicate that neuronal NOS inhibitor may be a candidate for promising therapy in lower motoneuron disease or motor neuropathy. PMID:9804111

  4. Hypocretin (orexin) input to trigeminal and hypoglossal motoneurons in the cat: a double-labeling immunohistochemical study.

    PubMed

    Fung, S J; Yamuy, J; Sampogna, S; Morales, F R; Chase, M H

    2001-06-01

    In trigeminal and hypoglossal motor nuclei of adult cats, hypocretin immunoreactive fiber varicosities were observed in apposition to retrogradely labeled motoneuron somata and dendrites. Among those lateral hypothalamus neurons that project to the hypoglossal nucleus some were determined to be hypocretin immunoreactive and were located amongst the single-labeled hypocretinergic neurons. These data suggest that hypocretin may play a role in the synaptic control of these motoneurons. PMID:11382413

  5. Decreased succinate dehydrogenase activity of gamma and alpha motoneurons in mouse spinal cords following 13 weeks of exposure to microgravity.

    PubMed

    Ishihara, Akihiko; Nagatomo, Fumiko; Fujino, Hidemi; Kondo, Hiroyo; Ohira, Yoshinobu

    2013-10-01

    Cell body size and succinate dehydrogenase activity of motoneurons in the dorsolateral region of the ventral horn in the lumbar and cervical segments of the mouse spinal cord were assessed after long-term exposure to microgravity and compared with those of ground-based controls. Mice were housed in a mouse drawer system on the International Space Station for 13 weeks. The mice were transported to the International Space Station by the Space Shuttle Discovery and returned to Earth by the Space Shuttle Atlantis. No changes in the cell body size of motoneurons were observed in either segment after exposure to microgravity, but succinate dehydrogenase activity of small-sized (<300 μm(2)) gamma and medium-sized (300-700 μm(2)) alpha motoneurons, which have higher succinate dehydrogenase activity than large-sized (>700 μm(2)) alpha motoneurons, in both segments was lower than that of ground-based controls. We concluded that exposure to microgravity for longer than 3 months induced decreased succinate dehydrogenase activity of both gamma and slow-type alpha motoneurons. In particular, the decreased succinate dehydrogenase activity of gamma motoneurons was observed only after long-term exposure to microgravity. PMID:23943522

  6. The afterhyperpolarization conductance exerts the same control over the gain and variability of motoneurone firing in anaesthetized cats

    PubMed Central

    Manuel, Marin; Meunier, Claude; Donnet, Maud; Zytnicki, Daniel

    2006-01-01

    Does the afterhyperpolarization current control the gain and discharge variability of motoneurones according to the same law? We investigated this issue in lumbar motoneurones of anaesthetized cats. Using dynamic clamp, we measured the conductance, time constant and driving force of the AHP current in a sample of motoneurones and studied how the gain was correlated to these quantities. To study the action of the AHP on the discharge variability and to compare it to its action on the gain, we injected an artificial AHP-like current in motoneurones. This increased the natural AHP. In three motoneurones, we abolished most of the natural AHP with the calcium chelator BAPTA to investigate the condition where the discharge was essentially controlled by the artificial AHP. Our results demonstrate that both the gain and the coefficient of variation of the firing rate are inversely proportional to the magnitude and to the time constant of the artificial AHP conductance. This indicates that the AHP exerts the same control over the gain and the variability. This mechanism ensures that the variability of the discharge is modulated with the gain. This guarantees a great regularity of the discharge when the motoneurone is in a low excitability state and hence good control of the force produced. PMID:16931549

  7. The influence of a 5-wk whole body vibration on electrophysiological properties of rat hindlimb spinal motoneurons.

    PubMed

    Baczyk, M; Hałuszka, A; Mrówczyński, W; Celichowski, J; Krutki, P

    2013-06-01

    The study aimed at determining the influence of a whole body vibration (WBV) on electrophysiological properties of spinal motoneurons. The WBV training was performed on adult male Wistar rats, 5 days a week, for 5 wk, and each daily session consisted of four 30-s runs of vibration at 50 Hz. Motoneuron properties were investigated intracellularly during experiments on deeply anesthetized animals. The experimental group subjected to the WBV consisted of seven rats, and the control group of nine rats. The WBV treatment induced no significant changes in the passive membrane properties of motoneurons. However, the WBV-evoked adaptations in excitability and firing properties were observed, and they were limited to fast-type motoneurons. A significant decrease in rheobase current and a decrease in the minimum and the maximum currents required to evoke steady-state firing in motoneurons were revealed. These changes resulted in a leftward shift of the frequency-current relationship, combined with an increase in slope of this curve. The functional relevance of the described adaptive changes is the ability of fast motoneurons of rats subjected to the WBV to produce series of action potentials at higher frequencies in a response to the same intensity of activation. Previous studies proved that WBV induces changes in the contractile parameters predominantly of fast motor units (MUs). The data obtained in our experiment shed a new light to possible explanation of these results, suggesting that neuronal factors also play a substantial role in MU adaptation. PMID:23486208

  8. The CES-2-related transcription factor E4BP4 is an intrinsic regulator of motoneuron growth and survival.

    PubMed

    Junghans, Dirk; Chauvet, Sophie; Buhler, Emmanuelle; Dudley, Keith; Sykes, Toby; Henderson, Christopher E

    2004-09-01

    The regulation of neuronal growth and survival during development requires interplay between extrinsic and intrinsic factors. Among the latter, transcription factors play a key role. In the nematode, the transcription factor CES-2 predisposes neurosecretory motoneurons to death, whereas E4BP4 (NFIL3), one of its vertebrate homologs, regulates survival of pro-B lymphocytes. We show that E4BP4 is expressed by embryonic rat and chicken motoneurons in vivo, with levels being highest in neurons that survive the period of naturally occurring cell death. Overexpression of E4BP4 by electroporation of purified motoneurons in culture protected them almost completely against cell death triggered by removal of neurotrophic factors or activation of death receptors. Moreover, E4BP4 strongly enhanced neuronal cell size and axonal growth. Axons of motoneurons transfected with E4BP4 were 3.5-fold longer than control neurons grown on laminin; this effect required the activity of PI3 kinase. In vivo, overexpression of E4BP4 in chicken embryos reduced the number of dying motoneurons by 45%. Our results define E4BP4 as a novel intrinsic regulator of motoneuron growth and survival. Pathways regulated by E4BP4 are of potential interest both for understanding neuromuscular development and for promoting neuronal survival and regeneration in pathological situations. PMID:15306565

  9. Projections of pyramidal tract cells to alpha-motoneurones innervating hind-limb muscles in the monkey.

    PubMed Central

    Jankowska, E; Padel, Y; Tanaka, R

    1975-01-01

    1. We have investigated the spatial organization of monosynaptic corticospinal projections to hind-limb motoneurones, using near threshold stimulation of the surface of the precentral gyrus to activate pyramidal tract (PT) cells and intracellular recording from motoneurones to detect the resulting e.p.s.p.s. 2. Monosynaptic e.p.s.p.s. of cortical origin were seen in all motoneurone species investigated, those of distal as well as of proximal hind-limb muscles. The proportion of motoneurones in which the e.s.p.s. were evoked and the amplitudes of the latter indicated a more extensive cortical projection to motor nuclei for distal than for proximal muscles, as previously found for forelimb motoneurones. 3. Cortical areas from which monosynaptic e.p.s.p.s. were evoked in individual motoneurones were remarkably large, most often between 3 and 7 mm2. Several motoneurones appeared to have two or three separate areas within the hind-limb division of the motor cortex. 4. Areas of location of pyramidal tract cells projecting to various motoneurones innervating one muscle were usually not identical. They overlapped often only partially or did not overlap at all. 5. Areas of location of pyramidal tract cells projecting to motor nuclei for different muscles often showed an extensive overlap. When it occurred, various motoneurones of a given motor nucleus had common cortical projection areas with motoneurones of other motor nuclei, either to synergistic or to antagonistic muscles. Our results give further evidence for overlapping of areas of cortical projections to motoneurones and speak against a mosaic-like organization of pyramidal tract cells projecting to different motor nuclei. 6. The rise times of cortically evoked e.p.s.p.s. indicate that the corticospinal tract fibres terminate on motoneurones at approximately similar distances from the soma as group Ia afferents. The small amplitudes of the majority of e.p.s.p.s. evoked by near threshold cortical stimulation therefore

  10. Physiological consequences of doublet discharges on motoneuronal firing and motor unit force.

    PubMed

    Mrówczyński, Włodzimierz; Celichowski, Jan; Raikova, Rositsa; Krutki, Piotr

    2015-01-01

    The double discharges are observed at the onset of contractions of mammalian motor units (MUs), especially during their recruitment to strong or fast movements. Doublets lead to MU force increase and improve ability of muscles to maintain high force during prolonged contractions. In this review we discuss an ability to produce doublets by fast and slow motoneurons (MNs), their influence on the course of action potential afterhyperpolarization (AHP) as well as its role in modulation of the initial stage of the firing pattern of MNs. In conclusion, a generation of doublets is an important strategy of motor control, responsible for fitting the motoneuronal firing rate to the optimal for MUs at the start of their contraction, necessary for increment of muscle force. PMID:25805972

  11. Descending pathways to the cutaneus trunci muscle motoneuronal cell group in the cat

    NASA Technical Reports Server (NTRS)

    Holstege, Gert; Blok, Bertil F.

    1989-01-01

    The descending pathways to the motoneuronal cell group of the cutaneous trunci muscle (CTM) of the cat were investigated by injecting H-3-labeled lucine into the brain stem, the diencephalon, or the C1, C2, C6, and C8 segments of the spinal cord, and examining fixed autoradiographic sections of the spinal cord and brain regions. Results demonstrate presence of specific supraspinal projectons to the CTM motor nucleus originating in the contralateral nucleus retroambiguous and the ipsilateral dorsolateral pontine tegmentum. Results also suggest that propriospinal pathways to the CTM motor nucleus originating in the cervical cord do not exist, although these propriospinal projections to all other motoneuronal cell groups surrounding the CTM nucleus are very strong.

  12. Neuropathology in respiratory-related motoneurons in young Pompe (Gaa(-/-)) mice.

    PubMed

    Turner, Sara M F; Hoyt, Aaron K; ElMallah, Mai K; Falk, Darin J; Byrne, Barry J; Fuller, David D

    2016-06-15

    Respiratory and/or lingual dysfunction are among the first motor symptoms in Pompe disease, a disorder resulting from absence or dysfunction of the lysosomal enzyme acid α-glucosidase (GAA). Here, we histologically evaluated the medulla, cervical and thoracic spinal cords in 6 weeks old asymptomatic Pompe (Gaa(-/-)) mice to determine if neuropathology in respiratory motor regions has an early onset. Periodic acid-Schiff (PAS) staining indicated glycogen accumulation was exclusively occurring in Gaa(-/-) hypoglossal, mid-cervical and upper thoracic motoneurons. Markers of DNA damage (Tunel) and ongoing apoptosis (Cleaved Caspase 3) did not co-localize with PAS staining, but were prominent in a medullary region which included the nucleus tractus solitarius, and also in the thoracic spinal dorsal horn. We conclude that respiratory-related motoneurons are particularly susceptible to GAA deficiency and that neuronal glycogen accumulation and neurodegeneration may occur independently in early stage disease. The data support early therapeutic intervention in Pompe disease. PMID:26921786

  13. Corticospinal Inputs to Primate Motoneurons Innervating the Forelimb from Two Divisions of Primary Motor Cortex and Area 3a

    PubMed Central

    Witham, Claire L.; Fisher, Karen M.; Edgley, Steve A.

    2016-01-01

    Previous anatomical work in primates has suggested that only corticospinal axons originating in caudal primary motor cortex (“new M1”) and area 3a make monosynaptic cortico-motoneuronal connections with limb motoneurons. By contrast, the more rostral “old M1” is proposed to control motoneurons disynaptically via spinal interneurons. In six macaque monkeys, we examined the effects from focal stimulation within old and new M1 and area 3a on 135 antidromically identified motoneurons projecting to the upper limb. EPSPs with segmental latency shorter than 1.2 ms were classified as definitively monosynaptic; these were seen only after stimulation within new M1 or at the new M1/3a border (incidence 6.6% and 1.3%, respectively; total n = 27). However, most responses had longer latencies. Using measures of the response facilitation after a second stimulus compared with the first, and the reduction in response latency after a third stimulus compared with the first, we classified these late responses as likely mediated by either long-latency monosynaptic (n = 108) or non-monosynaptic linkages (n = 108). Both old and new M1 generated putative long-latency monosynaptic and non-monosynaptic effects; the majority of responses from area 3a were non-monosynaptic. Both types of responses from new M1 had significantly greater amplitude than those from old M1. We suggest that slowly conducting corticospinal fibers from old M1 generate weak late monosynaptic effects in motoneurons. These may represent a stage in control of primate motoneurons by the cortex intermediate between disynaptic output via an interposed interneuron seen in nonprimates and the fast direct monosynaptic connections present in new M1. SIGNIFICANCE STATEMENT The corticospinal tract in Old World primates makes monosynaptic connections to motoneurons; previous anatomical work suggests that these connections come only from corticospinal tract (CST) neurons in the subdivision of primary motor cortex within the

  14. Activation patterns of embryonic chick hind-limb muscles following blockade of activity and motoneurone cell death.

    PubMed Central

    Landmesser, L T; Szente, M

    1986-01-01

    Motoneurone cell death and spontaneous embryonic motility were blocked in chick embryos by daily in ovo injections of d-tubocurarine from stage 28-36 (E5-10). Isolated spinal cord-hind-limb preparations were prepared from these embryos and movement sequences in response to electrical stimulation of the thoracic cord were assessed, after drug wash-out, by electromyogram (e.m.g.) or muscle-nerve recordings. In embryos in which complete blockade of lumbar motoneurone cell death was later confirmed histologically, flexor and extensor motoneurone pools were found to be activated in alternating bursts as occurs in control embryos. Thus the development of the basic cord circuits responsible for these patterns of motoneurone activation does not require motoneurone cell death. Partial blockade of motoneurone cell death by guanosine 3',5'-phosphate (cyclic GMP) was also without effect on muscle activation patterns. In ovo injection of d-tubocurarine or alpha-bungarotoxin in doses sufficient to block embryonic motility was found to have a direct effect on the spinal cord, preventing the patterned activation of motoneurone pools in alternating bursts. Cords removed from treated embryos behaved similarly to cords in which these drugs were applied acutely in the bath. Minor changes in muscle activation patterns that occurred with chronic drug treatment were also observed in acutely treated cords and appear to be a direct and persistent effect of the drugs on cord circuits. It is possible to conclude that cholinergic circuits within the chick lumbar cord play a role in the normal patterned activation of flexor and extensor motoneurone pools. Systemically applied drugs can have access to these circuits, indicating a need for caution when interpreting the results of drugs applied in this manner to developing embryos. We also conclude that neither the activation of motoneurones in patterned bursts, nor the afferent feed-back from the movements that result, are required to form the

  15. Calpain Inhibition Protected Spinal Cord Motoneurons against 1-methyl-4-phenylpyridinium ion and Rotenone

    PubMed Central

    Samantaray, Supriti; Knaryan, Varduhi H.; Le Gal, Charlene; Ray, Swapan K.; Banik, Naren L.

    2011-01-01

    Parkinson's disease (PD), characterized by selective midbrain nigrostriatal dopaminergic degeneration, is consistently associated with moderate systemic mitochondrial dysfunction. Downstream degeneration of spinal cord has also been suggested in PD, although the mechanisms have not been much investigated. In the present study, two mitochondrial toxicants, 1-methyl-4-phenylpyridinium ion (MPP+) and rotenone were tested in ventral spinal cord (VSC 4.1) motoneuronal cells. Cell death was assessed by morphological and biochemical means to discern a lower apoptosis-inducing concentration and LC50, which were subsequently compared in further cytoprotection experiments. Mitochondrial toxicants dose-dependently induced increase in intracellular free Ca2+ level, which was conducive for increased expression and activities of Ca2+-activated neutral protease calpain and downstream caspase-3. Thus, mitochondrial damage triggered apoptotic mechanisms in spinal cord motoneurons. Inhibition of calpain by calpeptin significantly attenuated damaging effects of MPP+ and rotenone on motoneurons, especially at low apoptosis-inducing concentrations of toxicants and partly at their LC50, as demonstrated by absence of DNA ladder formation and decrease in TUNEL-positive cells. Cytoprotection by calpeptin was observed with marked decreases in Bax:Bcl-2 ratio and activities of calpain and caspase-3, which affirmed the role of mitochondrial dysfunction and involvement of intrinsic pathway in mediation of apoptosis. These findings strongly suggested that parkinsonian toxicants MPP+ and rotenone at low doses induced cascade of cell damaging effects in spinal cord motoneurons, thus, highlighting the possibility of induction of apoptotic mechanisms in these cells, when subjected to mitochondrial stress. Cytoprotection rendered by calpeptin further validated the involvement of calpain in apoptosis and suggested calpain inhibition as a potential neuroprotective strategy. PMID:21723922

  16. Eye Movements and Abducens Motoneuron Behavior after Cholinergic Activation of the Nucleus Reticularis Pontis Caudalis

    PubMed Central

    Márquez-Ruiz, Javier; Escudero, Miguel

    2010-01-01

    Study Objectives: The aim of this work was to characterize eye movements and abducens (ABD) motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis (NRPC). Methods: Six female adult cats were prepared for chronic recording of eye movements (using the scleral search-coil technique), electroencephalography, electromyography, ponto-geniculo-occipital (PGO) waves in the lateral geniculate nucleus, and ABD motoneuron activities after microinjections of the cholinergic agonist carbachol into the NRPC. Results: Unilateral microinjections of carbachol in the NRPC induced tonic and phasic phenomena in the oculomotor system. Tonic effects consisted of ipsiversive rotation to the injected side, convergence, and downward rotation of the eyes. Phasic effects consisted of bursts of rhythmic rapid eye movements directed contralaterally to the injected side along with PGO-like waves in the lateral geniculate and ABD nuclei. Although tonic effects were dependent on the level of drowsiness, phasic effects were always present and appeared along with normal saccades when the animal was vigilant. ABD motoneurons showed phasic activities associated with ABD PGO-like waves during bursts of rapid eye movements, and tonic and phasic activities related to eye position and velocity during alertness. Conclusion The cholinergic activation of the NRPC induces oculomotor phenomena that are somewhat similar to those described during REM sleep. A precise comparison of the dynamics and timing of the eye movements further suggests that a temporal organization of both NRPCs is needed to reproduce the complexity of the oculomotor behavior during REM sleep. Citation: Márquez-Ruiz J; Escudero M. Eye movements and abducens motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis. SLEEP 2010;33(11):1517-1527. PMID:21102994

  17. Repetitive doublet firing of motor units: evidence for plateau potentials in human motoneurones?

    PubMed

    Kudina, Lydia P; Andreeva, Regina E

    2010-07-01

    During voluntary muscle contraction, human motoneurones can exhibit specific discharge patterns: single and repetitive doublets. Delayed depolarization has been accepted as the mechanism underlying single doublets. Repetitive doublet firing has been studied much less and its controlling mechanisms remain obscure. The aim of the present study was to examine properties of repetitive doublets in human motoneurones and to consider their underlying potential mechanisms. It was found that 22 of 41 (53.7%) lower-threshold motor units (MUs) in the trapezius and 15 of 42 (35.7%) MUs in triceps brachii displayed repetitive doublets with the mean interspike intervals (ISIs) of 5.5 +/- 1.1 and 6.4 +/- 2.6 ms, respectively. Each doublet was followed by a prolonged post-doublet ISI. The analysis of properties of repetitive doublets showed that they were typically initiated in quiescent motoneurones rather than in firing ones (appearing just at recruitment in an all-or-none manner) and could only be maintained at a certain level of muscle contraction. Repetitive doublets were interrupted either voluntarily (by the subject), or spontaneously with sudden transition from doublet firing to single discharges-the firing behaviour that may be referred to as a firing-pattern "jump". The properties of doublet firing seem to be consistent with traits of motoneurone firing in the presence of plateau potentials reported in animal studies. It was suggested that the potential mechanisms underlying repetitive doublet firing could include a delayed depolarization as the primary determinant, which likely could become persistent probably due to a plateau potential activated in parallel with a common synaptic input. PMID:20508919

  18. Synaptic action of R beta neurons on phrenic motoneurons studied with spike-triggered averaging.

    PubMed

    Lipski, J; Kubin, L; Jodkowski, J

    1983-12-12

    The functional role of dorsal medullary inspiratory neurons with excitatory input from lung stretch receptors (R beta neurons) is a matter of controversy. The present study, performed on chloralose-anesthetized and paralyzed cats, ventilated mainly with a phrenic-controlled servorespirator, deals with the spinal projection of these neurons, a property which suggests their involvement in the efferent part of the medullary respiratory complex. Out of 37 inspiratory neurons which could be excited antidromically following microstimulation within the contralateral C6 phrenic nucleus (latency 2.0 ms +/- 0.4, S.D.), 17 were classified by the 'no-inflation' test as R beta. Intracellular recording of synaptic potentials from phrenic motoneurons using the 'spike-triggered averaging' technique were made. In 10 phrenic motoneurons, the averaging revealed individual EPSPs (peak amplitude 150 +/- 110 microV, rise time 0.5 +/- 0.2 ms) time-locked to action potentials of 5 out of 7 R beta neurons tested. Cross-correlation of the R beta neurons firing with the activity of C5 and C6 phrenic rootlets indicated a divergence of excitatory action within the phrenic nucleus. For comparison, in 3 phrenic motoneurons individual EPSPs were recorded when the activity of 3 R alpha cells was used to trigger the averaging. It is concluded that at least some R beta neurons, similarly to R alpha neurons, project to the contralateral phrenic nucleus and can make monosynaptic excitatory connections with phrenic motoneurons. The finding that individual EPSPs were similar when averaging was triggered by the activity of either R beta or R alpha neurons provides new evidence for our earlier hypothesis that bulbospinal inspiratory neurons of the solitary tract nucleus may be subdivided into two categories only on a quantitative basis. PMID:6661613

  19. Influence of developmental nicotine exposure on spike-timing precision and reliability in hypoglossal motoneurons.

    PubMed

    Powell, Gregory L; Levine, Richard B; Frazier, Amanda M; Fregosi, Ralph F

    2015-03-15

    Smoothly graded muscle contractions depend in part on the precision and reliability of motoneuron action potential generation. Whether or not a motoneuron generates spikes precisely and reliably depends on both its intrinsic membrane properties and the nature of the synaptic input that it receives. Factors that perturb neuronal intrinsic properties and/or synaptic drive may compromise the temporal precision and the reliability of action potential generation. We have previously shown that developmental nicotine exposure (DNE) alters intrinsic properties and synaptic transmission in hypoglossal motoneurons (XIIMNs). Here we show that the effects of DNE also include alterations in spike-timing precision and reliability, and spike-frequency adaptation, in response to sinusoidal current injection. Current-clamp experiments in brainstem slices from neonatal rats show that DNE lowers the threshold for spike generation but increases the variability of spike-timing mechanisms. DNE is also associated with an increase in spike-frequency adaptation and reductions in both peak and steady-state firing rate in response to brief, square wave current injections. Taken together, our data indicate that DNE causes significant alterations in the input-output efficiency of XIIMNs. These alterations may play a role in the increased frequency of obstructive apneas and altered suckling strength and coordination observed in nicotine-exposed neonatal humans. PMID:25552642

  20. An Avirulent Mutant of Rabies Virus Is Unable To Infect Motoneurons In Vivo and In Vitro

    PubMed Central

    Coulon, Patrice; Ternaux, Jean-Pierre; Flamand, Anne; Tuffereau, Christine

    1998-01-01

    An antigenic double mutant of rabies virus (challenge virus standard [CVS] strain) was selected by successive use of two neutralizing antiglycoprotein monoclonal antibodies, both specific for antigenic site III. This mutant differed from the original virus strain by two amino acid substitutions in the ectodomain of the glycoprotein. The lysine in position 330 and the arginine in position 333 were replaced by asparagine and methionine, respectively. This double mutant was not pathogenic for adult mice. When injected intramuscularly into the forelimbs of adult mice, this virus could not penetrate the nervous system, either by the motor or by the sensory route, while respective single mutants infected motoneurons in the spinal cord and sensory neurons in the dorsal root ganglia. In vitro experiments showed that the double mutant was able to infect BHK cells, neuroblastoma cells, and freshly prepared embryonic motoneurons, albeit with a lower efficiency than the CVS strain. Upon further incubation at 37°C, the motoneurons became resistant to infection by the mutant while remaining permissive to CVS infection. These results suggest that rabies virus uses different types of receptors: a molecule which is ubiquitously expressed at the surface of continuous cell lines and which is recognized by both CVS and the double mutant and a neuron-specific molecule which is not recognized by the double mutant. PMID:9420224

  1. Concomitant changes in afterhyperpolarization and twitch following repetitive stimulation of fast motoneurones and motor units.

    PubMed

    Krutki, P; Mrówczyński, W; Raikova, R; Celichowski, J

    2014-02-01

    The study aimed at determining changes in a course of motoneuronal afterhyperpolarization (AHP) and in contractile twitches of motor units (MUs) during activity evoked by increasing number of stimuli (from 1 to 5), at short interspike intervals (5 ms). The stimulation was applied antidromically to spinal motoneurones or to isolated axons of MUs of the medial gastrocnemius muscle within two separate series of experiments on anesthetized rats. Alterations in the amplitude and time parameters of the AHP of successive spikes were compared to changes in force and time course of successive twitches obtained by mathematical subtraction of tetanic contractions evoked by one to five stimuli. The extent of changes of the studied parameters depended on a number of applied stimuli. The maximal modulation of the AHP and twitch parameters (a prolongation and an increase in the AHP and twitch amplitudes) was typically observed after the second pulse, while higher number of pulses at the same frequency did not induce so prominent changes. One may conclude that changes observed in parameters of action potentials of motoneurons are concomitant to changes in contractile properties of MU twitches. This suggests that both modulations of the AHP and twitch parameters reflect mechanisms leading to force development at the beginning of MU activity. PMID:24202237

  2. Axon-somatic back-propagation in detailed models of spinal alpha motoneurons

    PubMed Central

    Balbi, Pietro; Martinoia, Sergio; Massobrio, Paolo

    2015-01-01

    Antidromic action potentials following distal stimulation of motor axons occasionally fail to invade the soma of alpha motoneurons in spinal cord, due to their passing through regions of high non-uniformity. Morphologically detailed conductance-based models of cat spinal alpha motoneurons have been developed, with the aim to reproduce and clarify some aspects of the electrophysiological behavior of the antidromic axon-somatic spike propagation. Fourteen 3D morphologically detailed somata and dendrites of cat spinal alpha motoneurons have been imported from an open-access web-based database of neuronal morphologies, NeuroMorpho.org, and instantiated in neurocomputational models. An axon hillock, an axonal initial segment and a myelinated axon are added to each model. By sweeping the diameter of the axonal initial segment (AIS) and the axon hillock, as well as the maximal conductances of sodium channels at the AIS and at the soma, the developed models are able to show the relationships between different geometric and electrophysiological configurations and the voltage attenuation of the antidromically traveling wave. In particular, a greater than usually admitted sodium conductance at AIS is necessary and sufficient to overcome the dramatic voltage attenuation occurring during antidromic spike propagation both at the myelinated axon-AIS and at the AIS-soma transitions. PMID:25729362

  3. Modulation of recurrent inhibition from knee extensors to ankle motoneurones during human walking

    PubMed Central

    Lamy, Jean-Charles; Iglesias, Caroline; Lackmy, Alexandra; Nielsen, Jens Bo; Katz, Rose; Marchand-Pauvert, Véronique

    2008-01-01

    The neural control for muscle coordination during human locomotion involves spinal and supraspinal networks, but little is known about the exact mechanisms implicated. The present study focused on modulation of heteronymous recurrent inhibition from knee extensors to ankle motoneurones at different times in the gait cycle, when quadriceps (Quad) muscle activity overlaps that in tibialis anterior (TA) and soleus (Sol). The effects of femoral nerve stimulation on ankle motoneurones were investigated during treadmill walking and during tonic co-contraction of Quad and TA/Sol while standing. Recurrent inhibition of TA motoneurones depended on the level of background EMG, and was similar during walking and standing for matched background EMG levels. On the other hand, recurrent inhibition in Sol was reduced in early stance, with respect to standing, and enhanced in late stance. Reduced inhibition in Sol was also observed when Quad was coactivated with TA around the time of heel contact, compared to standing at matched background EMG levels in the two muscles. The modulation of recurrent inhibition of Sol during walking might reflect central and/or peripheral control of the Renshaw cells. These modulations could be implicated in the transition phases, from swing to stance to assist Sol activation during the stance phase, and from stance to swing, for its deactivation. PMID:18936080

  4. A putative neuronal network controlling the activity of the leg motoneurons of the stick insect.

    PubMed

    Toth, Tibor I; Daun-Gruhn, Silvia

    2011-12-21

    It is widely accepted that the electrical activity of motoneurons that drive locomotion in the stick insect are controlled by two separate mechanisms: (i) the frequency of the activity through the central pattern generator, which provides the rhythm of movement during locomotion and (ii) the 'magnitude' through circuits distinct from the earlier one. In this study, we show a possible way of how this control mechanism might be implemented in the nervous system of the stick insect by means of a network model. To do this, we had to define the 'magnitude' of the neuronal activity more precisely as the average number of spikes per unit time. The model was constructed on the basis of relevant electrophysiological and morphological data. However, only their integration in the model led to the novel properties that enable the network quickly to adapt the motoneuronal activity to central commands or sensory signals by changing both the firing pattern and intensity of the motoneuron discharges. The network would thus act as the controlling network for each of the muscle pairs that move the individual joints in each of the legs. Our model may contribute to a better understanding of the mechanisms that underlie the fast adaptive control of locomotion in this, and possibly in other types of locomotor systems. PMID:22089647

  5. Subthreshold excitatory activity and motoneuron discharge during REM periods of active sleep.

    PubMed

    Chase, M H; Morales, F R

    1983-09-16

    A striking paradox of the rapid eye movement periods of active sleep, which are typically characterized by the exacerbation of somatomotor atonia, is the occurrence of muscle twitches and jerks. The purpose of this study was to examine the specific motoneuron membrane potential processes responsible for these myoclonic patterns of activity. In lumbar motoneurons, examined intracellularly in the cat prepared for long-term study, these processes consisted of recurrent depolarizing membrane potential shifts and spontaneous action potentials that were either full-sized or of partial amplitude. In addition, the invasion of antidromically induced spikes into the soma was often blocked. Hyperpolarizing potentials were evident in the intervals between spontaneous spikes. Hyperpolarization was also observed immediately before depolarization and spike activity, in contrast to the gradual depolarization of the motoneuron membrane potential that always occurred during wakefulness. Thus, during rapid eye movement periods, in conjunction with muscle twitches and jerks, a strong excitatory input is superimposed on a background of inhibitory input. The unique patterns of membrane potential change that arise thus seem to result from the simultaneous coactivation of excitatory and inhibitory processes. PMID:6310749

  6. Respiratory neuroplasticity and cervical spinal cord injury: translational perspectives

    PubMed Central

    Lane, Michael A.; Fuller, David D.; White, Todd E.; Reier, Paul J.

    2008-01-01

    Paralysis of the diaphragm is a severe consequence of cervical spinal cord injury. This condition can be experimentally modeled by lateralized, high cervical lesions that interrupt descending inspiratory drive to the corresponding phrenic nucleus. Although partial recovery of ipsilateral diaphragm function occurs over time, recent findings show persisting chronic deficits in ventilation and phrenic motoneuron activity. Some evidence suggests, however, that spontaneous recovery can be enhanced by modulating neural pathways to phrenic motoneurons via synaptic circuitries which appear more complex than previously envisioned. The present review highlights these and other recent experimental multi-disciplinary findings pertaining to respiratory neuroplasticity in the rat. Translational considerations are also emphasized, with specific attention directed at the clinical and interpretational strengths of different lesion models and outcome measures. PMID:18775573

  7. Static γ-motoneurones couple group Ia and II afferents of single muscle spindles in anaesthetised and decerebrate cats

    PubMed Central

    Gladden, M H; Matsuzaki, H

    2002-01-01

    Ideas about the functions of static γ-motoneurones are based on the responses of primary and secondary endings to electrical stimulation of single static γ-axons, usually at high frequencies. We compared these effects with the actions of spontaneously active γ-motoneurones. In anaesthetised cats, afferents and efferents were recorded in intramuscular nerve branches to single muscle spindles. The occurrence of γ-spikes, identified by a spike shape recognition system, was linked to video-taped contractions of type-identified intrafusal fibres in the dissected muscle spindles. When some static γ-motoneurones were active at low frequency (< 15 Hz) they coupled the firing of group Ia and II afferents. Activity of other static γ-motoneurones which tensed the intrafusal fibres appeared to enhance this effect. Under these conditions the secondary ending responded at shorter latency than the primary ending. In another series of experiments on decerebrate cats, responses of primary and secondary endings of single muscle spindles to activation of γ-motoneurones by natural stimuli were compared with their responses to electrical stimulation of single γ-axons supplying the same spindle. Electrical stimulation mimicked the natural actions of γ-motoneurones on either the primary or the secondary ending, but not on both together. However, γ-activity evoked by natural stimuli coupled the firing of afferents with the muscle at constant length, and also when it was stretched. Analysis showed that the timing and tightness of this coupling determined the degree of summation of excitatory postsynaptic potentials (EPSPs) evoked by each afferent in α-motoneurones and interneurones contacted by terminals of both endings, and thus the degree of facilitation of reflex actions of group II afferents. PMID:12181298

  8. Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons.

    PubMed

    Oppenheim, R W; Wiese, S; Prevette, D; Armanini, M; Wang, S; Houenou, L J; Holtmann, B; Gotz, R; Pennica, D; Sendtner, M

    2001-02-15

    Developing motoneurons require trophic support from their target, the skeletal muscle. Despite a large number of neurotrophic molecules with survival-promoting activity for isolated embryonic motoneurons, those factors that are required for motoneuron survival during development are still not known. Cytokines of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor (LIF) family have been shown to play a role in motoneuron (MN) survival. Importantly, in mice lacking the LIFRbeta or the CNTFRalpha there is a significant loss of MNs during embryonic development. Because genetic deletion of either (or both) CNTF or LIF fails, by contrast, to perturb MN survival before birth, it was concluded that another ligand exists that is functionally inactivated in the receptor deleted mice, resulting in MN loss during development. One possible candidate for this ligand is the CNTF-LIF family member cardiotrophin-1 (CT-1). CT-1 is highly expressed in embryonic skeletal muscle, secreted by myotubes, and promotes the survival of cultured embryonic mouse and rat MNs. Here we show that ct-1 deficiency causes increased motoneuron cell death in spinal cord and brainstem nuclei of mice during a period between embryonic day 14 and the first postnatal week. Interestingly, no further loss was detectable during the subsequent postnatal period, and nerve lesion in young adult ct-1-deficient mice did not result in significant additional loss of motoneurons, as had been previously observed in mice lacking both CNTF and LIF. CT-1 is the first bona fide muscle-derived neurotrophic factor to be identified that is required for the survival of subgroups of developing motoneurons. PMID:11160399

  9. The pattern of excitation of human lower limb motoneurones by probable group II muscle afferents.

    PubMed

    Simonetta-Moreau, M; Marque, P; Marchand-Pauvert, V; Pierrot-Deseilligny, E

    1999-05-15

    1. Heteronymous group II effects were investigated in the human lower limb. Changes in firing probability of single motor units in quadriceps (Q), biceps (Bi), semitendinosus (ST), gastrocnemius medialis (GM) and tibialis anterior (TA) were studied after electrical stimuli between 1 and 3 times motor threshold (MT) applied to common peroneal (CP), superficial (SP) and deep (DP) peroneal, Bi and GM nerves in those nerve-muscle combinations without recurrent inhibition. 2. Stimulation of the CP and Bi nerves evoked in almost all of the explored Q motor units a biphasic excitation with a low-threshold early peak, attributable to non-monosynaptic group I excitation, and a higher threshold late peak. When the CP nerve was cooled (or the stimulation applied to a distal branch, DP), the increase in latency was greater for the late than for the early peak, indicating that the late excitation is due to stimulation of afferents with a slower conduction velocity than group I fibres, presumably in the group II range. In ST motor units the group II excitation elicited by stimulation of the GM and SP nerves was particularly large and frequent, and the non-monosynaptic group I excitation was often replaced by an inhibition. 3. A late group II-induced excitation from CP to Q motoneurones and from GM and SP to ST motoneurones was also observed when using the H reflex as a test. 4. The electrical threshold and conduction velocity of the largest diameter fibres evoking the group II excitation were estimated to be 2.1 and 0.65 times those of the fastest Ia afferents, respectively. In the combinations tested in the present investigation the group II input seemed to be primarily of muscle origin. 5. The potent heteronymous group II excitation of motoneurones of both flexors and extensors of the knee contrasted with the absence of a group II effect from DP to GM and from GM to TA. In none of the combinations explored was there any evidence for group II inhibition of motoneurones. The

  10. Trophism between C-type axon terminals and thoracic motoneurones in the cat

    PubMed Central

    Pullen, A. H.; Sears, T. A.

    1983-01-01

    1. Quantitative ultrastructural examinations of axon terminals synapsing with normal α-motoneurones in segment T9 of cat spinal cord provided estimates of their numbers, sizes and synaptic structure. One synapse, the C type, derived from short-axon propriospinal segmental interneurones, was studied in detail. 2. The numbers, sizes and post-synaptic structure of normal C-type synapses at T9 were compared with similar estimates from material provided by cats subjected to partial central deafferentation by double spinal hemisection at T5 and T10 between 7 days and 2 years previously. 3. The proportion of C-type synapses present progessively increased from 1% in normal cats to 8·8% 200 days following hemisection, and had still attained a level of 3·1% by 2 years; these increases imply that the absolute number of C-type synapses underwent increase. 4. Mean sizes of C-type synapses increased from 4·0 μm (normal) to 5·8 μm (200 days) and retained their enlarged sizes up to 2 years (5·9 μm). Furthermore, while 84% of C-type synapses were under 6 μm in length in normal motoneurones, 48% were over 6 μm long 200 days post-operatively. 5. The unique post-synaptic structure of C-type synapses also proliferated following partial central deafferentation of the motoneurones. The elongated cistern, increased numbers and individual lengths of lamellae of the associated underlying rough endoplasmic reticulum indicated a trophic interaction between the presynaptic C terminal and its post-synaptic motoneurone. 6. Counts of ribosomes `bound' to lamellae of the subsynaptic rough endoplasmic reticulum, and of the lamellae-associated polyribosomes interposed between individual lamellae for normal and 200 day post-operative C-type synapses indicated an over-all post-operative increase in capacity for local subsynaptic protein synthesis topographically directed towards this type of axon terminal. 7. The observed greater increase in frequency of ribosomes `bound' to the rough

  11. Intracellular autogenetic and synergistic effects of muscular contraction on flexor motoneurones

    PubMed Central

    Green, D. G.; Kellerth, J.-O.

    1967-01-01

    1. Intracellular records have been taken from cat motoneurones innervating flexor muscles of the hind limb. Contractions of the ankle flexors tibialis anterior and extensor digitorum longus were elicited by stimulation of the peripheral end of the cut L 7 ventral root and the reflex effects of these contractions were recorded in silent and repetitively firing motoneurones. 2. Contraction usually produces a hyperpolarizing response inside flexor motoneurones. This hyperpolarization is tension-sensitive in the sense that when, at constant muscle extension, the strength of the contraction is increased, the magnitude of the inhibitory response is augmented. 3. Increasing the resting length of the muscles, while using a stimulus of constant strength to the ventral root, causes this inhibitory response to increase in some cells. More often, however, the hyperpolarization caused by contraction is gradually reduced in duration and/or amplitude as the muscles are extended. 4. Even with the muscles slackened, so that they develop no tension at their ends, contraction usually produces prominent hyperpolarization of the motoneurones. 5. By passing polarizing currents or injecting chloride ions through the intracellular micro-electrode, the hyperpolarizing potentials produced by contraction of the slack and extended muscles are shown to be, at least in part, genuinely post-synaptic inhibitory events. 6. When the neurone is fired repetitively by injected current, the `silent period' in contraction corresponds to the hyperpolarization of the post-synaptic membrane. 7. Monosynaptic testing of the flexor motoneurone pool has been used to confirm the essential features of the intracellularly recorded activity. 8. Acutely spinalizing the animal increases the magnitude of the inhibitory responses caused by contraction. 9. Recordings from dorsal root fibres show that Golgi tendon organs of the ankle flexors are very sensitive to contraction and are indeed often activated by the

  12. Electrophysiological properties of lumbar motoneurons in the alpha-chloralose-anesthetized cat during carbachol-induced motor inhibition.

    PubMed

    Xi, M C; Liu, R H; Yamuy, J; Morales, F R; Chase, M H

    1997-07-01

    The present study was undertaken 1) to examine the neuronal mechanisms responsible for the inhibition of spinal cord motoneurons that occurs in alpha-chloralose-anesthetized cats following the microinjection of carbachol into the nucleus pontis oralis (NPO), and 2) to determine whether the inhibitory mechanisms are the same as those that are responsible for the postsynaptic inhibition of motoneurons that is present during naturally occurring active sleep. Accordingly, the basic electrophysiological properties of lumbar motoneurons were examined, with the use of intracellular recording techniques, in cats anesthetized with alpha-chloralose and compared with those present during naturally occurring active sleep. The intrapontine administration of carbachol resulted in a sustained reduction in the amplitude of the spinal cord Ia monosynaptic reflex. Discrete large-amplitude inhibitory postsynaptic potentials (IPSPs), which are only present during the state of active sleep in the chronic cat, were also observed in high-gain recordings from lumbar motoneurons after the injection of carbachol. During carbachol-induced motor inhibition, lumbar motoneurons exhibited a statistically significant decrease in input resistance, membrane time constant and a reduction in the amplitude of the action potential's afterhyperpolarization. In addition, there was a statistically significant increase in rheobase and in the delay between the initial-segment (IS) and somadendritic (SD) portions of the action potential (IS-SD delay). There was a significant increase in the mean motoneuron resting membrane potential (i.e., hyperpolarization). The preceding changes in the electrophysiological properties of motoneurons, as well as the development of discrete IPSPs, indicate that lumbar motoneurons are postsynaptically inhibited after the intrapontine administration of carbachol in cats that are anesthetized with alpha-chloralose. These changes in the electrophysiological properties of lumbar

  13. Repeated stimuli for axonal growth causes motoneuron death in adult rats: the effect of botulinum toxin followed by partial denervation.

    PubMed

    White, C M; Greensmith, L; Vrbová, G

    2000-01-01

    Axons of motoneurons to tibialis anterior and extensor digitorum longus muscles of adult rats were induced to sprout by injecting botulinum toxin into them, by partial denervation or by a combination of the two procedures. Ten weeks later, the number of motoneurons innervating the control and operated tibialis anterior and extensor digitorum longus muscles was established by retrograde labelling with horseradish peroxidase. In the same preparations, the motoneurons were also stained with a Nissl stain (gallocyanin) to reveal motoneurons in the sciatic pool. Examination of the spinal cords from animals treated with botulinum toxin showed that the number of retrogradely labelled cells and those stained with gallocyanin in the ventral horn on the treated compared to the control side was unchanged. In rats that had their L4 spinal nerve sectioned on one side, the number of retrogradely labelled cells on the operated side was 48+/-3% (n = 5) of that present in the control unoperated ventral horn. Thus, just over half the innervation was removed by cutting the L4 spinal nerve. Counts made from gallocyanin-stained sections showed that 94+/-4% (n = 5) of motoneurons were present in the ventral horn on the operated side. Thus, section of the L4 spinal nerve did not lead to any death of motoneurons. In rats that had their muscles injected with botulinum toxin three weeks prior to partial denervation, the number of retrogradely labelled cells was reduced from 48+/-3% (n = 5) to 35+/-4% (n = 5). Moreover, only 67+/-5% (n = 5) of motoneurons stained with gallocyanin, suggesting that a proportion of motoneurons died after this combined procedure. This result was supported by experiments in which motor unit numbers in extensor digitorum longus muscles were determined by measurements of stepwise increments of force in response to stimulation of the motor nerve with increasing stimulus intensity. In partially denervated extensor digitorum longus muscles, 16.6+/-0.7 (n = 5) motor

  14. Increased incidence of gap junctional coupling between spinal motoneurones following transient blockade of NMDA receptors in neonatal rats

    PubMed Central

    Mentis, George Z; Díaz, Eugenia; Moran, Linda B; Navarrete, Roberto

    2002-01-01

    Neonatal rat motoneurones are electrically coupled via gap junctions and the incidence of this coupling declines during postnatal development. The mechanisms involved in this developmental regulation of gap junctional communication are largely unknown. Here we have studied the role of NMDA receptor-mediated glutamatergic synaptic activity in the regulation of motoneurone coupling. Gap junctional coupling was demonstrated by the presence of graded, short latency depolarising potentials following ventral root stimulation, and by the transfer of the low molecular weight tracer Neurobiotin to neighbouring motoneurones. Sites of close apposition between the somata and/or dendrites of the dye-coupled motoneurones were identified as potential sites of gap junctional coupling. Early postnatal blockade of the NMDA subtype of glutamate receptors using the non-competitive antagonist dizocilpine maleate (MK801) arrested the developmental decrease in electrotonic and dye coupling during the first postnatal week. These results suggest that the postnatal increase in glutamatergic synaptic activity associated with the onset of locomotion promote the loss of gap junctional connections between developing motoneurones. PMID:12411521

  15. Neuroprotective and Neurorestorative Processes after Spinal Cord Injury: The Case of the Bulbospinal Respiratory Neurons

    PubMed Central

    2016-01-01

    High cervical spinal cord injuries interrupt the bulbospinal respiratory pathways projecting to the cervical phrenic motoneurons resulting in important respiratory defects. In the case of a lateralized injury that maintains the respiratory drive on the opposite side, a partial recovery of the ipsilateral respiratory function occurs spontaneously over time, as observed in animal models. The rodent respiratory system is therefore a relevant model to investigate the neuroplastic and neuroprotective mechanisms that will trigger such phrenic motoneurons reactivation by supraspinal pathways. Since part of this recovery is dependent on the damaged side of the spinal cord, the present review highlights our current understanding of the anatomical neuroplasticity processes that are developed by the surviving damaged bulbospinal neurons, notably axonal sprouting and rerouting. Such anatomical neuroplasticity relies also on coordinated molecular mechanisms at the level of the axotomized bulbospinal neurons that will promote both neuroprotection and axon growth. PMID:27563469

  16. Neuroprotective and Neurorestorative Processes after Spinal Cord Injury: The Case of the Bulbospinal Respiratory Neurons.

    PubMed

    Kastner, Anne; Matarazzo, Valéry

    2016-01-01

    High cervical spinal cord injuries interrupt the bulbospinal respiratory pathways projecting to the cervical phrenic motoneurons resulting in important respiratory defects. In the case of a lateralized injury that maintains the respiratory drive on the opposite side, a partial recovery of the ipsilateral respiratory function occurs spontaneously over time, as observed in animal models. The rodent respiratory system is therefore a relevant model to investigate the neuroplastic and neuroprotective mechanisms that will trigger such phrenic motoneurons reactivation by supraspinal pathways. Since part of this recovery is dependent on the damaged side of the spinal cord, the present review highlights our current understanding of the anatomical neuroplasticity processes that are developed by the surviving damaged bulbospinal neurons, notably axonal sprouting and rerouting. Such anatomical neuroplasticity relies also on coordinated molecular mechanisms at the level of the axotomized bulbospinal neurons that will promote both neuroprotection and axon growth. PMID:27563469

  17. Proper migration and axon outgrowth of zebrafish cranial motoneuron subpopulations require the cell adhesion molecule MDGA2A

    PubMed Central

    Ingold, Esther; vom Berg-Maurer, Colette M.; Burckhardt, Christoph J.; Lehnherr, André; Rieder, Philip; Keller, Philip J.; Stelzer, Ernst H.; Greber, Urs F.; Neuhauss, Stephan C. F.; Gesemann, Matthias

    2015-01-01

    ABSTRACT The formation of functional neuronal circuits relies on accurate migration and proper axonal outgrowth of neuronal precursors. On the route to their targets migrating cells and growing axons depend on both, directional information from neurotropic cues and adhesive interactions mediated via extracellular matrix molecules or neighbouring cells. The inactivation of guidance cues or the interference with cell adhesion can cause severe defects in neuronal migration and axon guidance. In this study we have analyzed the function of the MAM domain containing glycosylphosphatidylinositol anchor 2A (MDGA2A) protein in zebrafish cranial motoneuron development. MDGA2A is prominently expressed in distinct clusters of cranial motoneurons, especially in the ones of the trigeminal and facial nerves. Analyses of MDGA2A knockdown embryos by light sheet and confocal microscopy revealed impaired migration and aberrant axonal outgrowth of these neurons; suggesting that adhesive interactions mediated by MDGA2A are required for the proper arrangement and outgrowth of cranial motoneuron subtypes. PMID:25572423

  18. Revisiting Antagonist Effects in Hypoglossal Nucleus: Brainstem Circuit for the State-Dependent Control of Hypoglossal Motoneurons: A Hypothesis

    PubMed Central

    Fenik, Victor B.

    2015-01-01

    We reassessed and provided new insights into the findings that were obtained in our previous experiments that employed the injections of combined adrenergic, serotonergic, GABAergic, and glycinergic antagonists into the hypoglossal nucleus in order to pharmacologically abolish the depression of hypoglossal nerve activity that occurred during carbachol-induced rapid-eye-movement (REM) sleep-like state in anesthetized rats. We concluded that noradrenergic disfacilitation is the major mechanism that is responsible for approximately 90% of the depression of hypoglossal motoneurons, whereas the remaining 10% can be explained by serotonergic mechanisms that have net inhibitory effect on hypoglossal nerve activity during REM sleep-like state. We hypothesized that both noradrenergic and serotonergic state-dependent mechanisms indirectly control hypoglossal motoneuron excitability during REM sleep; their activities are integrated and mediated to hypoglossal motoneurons by reticular formation neurons. In addition, we proposed a brainstem neural circuit that can explain the new findings. PMID:26648908

  19. Motoneuronal and muscle synergies involved in cat hindlimb control during fictive and real locomotion: a comparison study.

    PubMed

    Markin, Sergey N; Lemay, Michel A; Prilutsky, Boris I; Rybak, Ilya A

    2012-04-01

    We compared the activity profiles and synergies of spinal motoneurons recorded during fictive locomotion evoked in immobilized decerebrate cat preparations by midbrain stimulation to the activity profiles and synergies of the corresponding hindlimb muscles obtained during forward level walking in cats. The fictive locomotion data were collected in the Spinal Cord Research Centre, University of Manitoba, and provided by Dr. David McCrea; the real locomotion data were obtained in the laboratories of M. A. Lemay and B. I. Prilutsky. Scatterplot representation and minimum spanning tree clustering algorithm were used to identify the possible motoneuronal and muscle synergies operating during both fictive and real locomotion. We found a close similarity between the activity profiles and synergies of motoneurons innervating one-joint muscles during fictive locomotion and the profiles and synergies of the corresponding muscles during real locomotion. However, the activity patterns of proximal nerves controlling two-joint muscles, such as posterior biceps and semitendinosus (PBSt) and rectus femoris (RF), were not uniform in fictive locomotion preparations and differed from the activity profiles of the corresponding two-joint muscles recorded during forward level walking. Moreover, the activity profiles of these nerves and the corresponding muscles were unique and could not be included in the synergies identified in fictive and real locomotion. We suggest that afferent feedback is involved in the regulation of locomotion via motoneuronal synergies controlled by the spinal central pattern generator (CPG) but may also directly affect the activity of motoneuronal pools serving two-joint muscles (e.g., PBSt and RF). These findings provide important insights into the organization of the spinal CPG in mammals, the motoneuronal and muscle synergies engaged during locomotion, and their afferent control. PMID:22190626

  20. Motoneuronal and muscle synergies involved in cat hindlimb control during fictive and real locomotion: a comparison study

    PubMed Central

    Markin, Sergey N.; Lemay, Michel A.; Prilutsky, Boris I.

    2012-01-01

    We compared the activity profiles and synergies of spinal motoneurons recorded during fictive locomotion evoked in immobilized decerebrate cat preparations by midbrain stimulation to the activity profiles and synergies of the corresponding hindlimb muscles obtained during forward level walking in cats. The fictive locomotion data were collected in the Spinal Cord Research Centre, University of Manitoba, and provided by Dr. David McCrea; the real locomotion data were obtained in the laboratories of M. A. Lemay and B. I. Prilutsky. Scatterplot representation and minimum spanning tree clustering algorithm were used to identify the possible motoneuronal and muscle synergies operating during both fictive and real locomotion. We found a close similarity between the activity profiles and synergies of motoneurons innervating one-joint muscles during fictive locomotion and the profiles and synergies of the corresponding muscles during real locomotion. However, the activity patterns of proximal nerves controlling two-joint muscles, such as posterior biceps and semitendinosus (PBSt) and rectus femoris (RF), were not uniform in fictive locomotion preparations and differed from the activity profiles of the corresponding two-joint muscles recorded during forward level walking. Moreover, the activity profiles of these nerves and the corresponding muscles were unique and could not be included in the synergies identified in fictive and real locomotion. We suggest that afferent feedback is involved in the regulation of locomotion via motoneuronal synergies controlled by the spinal central pattern generator (CPG) but may also directly affect the activity of motoneuronal pools serving two-joint muscles (e.g., PBSt and RF). These findings provide important insights into the organization of the spinal CPG in mammals, the motoneuronal and muscle synergies engaged during locomotion, and their afferent control. PMID:22190626

  1. Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress

    PubMed Central

    Rojas, Fabiola; Cortes, Nicole; Abarzua, Sebastian; Dyrda, Agnieszka; van Zundert, Brigitte

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder caused by dysfunction and degeneration of motor neurons. Multiple disease-causing mutations, including in the genes for SOD1 and TDP-43, have been identified in ALS. Astrocytes expressing mutant SOD1 are strongly implicated in the pathogenesis of ALS: we have shown that media conditioned by astrocytes carrying mutant SOD1G93A contains toxic factor(s) that kill motoneurons by activating voltage-sensitive sodium (Nav) channels. In contrast, a recent study suggests that astrocytes expressing mutated TDP43 contribute to ALS pathology, but do so via cell-autonomous processes and lack non-cell-autonomous toxicity. Here we investigate whether astrocytes that express diverse ALS-causing mutations release toxic factor(s) that induce motoneuron death, and if so, whether they do so via a common pathogenic pathway. We exposed primary cultures of wild-type spinal cord cells to conditioned medium derived from astrocytes (ACM) that express SOD1 (ACM-SOD1G93A and ACM-SOD1G86R) or TDP43 (ACM-TDP43A315T) mutants; we show that such exposure rapidly (within 30–60 min) increases dichlorofluorescein (DCF) fluorescence (indicative of nitroxidative stress) and leads to extensive motoneuron-specific death within a few days. Co-application of the diverse ACMs with anti-oxidants Trolox or esculetin (but not with resveratrol) strongly improves motoneuron survival. We also find that co-incubation of the cultures in the ACMs with Nav channel blockers (including mexiletine, spermidine, or riluzole) prevents both intracellular nitroxidative stress and motoneuron death. Together, our data document that two completely unrelated ALS models lead to the death of motoneuron via non-cell-autonomous processes, and show that astrocytes expressing mutations in SOD1 and TDP43 trigger such cell death through a common pathogenic pathway that involves nitroxidative stress, induced at least in part by Nav channel activity. PMID:24570655

  2. Comparison of dendritic calcium transients in juvenile wild type and SOD1(G93A) mouse lumbar motoneurons.

    PubMed

    Quinlan, Katharina A; Lamano, Jonathan B; Samuels, Julienne; Heckman, C J

    2015-01-01

    Previous studies of spinal motoneurons in the SOD1 mouse model of amyotrophic lateral sclerosis have shown alterations long before disease onset, including increased dendritic branching, increased persistent Na(+) and Ca(2+) currents, and impaired axonal transport. In this study dendritic Ca(2+) entry was investigated using two photon excitation fluorescence microscopy and whole-cell patch-clamp of juvenile (P4-11) motoneurons. Neurons were filled with both Ca(2+) Green-1 and Texas Red dextrans, and line scans performed throughout. Steps were taken to account for different sources of variability, including (1) dye filling and laser penetration, (2) dendritic anatomy, and (3) the time elapsed from the start of recording. First, Ca(2+) Green-1 fluorescence was normalized by Texas Red; next, neurons were reconstructed so anatomy could be evaluated; finally, time was recorded. Customized software detected the largest Ca(2+) transients (area under the curve) from each line scan and matched it with parameters above. Overall, larger dendritic diameter and shorter path distance from the soma were significant predictors of larger transients, while time was not significant up to 2 h (data thereafter was dropped). However, Ca(2+) transients showed additional variability. Controlling for previous factors, significant variation was found between Ca(2+) signals from different processes of the same neuron in 3/7 neurons. This could reflect differential expression of Ca(2+) channels, local neuromodulation or other variations. Finally, Ca(2+) transients in SOD1(G93A) motoneurons were significantly smaller than in non-transgenic motoneurons. In conclusion, motoneuron processes show highly variable Ca(2+) transients, but these transients are smaller overall in SOD1(G93A) motoneurons. PMID:25914627

  3. Motoneuron properties during motor inhibition produced by microinjection of carbachol into the pontine reticular formation of the decerebrate cat.

    PubMed

    Morales, F R; Engelhardt, J K; Soja, P J; Pereda, A E; Chase, M H

    1987-04-01

    It is well established that cholinergic agonists, when injected into the pontine reticular formation in cats, produce a generalized suppression of motor activity (1, 3, 6, 14, 18, 27, 33, 50). The responsible neuronal mechanisms were explored by measuring ventral root activity, the amplitude of the Ia-monosynaptic reflex, and the basic electrophysiological properties of hindlimb motoneurons before and after carbachol was microinjected into the pontine reticular formation of decerebrate cats. Intrapontine microinjections of carbachol (0.25-1.0 microliter, 16 mg/ml) resulted in the tonic suppression of ventral root activity and a decrease in the amplitude of the Ia-monosynaptic reflex. An analysis of intracellular records from lumbar motoneurons during the suppression of motor activity induced by carbachol revealed a considerable decrease in input resistance and membrane time constant as well as a reduction in motoneuron excitability, as evidenced by a nearly twofold increase in rheobase. Discrete inhibitory postsynaptic potentials were also observed following carbachol administration. The changes in motoneuron properties (rheobase, input resistance, and membrane time constant), as well as the development of discrete inhibitory postsynaptic potentials, indicate that spinal cord motoneurons were postsynaptically inhibited following the pontine administration of carbachol. In addition, the inhibitory processes that arose after carbachol administration in the decerebrate cat were remarkably similar to those that are present during active sleep in the chronic cat. These findings suggest that the microinjection of carbachol into the pontine reticular formation activates the same brain stem-spinal cord system that is responsible for the postsynaptic inhibition of alpha-motoneurons that occurs during active sleep. PMID:3585456

  4. Motoneuron axon pathfinding errors in zebrafish: differential effects related to concentration and timing of nicotine exposure.

    PubMed

    Menelaou, Evdokia; Paul, Latoya T; Perera, Surangi N; Svoboda, Kurt R

    2015-04-01

    Nicotine exposure during embryonic stages of development can affect many neurodevelopmental processes. In the developing zebrafish, exposure to nicotine was reported to cause axonal pathfinding errors in the later born secondary motoneurons (SMNs). These alterations in SMN axon morphology coincided with muscle degeneration at high nicotine concentrations (15-30 μM). Previous work showed that the paralytic mutant zebrafish known as sofa potato exhibited nicotine-induced effects onto SMN axons at these high concentrations but in the absence of any muscle deficits, indicating that pathfinding errors could occur independent of muscle effects. In this study, we used varying concentrations of nicotine at different developmental windows of exposure to specifically isolate its effects onto subpopulations of motoneuron axons. We found that nicotine exposure can affect SMN axon morphology in a dose-dependent manner. At low concentrations of nicotine, SMN axons exhibited pathfinding errors, in the absence of any nicotine-induced muscle abnormalities. Moreover, the nicotine exposure paradigms used affected the 3 subpopulations of SMN axons differently, but the dorsal projecting SMN axons were primarily affected. We then identified morphologically distinct pathfinding errors that best described the nicotine-induced effects on dorsal projecting SMN axons. To test whether SMN pathfinding was potentially influenced by alterations in the early born primary motoneuron (PMN), we performed dual labeling studies, where both PMN and SMN axons were simultaneously labeled with antibodies. We show that only a subset of the SMN axon pathfinding errors coincided with abnormal PMN axonal targeting in nicotine-exposed zebrafish. We conclude that nicotine exposure can exert differential effects depending on the levels of nicotine and developmental exposure window. PMID:25668718

  5. Antagonism of mGlu receptors and potentiation of EPSCs at rat spinal motoneurones in vitro.

    PubMed

    Cao, C Q; Tse, H W; Jane, D E; Evans, R H; Headley, P M

    1997-03-01

    The patch-clamp technique has been used to record synaptic responses, elicited by electrical stimulation of dorsal roots, in 28 single motoneurones of in vitro spinal cord preparations from neonate (P5 to P8) rats. The effects of (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) (200 microM), a potent antagonist at L-2-amino-4-phosphonobutanoate (AP4)-sensitive receptors, and (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) (500 microM), which is a less selective antagonist of mGluRs, were tested on EPSCs alone and as antagonists of AP4-induced depression of EPSCs. The EC50 for depression of EPSCs by AP4 (1.16 +/- 0.12 microM, n = 8) was increased to 18.9 +/- 0.7 microM (n = 6) by MPPG. MCPG (500 microM) had no significant effect on the depressant potency of AP4. Under control conditions, EPSCs had mean peak amplitudes of 983 pA +/- 64 SEM and mean charge transferred of 306 +/- 37 pC (n = 28). These values were increased significantly (p < 0.05) to 1168 +/- 68 pA and 363 +/- 39 pC by MPPG (n = 6), and 1150 +/- 54 pA and 358 +/- 33 pC (n = 6) by MCPG. There was no significant difference between the enhancement of the initial peak of the EPSCs (mean latency from stimulus artifact 5.9 +/- 0.3 ms) and later components, suggesting mGluRs to be present on primary afferent terminals presynaptic to motoneurones as well as in pathways via interneurones. These results are consistent with the presence of at least two types of presynaptic mGluR that modulate release of glutamate in segmental pathways convergent onto motoneurones. These receptors appear to be activated by interstitial glutamate tonically present in the present preparations. PMID:9175609

  6. Persistent GABAA/C responses to gabazine, taurine and beta-alanine in rat hypoglossal motoneurons.

    PubMed

    Chesnoy-Marchais, D

    2016-08-25

    In hypoglossal motoneurons, a sustained anionic current, sensitive to a blocker of ρ-containing GABA receptors, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and insensitive to bicuculline, was previously shown to be activated by gabazine. In order to better characterize the receptors involved, the sensitivity of this atypical response to pentobarbital (30μM), allopregnanolone (0.3μM) and midazolam (0.5μM) was first investigated. Pentobarbital potentiated the response, whereas the steroid and the benzodiazepine were ineffective. The results indicate the involvement of hybrid heteromeric receptors, including at least a GABA receptor ρ subunit and a γ subunit, accounting for the pentobarbital-sensitivity. The effects of the endogenous β amino acids, taurine and β-alanine, which are released under various pathological conditions and show neuroprotective properties, were then studied. In the presence of the glycine receptor blocker strychnine (1μM), both taurine (0.3-1mM) and β-alanine (0.3mM) activated sustained anionic currents, which were partly blocked by TPMPA (100μM). Thus, both β amino acids activated ρ-containing GABA receptors in hypoglossal motoneurons. Bicuculline (20μM) reduced responses to taurine and β-alanine, but small sustained responses persisted in the presence of both strychnine and bicuculline. Responses to β-alanine were slightly increased by allopregnanolone, indicating a contribution of the bicuculline- and neurosteroid-sensitive GABAA receptors underlying tonic inhibition in these motoneurons. Since sustained activation of anionic channels inhibits most mature principal neurons, the ρ-containing GABA receptors permanently activated by taurine and β-alanine might contribute to some of their neuroprotective properties under damaging overexcitatory situations. PMID:27246441

  7. The effect of altered peripheral field on motoneurone function in developing rat soleus muscles.

    PubMed Central

    Lowrie, M B; O'Brien, R A; Vrbová, G

    1985-01-01

    In soleus muscles of 4- to 5-day-old rats the quantum content of axon terminals from L4 spinal roots is less than half that from L5. With development the size of L4 motor units decreases and the quantum content of L4 nerves increases to become similar to that of L5 axons. During this time the overlap of territories of L4 and L5 axons is reduced from 46% at 4-6 days to 2% at 18-20 days. This reduction occurs entirely at the expense of L4 territory. Removal of the L5 ventral ramus (v.r.) at 4-6 days prevents the reduction of L4 territory so that at 18 days L4 motor units are about 4 X normal size. In spite of this enlarged peripheral field of L4 axons the quantum content of their terminals increases to normal levels. When L5 v.r. was removed at 16-18 days, i.e. when the reduction of the L4 peripheral field was complete, expansion of L4 motor units was also seen, but in this case the quantum content of L4 terminals was less than normal. Thus it appears that during early stages of development, before synaptic reorganization within the muscle is complete, motoneurones are able to adapt their function to increased peripheral demands more effectively than at later stages of post-natal development. Retrograde labelling of soleus motor pool with horseradish peroxidase (HRP) showed that removal of L5 v.r. either at 4 or 15 days of age reduced the number of motoneurones supplying soleus muscle to less than 20%. No change in size of the remaining motoneurones was seen, indicating that the adjustment of transmitter output at the neuromuscular junctions in the younger group had no effect on the size of the cell. PMID:2867219

  8. Spinal inhibition of descending command to soleus motoneurons is removed prior to dorsiflexion

    PubMed Central

    Geertsen, Svend S; van de Ruit, Mark; Grey, Michael J; Nielsen, Jens B

    2011-01-01

    Abstract It has recently been demonstrated that soleus motor-evoked potentials (MEPs) are facilitated prior to the onset of dorsiflexion. The purpose of this study was to examine if this could be explained by removal of spinal inhibition of the descending command to soleus motoneurons. To test this, we investigated how afferent inputs from the tibialis anterior muscle modulate the corticospinal activation of soleus spinal motoneurons at rest, during static contraction and prior to movement. MEPs activated by transcranial magnetic stimulation (TMS) and Hoffmann reflexes (H-reflexes), activated by electrical stimulation of the posterior tibial nerve (PTN), were conditioned by prior stimulation of the common peroneal nerve (CPN) at a variety of conditioning–test (CT) intervals. MEPs in the precontracted soleus muscle were inhibited when the TMS pulse was preceded by CPN stimulation with a CT interval of 35 ms, and they were facilitated for CT intervals of 50–55 ms. A similar inhibition of the soleus H-reflex was not observed. To investigate which descending pathways might be responsible for the afferent-evoked inhibition and facilitation, we examined the effect of CPN stimulation on short-latency facilitation (SLF) and long-latency facilitation (LLF) of the soleus H-reflex induced by a subthreshold TMS pulse at different CT intervals. SLF is known to reflect the excitability of the fastest conducting, corticomotoneuronal cells whereas LLF is believed to be caused by more indirect descending pathways. At CT intervals of 40–45 ms, the LLF was significantly more inhibited compared to the SLF when taking the effect on the H-reflex into account. Finally, we investigated how the CPN-induced inhibition and facilitation of the soleus MEP were modulated prior to dorsiflexion. Whereas the late facilitation (CT interval: 55 ms) was similar prior to dorsiflexion and at rest, no inhibition could be evoked at the earlier latency (CT interval: 35 ms) prior to onset of

  9. Pharmacologically induced enhancement of recurrent inhibition in humans: effects on motoneurone discharge patterns.

    PubMed

    Mattei, Benjamin; Schmied, Annie; Mazzocchio, Riccardo; Decchi, Barbara; Rossi, Alessandro; Vedel, Jean-Pierre

    2003-04-15

    The aim of the present study was to investigate the effects of spinal recurrent inhibition on human motoneurone discharge patterns. The tonic discharge activity of motor unit pairs was recorded in the extensor carpi radialis (ECR) and abductor digiti minimi (ADM) muscles during voluntary isometric contraction. While undergoing continuous intravenous saline (NaCl 0.9 %) perfusion, the subjects were given a short lasting injection of L-acetylcarnitine (L-Ac), which has been found to potentiate recurrent inhibition in humans. The variability, synchronization and coherence of the motor unit discharges were analysed during four successive test periods (lasting 2-3 min each). A significant decrease in the inter-spike interval (ISI) coefficient of variation was observed in the discharge patterns of the motor units tested in the ECR and not in the ADM, which were not accompanied by any consistent changes in the mean ISIs of the motor unit activity in either muscle. The L-Ac injection also led to a significant increase in the synchronization in half of the motor unit pairs tested in the ECR muscle (n = 29), whereas no consistent changes were observed with the ADM motor units (n = 25). However, coherence analysis failed to reveal any consistent differences in the incidence of significant values of coherence spectrum between the pre-injection and injection periods among the motor unit pairs tested with either saline or L-Ac injections, in either the ECR or ADM muscles. The contrasting effects on the variability and the synchronization of the motor unit discharges observed with ECR motoneurones known to undergo recurrent inhibition and with ADM motoneurones known to lack recurrent inhibition suggest that the drug may have specific effects which are mediated by an enhancement of the Renshaw cell activity. The decrease in the ISI variability is in line with the hypothesis that recurrent inhibition may contribute along with the post-spike after-hyperpolarization to limiting the

  10. Urethral Injuries

    MedlinePlus

    ... Injuries Ureteral Injuries Urethral Injuries Injuries to the Penis and Scrotum Most urethral injuries occur in men. ... leakage of urine into the tissues of the penis, scrotum, abdominal wall, or perineum (the area between ...

  11. The effects of tetrodotoxin-induced muscle paralysis on the physiological properties of muscle units and their innervating motoneurons in rat.

    PubMed Central

    Gardiner, P F; Seburn, K L

    1997-01-01

    1. Although the inactivity of a slow muscle (cat soleus) induced via nerve impulse blockade has been demonstrated to have some axotomy-like effects (decreased after-hyperpolarization (AHP) duration) on its innervating motoneurons, the reported effects of inactivity on motoneurons which innervate fast muscles containing mixtures of motor unit types are equivocal. This study was designed to determine the effect of a period (2 weeks) of complete hindlimb muscle paralysis, via tetrodotoxin (TTX) blockade of sciatic nerve impulses, on the contractile (muscle units) and electrophysiological (motoneurons) properties of motor units in the rat gastrocnemius. Motoneuron properties were also compared with those of rats subjected to sciatic nerve axotomy 2 weeks earlier. 2. At the time of the terminal experiment (24 h after the removal of the TTX delivery system) in anaesthetized animals, properties of tibial motoneurons (i.e. rheobase current, input resistance, time course of after-potentials) were determined using conventional microelectrode techniques. For those tibial motoneurons innervating the gastrocnemius, muscle unit responses (i.e. twitch force and time course, maximum tetanic tension, fatigability) were also recorded in response to current injection. 3. Consistent with previously reported whole-muscle responses to TTX-induced disuse, the TTX-treated gastrocnemius muscle units showed weaker tetanic forces, prolonged twitches and elevated twitch/tetanic ratios. These effects were similar for motor units classified as small, medium and large according to their tetanic tension-generating capacities. Muscle unit fatigue resistances appeared to be unchanged. 4. The mean values, distributions and ranges of tibial motoneuron properties were similar between control and TTX-treated groups for rheobase, input resistance and AHP half-decay time. In the case of the latter, the proportion of motoneurons possessing "slow' AHP half-decay times (> 20 ms) was not significantly

  12. Motoneurons of the adult marmoset can grow axons and reform motor endplates through a peripheral nerve bridge joining the locally injured cervical spinal cord to the denervated biceps brachii muscle.

    PubMed

    Emery, E; Rhrich-Haddout, F; Kassar-Duchossoy, L; Lyoussi, B; Tadié, M; Horvat, J C

    2000-12-15

    Reconnection of the injured spinal cord (SC) of the marmoset with the denervated biceps brachii muscle (BB) was obtained by using a peripheral nerve (PN) bridge. In 13 adult males, a 45 mm segment of the peroneal nerve was removed: one end was implanted unilaterally into the cervical SC of the same animal (autograft), determining a local injury, although the other end was either directly inserted into the BB (Group A) or, alternatively, sutured to its transected motor nerve, the musculocutaneous nerve (Group B). From 2-4 months post-surgery, eight out of the 10 surviving animals responded by a contraction of the BB to electrical stimulations of the PN bridge. All ten were then processed for a morphological study. As documented by retrograde axonal tracing studies using horse radish peroxidase or Fast Blue (FB), a mean number of 314 (Group A) or 45 (Group B) spinal neurons, mainly located close to the site of injury and grafting, re-expressed a capacity to grow and extend axons into the PN bridge. Most of these regenerated axons were able to grow up to the BB and form or reform functional motor endplates. Many of the spinal neurons that were retrogradely labeled with FB simultaneously displayed immunoreactivity for choline acetyl-transferase and consequently were assumed to be motoneurons. Reinnervation and regeneration of the BB were documented by methods revealing axon terminals, endplates and myofibrillary ATPase activity. Our results indicate that motoneurons of the focally injured SC of a small-sized primate can, following the example of the adult rat, re-establish a lost motor function by extending new axons all the way through a PN bridge connected to a denervated skeletal muscle. PMID:11107167

  13. Fast axonal transport of labeled proteins in motoneurons of exercise-trained rats

    SciTech Connect

    Jasmin, B.J.; Lavoie, P.A.; Gardiner, P.F.

    1988-12-01

    In this study, the fast orthograde axonal transport of radiolabeled proteins was measured to determine the effects of endurance-running training on transport velocity and amounts of transported proteins in rat sciatic motoneurons. Female rats were subjected to a progressive running-training program for 10-12 wk. Twenty-four hours after the last training session, rats underwent right L4-L5 dorsal root ganglionectomy. The next day, 20 microCi of (3H)leucine was injected bilaterally in the vicinity of the motoneuronal cell bodies supplying the sciatic nerve, to study axonal transport parameters. Results showed that peak and average transport velocities of labeled proteins were significantly (P less than 0.05) increased by 22 and 29%, respectively, in the deafferented nerves of the runners as compared with controls. Moreover, the amount of total transported protein-bound radioactivity was increased in both left (40%) and right (37%) sciatic nerves of the runners. An exhaustive exercise session reduced (P less than 0.05) peak displacement (8%) and total transported protein-bound radioactivity (36%) in the sciatic nerves of control rats, whereas no changes were noticed in trained animals. The data suggest that chronic endurance running induces significant adaptations in the fast axonal transport of labeled proteins.

  14. Perineal striated muscles: Anatomy, spinal motoneurons, and participation on copulatory behavior in male rabbits (Oryctolagus cuniculus).

    PubMed

    Zempoalteca, R; Lucio, R A; Eguibar, J R

    2008-09-01

    Despite the importance of rabbits in reproductive studies, little information is available on the anatomy and participation of the striated-perineal muscles in male copulatory behavior. In our study, we describe the gross anatomy of two striated-perineal muscles: the ischiocavernosus (ICm) and the bulbospongiosus (BSm). Both muscles have their origin at the ischiadic arc, but the ICm is inserted into the penile crura and the BSm onto the ligamentum suspensorium of the penis. The motoneurons of both muscles were identified using retrograde labeling with horseradish peroxidase coupled to wheat-germ agglutinin. Motoneurons were dispersed in the lower-lumbar and upper-sacral spinal-cord segments, instead of being aggregated in the neuronal nucleus as in other species: the rat, mouse, gerbil, cat, and man. Bilateral dennervation of the ICm or BSm or both in sexually experienced male rabbits did not affect copulatory variables measured at 10, 20, and 30 days after surgery. However, muscular dennervation produced extravaginal ejaculations in 42% of copulatory tests and no ejaculation in 7% of tests, although male pelvic thrusting occurred. These results suggest the participation of the ICm and BSm perineal muscles in penile orientation during copulation but not in seminal emission as described in other mammalian species. PMID:18563835

  15. Epsin 1 Promotes Synaptic Growth by Enhancing BMP Signal Levels in Motoneuron Nuclei

    PubMed Central

    Chastain, Lerin R.; Royer, Suzanne M.; Bao, Hong; Reist, Noreen E.; Zhang, Bing

    2013-01-01

    Bone morphogenetic protein (BMP) retrograde signaling is crucial for neuronal development and synaptic plasticity. However, how the BMP effector phospho-Mother against decapentaplegic (pMad) is processed following receptor activation remains poorly understood. Here we show that Drosophila Epsin1/Liquid facets (Lqf) positively regulates synaptic growth through post-endocytotic processing of pMad signaling complex. Lqf and the BMP receptor Wishful thinking (Wit) interact genetically and biochemically. lqf loss of function (LOF) reduces bouton number whereas overexpression of lqf stimulates bouton growth. Lqf-stimulated synaptic overgrowth is suppressed by genetic reduction of wit. Further, synaptic pMad fails to accumulate inside the motoneuron nuclei in lqf mutants and lqf suppresses synaptic overgrowth in spinster (spin) mutants with enhanced BMP signaling by reducing accumulation of nuclear pMad. Interestingly, lqf mutations reduce nuclear pMad levels without causing an apparent blockage of axonal transport itself. Finally, overexpression of Lqf significantly increases the number of multivesicular bodies (MVBs) in the synapse whereas lqf LOF reduces MVB formation, indicating that Lqf may function in signaling endosome recycling or maturation. Based on these observations, we propose that Lqf plays a novel endosomal role to ensure efficient retrograde transport of BMP signaling endosomes into motoneuron nuclei. PMID:23840387

  16. Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit.

    PubMed

    Kuner, Rohini; Groom, Anthony J; Bresink, Iris; Kornau, Hans-Christian; Stefovska, Vanya; Müller, Gerald; Hartmann, Bettina; Tschauner, Karsten; Waibel, Stefan; Ludolph, Albert C; Ikonomidou, Chrysanthy; Seeburg, Peter H; Turski, Lechoslaw

    2005-04-19

    Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca(2+) permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca(2+) influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans. PMID:15827116

  17. Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

    PubMed Central

    Kuner, Rohini; Groom, Anthony J.; Bresink, Iris; Kornau, Hans-Christian; Stefovska, Vanya; Müller, Gerald; Hartmann, Bettina; Tschauner, Karsten; Waibel, Stefan; Ludolph, Albert C.; Ikonomidou, Chrysanthy; Seeburg, Peter H.; Turski, Lechoslaw

    2005-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu2+/Zn2+ superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing l-α-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca2+ permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca2+ influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans. PMID:15827116

  18. Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior.

    PubMed

    Feiguin, Fabian; Godena, Vinay K; Romano, Giulia; D'Ambrogio, Andrea; Klima, Raffaella; Baralle, Francisco E

    2009-05-19

    Pathological modifications in the highly conserved and ubiquitously expressed heterogeneous ribonucleoprotein TDP-43 were recently associated to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a late-onset disorder that affects predominantly motoneurons [Neumann, M. et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133, Sreedharan, J. et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672, Kabashi, E. et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572-574]. However, the function of TDP-43 in vivo is unknown and a possible direct role in neurodegeneration remains speculative. Here, we report that flies lacking Drosophila TDP-43 appeared externally normal but presented deficient locomotive behaviors, reduced life span and anatomical defects at the neuromuscular junctions. These phenotypes were rescued by expression of the human protein in a restricted group of neurons including motoneurons. Our results demonstrate the role of this protein in vivo and suggest an alternative explanation to ALS pathogenesis that may be more due to the lack of TDP 43 function than to the toxicity of the aggregates. PMID:19379745

  19. Neuropathology in respiratory-related motoneurons in young Pompe (Gaa−/−) mice

    PubMed Central

    Turner, Sara M.F.; Hoyt, Aaron K.; ElMallah, Mai K.; Falk, Darin J.; Byrne, Barry J.; Fuller, David D.

    2016-01-01

    Respiratory and/or lingual dysfunction are among the first motor symptoms in Pompe disease, a disorder resulting from absence or dysfunction of the lysosomal enzyme acid α-glucosidase (GAA). Here, we histologically evaluated the medulla, cervical and thoracic spinal cords in 6 weeks old asymptomatic Pompe (Gaa−/−) mice to determine if neuropathology in respiratory motor regions has an early onset. Periodic acid-Schiff (PAS) staining indicated glycogen accumulation was exclusively occurring in Gaa−/− hypoglossal, mid-cervical and upper thoracic motoneurons. Markers of DNA damage (Tunel) and ongoing apoptosis (Cleaved Caspase 3) did not co-localize with PAS staining, but were prominent in a medullary region which included the nucleus tractus solitarius, and also in the thoracic spinal dorsal horn. We conclude that respiratory-related motoneurons are particularly susceptible to GAA deficiency and that neuronal glycogen accumulation and neurodegeneration may occur independently in early stage disease. The data support early therapeutic intervention in Pompe disease. PMID:26921786

  20. Differential facilitation of high- and low-output nerve terminals from a single motoneuron.

    PubMed

    Crider, M E; Cooper, R L

    2000-03-01

    In the crayfish opener neuromuscular preparation, regional differences in synaptic transmission are observed among the terminals of a single motoneuron. With a single stimulus, the high-output terminals of the proximal region of the muscle produce a larger excitatory postsynaptic potential than do the low-output terminals of the central region of the muscle. We tested the hypothesis that the low-output terminals exhibit more facilitation than do high-output terminals for twin-pulse, train, and continuous-stimulation paradigms. Previous studies have not employed several stimulation paradigms to induce facilitation among high- and low-output terminals of a single motoneuron. We found that the high-output terminals on the proximal fibers facilitate more than the low-output terminals on the central muscle fibers, in contrast with previous studies on similar muscles. The difference in measured facilitation is dependent on the stimulation paradigm. These results are important because ultrastructural differences between these high- and low-output terminals are known and can be used for correlation with physiological measurements. Short-term facilitation is a form of short-term memory at the synaptic level, and the processes understood at the crayfish neuromuscular junction may well be applicable to all chemical synapses. PMID:10710395

  1. Experimental and clinical evidence for the protective role of progesterone in motoneuron degeneration and neuroinflammation.

    PubMed

    Gonzalez Deniselle, M C; Garay, L; Meyer, M; Gargiulo-Monachelli, G; Labombarda, F; Gonzalez, S; Guennoun, R; Schumacher, M; De Nicola, Alejandro F

    2011-10-01

    Far beyond its role in reproduction, progesterone exerts neuro-protective, promyelinating, and anti-inflammatory effects in the nervous system. These effects are amplified under pathological conditions, implying that changes of the local environment sensitize nervous tissues to steroid therapy. The present survey covers our results of progesterone neuroprotection in a motoneuron neurodegeneration model and a neuroinflammation model. In the degenerating spinal cord of the Wobbler mouse, progesterone reverses the impaired expression of neurotrophins, increases enzymes of neurotransmission and metabolism, prevents oxidative damage of motoneurons and their vacuolar degeneration (paraptosis), and attenuates the development of mitochondrial abnormalities. After long-term treatment, progesterone also increases muscle strength and the survival of Wobbler mice. Subsequently, this review describes the effects of progesterone in mice with induced experimental autoimmune encephalomyelitis (EAE), a commonly used model of multiple sclerosis. In EAE mice, progesterone attenuates the clinical severity, decreases demyelination and neuronal dysfunction, increases axonal counts, reduces the formation of amyloid precursor protein profiles, and decreases the aberrant expression of growth-associated proteins. These actions of progesterone may be due to multiple mechanisms, considering that classic nuclear receptors, extranuclear receptors, and membrane receptors are all expressed in the spinal cord. Although many aspects of progesterone action in humans remain unsolved, data provided by experimental models makes getting to this objective closer than previously expected. PMID:25961276

  2. Dendrites are dispensable for basic motoneuron function but essential for fine tuning of behavior

    PubMed Central

    Ryglewski, Stefanie; Kadas, Dimitrios; Hutchinson, Katie; Schuetzler, Natalie; Vonhoff, Fernando; Duch, Carsten

    2014-01-01

    Dendrites are highly complex 3D structures that define neuronal morphology and connectivity and are the predominant sites for synaptic input. Defects in dendritic structure are highly consistent correlates of brain diseases. However, the precise consequences of dendritic structure defects for neuronal function and behavioral performance remain unknown. Here we probe dendritic function by using genetic tools to selectively abolish dendrites in identified Drosophila wing motoneurons without affecting other neuronal properties. We find that these motoneuron dendrites are unexpectedly dispensable for synaptic targeting, qualitatively normal neuronal activity patterns during behavior, and basic behavioral performance. However, significant performance deficits in sophisticated motor behaviors, such as flight altitude control and switching between discrete courtship song elements, scale with the degree of dendritic defect. To our knowledge, our observations provide the first direct evidence that complex dendrite architecture is critically required for fine-tuning and adaptability within robust, evolutionarily constrained behavioral programs that are vital for mating success and survival. We speculate that the observed scaling of performance deficits with the degree of structural defect is consistent with gradual increases in intellectual disability during continuously advancing structural deficiencies in progressive neurological disorders. PMID:25453076

  3. Behavioral state-specific inhibitory postsynaptic potentials impinge on cat lumbar motoneurons during active sleep.

    PubMed

    Morales, F R; Boxer, P; Chase, M H

    1987-11-01

    High-gain intracellular records were obtained from lumbar motoneurons in intact, undrugged cats during naturally occurring states of wakefulness, quiet sleep, and active sleep. Spontaneous, discrete, inhibitory postsynaptic potentials (IPSPs) were found to impinge on lumbar motoneurons during all states of sleep and wakefulness. IPSPs which occurred during wakefulness and quiet sleep were of relatively low amplitude and had a low frequency of occurrence. During the state of active sleep there occurred a great increase in inhibitory input. This was the result of the appearance of large-amplitude IPSPs and of an increase in the frequency of low-amplitude IPSPs which were indistinguishable from those recorded during wakefulness and quiet sleep. In addition to a difference in amplitude, the time course of the large IPSPs recorded during active sleep further differentiated them from the smaller IPSPs recorded during wakefulness, quiet sleep, and active sleep; i.e., their rise-time and half-width were of longer duration and their rate-of-rise was significantly faster. We suggest that the large, active sleep-specific IPSPs reflect the activity of a group of inhibitory interneurons which are inactive during wakefulness and quiet sleep and which discharge during active sleep. These as yet unidentified interneurons would then serve as the last link in the brain stem-spinal cord inhibitory system which is responsible for producing muscle atonia during the state of active sleep. PMID:3666087

  4. Use of spike triggered averaging of muscle activity to quantify inputs to motoneuron pools.

    PubMed

    Fortier, P A

    1994-07-01

    1. The goal of this study was to determine the extent to which postspike facilitation (PSpF) of electromyograms (EMGs) could be used to estimate the inputs to separate motoneuron pools, under conditions where there was wide variability in the parameters of muscle activity. These parameters included cancellation of motor unit action potentials (MUAPs), variations in EMG noise, and changes in MUAP amplitude and duration. A systematic series of computer simulations with increasing complexity were used to achieve this goal. The initial simulations (model I) included a premotoneuronal (PreM) cell connected to a single postsynaptic motoneuron (Mn), which in turn projected to a muscle. The next simulations (model II) included other target motoneurons with their efferents each projecting to separate muscles. The last simulations (model III) included more than one postsynaptic motoneuron per Mn-pool, as is the case in mammalian neuromuscular systems. 2. A sample simulation (model I) was performed to determine if the PreM-evoked effects were within physiologically observed values. A cross-correlogram (XC) calculated from a PreM cell and its target Mn, receiving a PreM-evoked excitatory postsynaptic potential (EPSP) of 0.5 mV, produced a XC peak area of 0.04 Mn-spikes/PreM-trigger. The PSpF of EMG activity evoked by this PreM cell had a mean percent increase of 4.6% (MPI = mean bin amplitude of PSpF above baseline/mean baseline level x 100). These XC and PSpF values were within the range of values previously obtained from animal experiments. 3. The magnitude of MUAP cancellation in the EMG was tested by calculating two spike-triggered averages (SpTAs) of EMGs from Mn-triggers (not PreM-triggers as in the other SpTAs): one using typical bipolar MUAPs and another using their rectified counterpart of only positive polarity to eliminate the possibility of MUAP cancellation. The PSpF calculated from bipolar spikes was 24.8% smaller than the one calculated using unipolar spikes

  5. Selective Requirement for Maintenance of Synaptic Contacts onto Motoneurons by Target-Derived trkB Receptors

    PubMed Central

    2016-01-01

    Synaptic contacts onto motoneurons were studied in mice in which the gene for the trkB neurotrophin receptor was knocked out selectively in a subset of spinal motoneurons. The extent of contacts by structures immunoreactive for either of two different vesicular glutamate transporters (VGLUT1 and VGLUT2), the vesicular GABA transporter, or glutamic acid decarboxylase 67 (GAD67) with the somata of motoneurons, was studied in wild type and trkB knockout cells in tamoxifen treated male and female SLICK-trkB−/− mice. Selective knockout of the trkB gene resulted in a marked reduction in contacts made by VGLUT2- and GAD67-immunoreactive structures in both sexes and a significant reduction in contacts containing only glycine in male mice. No reduction was found for glycinergic contacts in female mice or for VGLUT1 immunoreactive contacts in either sex. Signaling through postsynaptic trkB receptors is considered to be an essential part of a cellular mechanism for maintaining the contacts of some, but not all, synaptic contacts onto motoneurons. PMID:27433358

  6. Localisation of motoneurons supplying the extra-ocular muscles of the rat using horseradish peroxidase and fluorescent double labelling.

    PubMed Central

    Labandeira Garcia, J L; Gomez Segade, L A; Suarez Nuñez, J M

    1983-01-01

    This paper describes a qualitative and quantitative investigation into the location of the motoneurons innervating the extra-ocular muscles of the rat. Injections of horseradish peroxidase, bisbenzimide, propidium iodide and DAPI-primuline were made either in one or simultaneously in two muscles. Unlike those of the cat, rabbit and monkey, the motoneurons which make up the oculomotor nucleus of the rat are not arranged in spatially separate subgroups belonging each to its corresponding extra-ocular muscle, but instead allow a high degree of superposition among the motor pools which they compose. The motoneurons innervating the lateral rectus and inferior oblique muscles are all homolateral; those of the medial and inferior rectus muscles are mainly homolateral with a few contralateral exceptions; and those of the superior rectus, levator palpebrae and superior oblique muscles are mainly contralateral with a small minority of homolateral exceptions. As well as from the main motor pools with which they are associated, the medial rectus, inferior rectus, superior rectus, levator palpebrae, superior oblique and lateral rectus muscles all receive innervation from motoneurons lying among the fibres of the fasciculus longitudinalis medialis. All these observations are supported by quantitative data. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:6195140

  7. Naloxone reduces the amplitude of IPSPs evoked in lumbar motoneurons by reticular stimulation during carbachol-induced motor inhibition.

    PubMed

    Xi, M C; Liu, R H; Yamuy, J; Morales, F R; Chase, M H

    1999-02-20

    During active sleep or carbachol-induced motor inhibition, electrical stimulation of the medullary nucleus reticularis gigantocellularis (NRGc) evoked large amplitude, glycinergic inhibitory postsynaptic potentials (IPSPs) in cat motoneurons. The present study was directed to determine whether these IPSPs, that are specific to the state of active sleep, are modulated by opioid peptides. Accordingly, intracellular recordings were obtained from lumbar motoneurons of acute decerebrate cats during carbachol-induced motor inhibition while an opiate receptor antagonist, naloxone, was microiontophoretically released next to the recorded cells. Naloxone reversibly reduced by 26% the mean amplitude of NRGc-evoked IPSPs (1.9+/-0.2 mV (S.E.M.) vs. 1.4+/-0.2 mV; n=11, control and naloxone, respectively, p<0.05), but had no effect on the other waveform parameters of these IPSPs (e.g., latency-to-onset, latency-to-peak, duration, etc.). The mean resting membrane potential, input resistance and membrane time constant of motoneurons following naloxone ejection were not statistically different from those of the control. These data indicate that opioid peptides have a modulatory effect on NRGc-evoked IPSPs during carbachol-induced motor inhibition. We therefore suggest that endogenous opioid peptides may act as neuromodulators to regulate inhibitory glycinergic synaptic transmission at motoneurons during active sleep. PMID:10082872

  8. Cervical spinal cord injury upregulates ventral spinal 5-HT2A receptors.

    PubMed

    Fuller, David D; Baker-Herman, Tracy L; Golder, Francis J; Doperalski, Nicholas J; Watters, Jyoti J; Mitchell, Gordon S

    2005-02-01

    Following chronic C2 spinal hemisection (C2HS), crossed spinal pathways to phrenic motoneurons exhibit a slow, spontaneous increase in efficacy by a serotonin (5-HT)-dependent mechanism associated with 5-HT2A receptor activation. Further, the spontaneous appearance of cross-phrenic activity following C2HS is accelerated and enhanced by exposure to chronic intermittent hypoxia (CIH). We hypothesized that chronic C2HS would increase 5-HT and 5-HT2A receptor expression in ventral cervical spinal segments containing phrenic motoneurons. In addition, we hypothesized that CIH exposure would further increase 5-HT and 5-HT2A receptor density in this region. Control, sham-operated, and C2HS Sprague-Dawley rats were studied following normoxia or CIH (11% O2-air; 5-min intervals; nights 7-14 post-surgery). At 2 weeks post-surgery, ventral spinal gray matter extending from C4 and C5 was isolated ipsilateral and contralateral to C2HS. Neither C2HS nor CIH altered 5-HT concentration measured with an ELISA on either side of the spinal cord. However, 5-HT2A receptor expression assessed with immunoblots increased in ipsilateral gray matter following C2HS, an effect independent of CIH. Immunocytochemistry revealed increased 5-HT2A receptor expression on identified phrenic motoneurons (p<0.05), as well as in the surrounding gray matter. Contralateral to injury, 5-HT2A receptor expression was elevated in CIH, but not normoxic C2HS rats (p<0.05). Our data are consistent with the hypothesis that spontaneous increase in 5-HT2A receptor expression on or near phrenic motoneurons contributes to strengthened crossed-spinal synaptic pathways to phrenic motoneurons following C2HS. PMID:15716627

  9. Immunohistochemical study of motoneurons in lumbar spinal cord of c57black/6 mice after 30-days space flight

    NASA Astrophysics Data System (ADS)

    Tyapkina, Oksana; Islamov, Rustem; Nurullin, Leniz; Petrov, Konstantin.; Rezvyakov, Pavel; Nikolsky, Evgeny

    To investigate mechanisms of hypogravity motor syndrome development the immunoexpression of heat shock proteins (Hsp27 and Hsp70), proteins of synaptic transmission (Synaptophysin and PSD95) and neuroprotective proteins (VEGF and Flt-1) in motoneurons of lumbar spinal cord in c57black/6 control mice (n=2) and after 30-days space flight (n=2) was studied. For a quantitative assessment of target proteins level in motoneurons frozen cross sections of lumbar spinal cord were underwent to immunohistochemical staining. Primary antibodies against VEGF, Flt-1, Hsp27 and Hsp70 (SantaCruz Biotechnology, inc. USA), against Synaptophysin and PSD95 (Abcam plc, UK) were visualized by streptavidin-biotin method. Images of spinal cords were received using OlympusBX51WI microscope with AxioCamMRm camera (CarlZeiss, Germany) and the AxioVisionRel. 4.6.3 software (CarlZeiss, Germany). The digitized data were analyzed using ImageJ 1.43 software (NIH, the USA). Quantitively, protein level in motoneurons was estimated by the density of immunoprecipitation. Results of research have not revealed any reliable changes in the immunnoexpression of vascular endothelial growth factor (VEGF) and its Flt-1 receptor in motoneurons of lumbar spinal cord in control and in mice after 30-day space flight. Studying of heat shock proteins, such as Hsp27 and Hsp70, revealed the decrease in level of these proteins immunoexpression in motoneurons of mice from flight group by 15% and 10%, respectively. Some decrease in level of immunnoexpression of presynaptic membrane proteins (synaptophysin, by 21%) and proteins of postsynaptic area (PSD95, by 55%) was observed after space flight. The data obtained testify to possible changes in a functional state (synaptic activity and stress resistance) of motoneurons of lumbar spinal cord in mice after space flight. Thus, we obtained new data on involvement of motoneurons innervating skeletal muscles in development of hypogravity motor syndrome. Research was supported

  10. Voltage-gated calcium channels are abnormal in cultured spinal motoneurons in the G93A-SOD1 transgenic mouse model of ALS.

    PubMed

    Chang, Qing; Martin, Lee J

    2016-09-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motoneurons. Hyperexcitability and excitotoxicity have been implicated in the early pathogenesis of ALS. Studies addressing excitotoxic motoneuron death and intracellular Ca(2+) overload have mostly focused on Ca(2+) influx through AMPA glutamate receptors. However, intrinsic excitability of motoneurons through voltage-gated ion channels may also have a role in the neurodegeneration. In this study we examined the function and localization of voltage-gated Ca(2+) channels in cultured spinal cord motoneurons from mice expressing a mutant form of human superoxide dismutase-1 with a Gly93→Ala substitution (G93A-SOD1). Using whole-cell patch-clamp recordings, we showed that high voltage activated (HVA) Ca(2+) currents are increased in G93A-SOD1 motoneurons, but low voltage activated Ca(2+) currents are not affected. G93A-SOD1 motoneurons also have altered persistent Ca(2+) current mediated by L-type Ca(2+) channels. Quantitative single-cell RT-PCR revealed higher levels of Ca1a, Ca1b, Ca1c, and Ca1e subunit mRNA expression in G93A-SOD1 motoneurons, indicating that the increase of HVA Ca(2+) currents may result from upregulation of Ca(2+) channel mRNA expression in motoneurons. The localizations of the Ca1B N-type and Ca1D L-type Ca(2+) channels in motoneurons were examined by immunocytochemistry and confocal microscopy. G93A-SOD1 motoneurons had increased Ca1B channels on the plasma membrane of soma and dendrites. Ca1D channels are similar on the plasma membrane of soma and lower on the plasma membrane of dendrites of G93A-SOD1 motoneurons. Our study demonstrates that voltage-gated Ca(2+) channels have aberrant functions and localizations in ALS mouse motoneurons. The increased HVA Ca(2+) currents and PCCa current could contribute to early pathogenesis of ALS. PMID:27151771

  11. Glycinergic and GABA(A)-mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia.

    PubMed

    Brooks, Patricia L; Peever, John H

    2008-04-01

    A hallmark of rapid eye movement (REM) sleep is a potent suppression of postural muscle tone. Motor control in REM sleep is unique because it is characterized by flurries of intermittent muscle twitches that punctuate muscle atonia. Because somatic motoneurons are bombarded by strychnine-sensitive IPSPs during REM sleep, it is assumed that glycinergic inhibition underlies REM atonia. However, it has never been determined whether glycinergic inhibition of motoneurons is indeed responsible for triggering the loss of postural muscle tone during REM sleep. Therefore, we used reverse microdialysis, electrophysiology, and pharmacological and histological methods to determine whether glycinergic and/or GABA(A)-mediated neurotransmission at the trigeminal motor pool mediates masseter muscle atonia during REM sleep in rats. By antagonizing glycine and GABA(A) receptors on trigeminal motoneurons, we unmasked a tonic glycinergic/GABAergic drive at the trigeminal motor pool during waking and non-rapid eye movement (NREM) sleep. Blockade of this drive potently increased masseter muscle tone during both waking and NREM sleep. This glycinergic/GABAergic drive was immediately switched-off and converted into a phasic glycinergic drive during REM sleep. Blockade of this phasic drive potently provoked muscle twitch activity in REM sleep; however, it did not prevent or reverse REM atonia. Muscle atonia in REM even persisted when glycine and GABA(A) receptors were simultaneously antagonized and trigeminal motoneurons were directly activated by glutamatergic excitation, indicating that a powerful, yet unidentified, inhibitory mechanism overrides motoneuron excitation during REM sleep. Our data refute the prevailing hypothesis that REM atonia is caused by glycinergic inhibition. The inhibitory mechanism mediating REM atonia therefore requires reevaluation. PMID:18385312

  12. Contribution of intrinsic motoneuron properties to discharge hysteresis and its estimation based on paired motor unit recordings: a simulation study.

    PubMed

    Powers, Randall K; Heckman, C J

    2015-07-01

    Motoneuron activity is strongly influenced by the activation of persistent inward currents (PICs) mediated by voltage-gated sodium and calcium channels. However, the amount of PIC contribution to the activation of human motoneurons can only be estimated indirectly. Simultaneous recordings of pairs of motor units have been used to provide an estimate of the PIC contribution by using the firing rate of the lower threshold unit to provide an estimate of the common synaptic drive to both units, and the difference in firing rate (ΔF) of this lower threshold unit at recruitment and de-recruitment of the higher threshold unit to estimate the PIC contribution to activation of the higher threshold unit. It has recently been suggested that a number of factors other than PIC can contribute to ΔF values, including mechanisms underlying spike frequency adaptation and spike threshold accommodation. In the present study, we used a set of compartmental models representing a sample of 20 motoneurons with a range of thresholds to investigate how several different intrinsic motoneuron properties can potentially contribute to variations in ΔF values. We drove the models with linearly increasing and decreasing noisy conductance commands of different rate of rise and duration and determined the influence of different intrinsic mechanisms on discharge hysteresis (the difference in excitatory drive at recruitment and de-recruitment) and ΔF. Our results indicate that, although other factors can contribute, variations in discharge hysteresis and ΔF values primarily reflect the contribution of dendritic PICs to motoneuron activation. PMID:25904704

  13. Motoneuronal Sema3C is essential for setting stereotyped motor tract positioning in limb-derived chemotropic semaphorins.

    PubMed

    Sanyas, Isabelle; Bozon, Muriel; Moret, Frédéric; Castellani, Valérie

    2012-10-01

    The wiring of neuronal circuits requires complex mechanisms to guide axon subsets to their specific target with high precision. To overcome the limited number of guidance cues, modulation of axon responsiveness is crucial for specifying accurate trajectories. We report here a novel mechanism by which ligand/receptor co-expression in neurons modulates the integration of other guidance cues by the growth cone. Class 3 semaphorins (Sema3 semaphorins) are chemotropic guidance cues for various neuronal projections, among which are spinal motor axons navigating towards their peripheral target muscles. Intriguingly, Sema3 proteins are dynamically expressed, forming a code in motoneuron subpopulations, whereas their receptors, the neuropilins, are expressed in most of them. Targeted gain- and loss-of-function approaches in the chick neural tube were performed to enable selective manipulation of Sema3C expression in motoneurons. We show that motoneuronal Sema3C regulates the shared Sema3 neuropilin receptors Nrp1 and Nrp2 levels in opposite ways at the growth cone surface. This sets the respective responsiveness to exogenous Nrp1- and Nrp2-dependent Sema3A, Sema3F and Sema3C repellents. Moreover, in vivo analysis revealed a context where this modulation is essential. Motor axons innervating the forelimb muscles are exposed to combined expressions of semaphorins. We show first that the positioning of spinal nerves is highly stereotyped and second that it is compromised by alteration of motoneuronal Sema3C. Thus, the role of the motoneuronal Sema3 code could be to set population-specific axon sensitivity to limb-derived chemotropic Sema3 proteins, therefore specifying stereotyped motor nerve trajectories in their target field. PMID:22899844

  14. Semaphorin and neuropilin co-expression in motoneurons sets axon sensitivity to environmental semaphorin sources during motor axon pathfinding.

    PubMed

    Moret, Frédéric; Renaudot, Christelle; Bozon, Muriel; Castellani, Valérie

    2007-12-01

    Class III semaphorins (SemaIIIs) are intercellular cues secreted by surrounding tissues to guide migrating cells and axons in the developing organism. This chemotropic activity is crucial for the formation of nerves and vasculature. Intriguingly, SemaIIIs are also synthesized by neurons during axon pathfinding, but their function as intrinsic cues remains unknown. We have explored the role of Sema3A expression in motoneurons during spinal nerve development. Loss- and gain-of-function in the neural tube of the chick embryo were undertaken to target Sema3A expression in motoneurons while preserving Sema3A sources localized in peripheral tissues, known to provide important repulsive information for delineating the routes of motor axons towards their ventral or dorsal targets. Strikingly, Sema3A overexpression induced defasciculation and exuberant growth of motor axon projections into these normally non-permissive territories. Moreover, knockdown studies showed that motoneuronal Sema3A is required for correct spinal nerve compaction and dorsal motor axon extension. Further analysis of Sema3A gain- and loss-of-function in ex vivo models revealed that Sema3A in motoneurons sets the level of sensitivity of their growth cones to exogenous Sema3A exposure. This regulation is associated with post-transcriptional and local control of the availability of the Sema3A receptor neuropilin 1 at the growth cone surface. Thus, by modulating the strength of Sema3A-mediated environmental repulsive constraints, Sema3A in motoneurons enables axons to extend more or less far away from these repulsive sources. Such interplay between intrinsic and extrinsic Sema3A may represent a fundamental mechanism in the accurate specification of axon pathways. PMID:18039974

  15. Recovery of slow and fast muscles following nerve injury during early post-natal development in the rat.

    PubMed Central

    Lowrie, M B; Krishnan, S; Vrbová, G

    1982-01-01

    1. The sciatic nerve was crushed in 5-6-day-old rats and the recovery of function of slow and fast muscles was studied. The first signs of recovery of function were seen 10-12 days after the operation. 2. Maximal tetanic tension developed by the reinnervated muscles was recorded and taken as an indication of their recovery. Two months after nerve crush, slow soleus muscles developed only slightly less tension than the control unoperated soleus muscles. The reinnervated fast muscles tibialis anterior (t.a.) and extensor digitorum longus (e.d.l.) developed only about 50% of the tension of the unoperated controls. 3. The fast muscles never recovered, remaining weaker and smaller throughout the animals' life. 4. The number of muscle fibres in the reinnervated fast muscles was substantially reduced and their fibre composition altered in that they contained mainly muscle fibres with high levels of oxidative enzymes. 5. The reinnervated fast muscles became much more fatigue resistant than the unoperated controls. 6. The possibility that these changes are due to motoneurone death was examined. The motoneurones innervating the fast muscles were labelled by retrograde transport of HRP. No significant reduction in the number of motoneurones innervating the operated muscles was found. 7. These results show that nerve injury during early post-natal life causes permanent changes in fast muscles that are not caused by motoneurone death. Images PLATE 1 (cont.) PLATE 1 PLATE 2 PMID:7153915

  16. Properties of inward and outward potassium currents in cultured mouse motoneurons.

    PubMed

    McLarnon, J G; Kim, S U; Michikawa, M; Xu, R

    1995-01-01

    Inward rectifier potassium currents and calcium-dependent potassium currents have been studied in cultured embryonic mouse motoneurons. Sustained unitary inward rectifier potassium currents were recorded from cell-attached patches and the channel conductance was dependent on external K+ concentration with a value of 25 pS when external K+ was 140 mM. The channel open probability exhibited a sigmoidal dependence on potential with the largest values (near 0.7) at depolarizing patch potentials. Inactivating inward rectifier potassium currents were also recorded in some cell-attached patches following voltage steps to hyperpolarizing potentials with the rate of inactivation faster with larger hyperpolarizing steps. Whole-cell inward rectifier potassium currents increased from an initial level to a steady-state level with hyperpolarizing steps to -120 mV from a holding potential of -60 mV; with larger hyperpolarizing commands the peak currents decayed to the steady-state. The steady-state current-voltage relation exhibited a region of negative slope resistance. External Cs+ (0.5-1 mM) reduced the amplitudes of macroscopic currents and diminished the open times of unitary currents consistent with block of open rectifying channels with an estimated KD for channel block of 1 mM. A large conductance calcium-dependent potassium channel was isolated in inside-out patches with a conductance of 240 pS with symmetrical 140 mM K+ across the patches and a conductance of 110 pS when the external K+ was reduced to 5 mM. With symmetrical K+ the channel open probability exhibited a sigmoid dependence on potential with the largest values, in excess of 0.8, associated with patch depolarization. The dependence of open probability on potential was dependent on the concentrations of internal Ca2+ and external K+. Properties of inward rectifier and calcium-dependent K+ channels, such as the voltage dependence of open probability, are involved in the establishment of cellular excitability in

  17. Ionic and pharmacological properties of reciprocal inhibition in Xenopus embryo motoneurones.

    PubMed Central

    Soffe, S R

    1987-01-01

    1. Properties of rhythmic, compound mid-cycle inhibitory post-synaptic potentials (i.p.s.p.s), which constitute one of the three main synaptic drives to motoneurones during fictive swimming in Xenopus embryos, have been examined using ionic and pharmacological manipulation. 2. Mid-cycle i.p.s.p.s are Cl- dependent. They are reversed by intracellular Cl- injection and attenuated by lowered extracellular Cl- concentration. 3. In response to bath application of 100 microM-glycine or 100 microM-gamma-aminobutyric acid (GABA), motoneurones show a decrease in cell input resistance of 24 +/- 2.9 M omega (mean +/- S.E. of mean) or 16 +/- 3.7% and 26 +/- 6.0 M omega or 14 +/- 2.0% respectively. This is associated with a weak hyperpolarization or depolarization of 0 +/- 1.5 mV and -3 +/- 1.4 mV respectively. Both responses can be made strongly depolarizing by intracellular Cl- injection. 4. The response to glycine is blocked by 1 microM-strychnine but is largely unaffected by bicuculline below 50 microM. The response to GABA is largely blocked by 10 microM-bicuculline but is unaffected by 1 microM-strychnine. Both strychnine and bicuculline are therefore specific antagonists in the amphibian embryo preparation. Glycine and GABA are both partially antagonized by 10 microM-picrotoxin. 5. Mid-cycle i.p.s.p.s recorded in motoneurones during fictive swimming are reduced in amplitude by 0.5-1 microM-strychnine but are largely unaffected by 40 microM-bicuculline. In embryos immobilized by ventral root transection, 100 microM-tubocurarine, a likely GABA antagonist in the embryo, has no effect on mid-cycle inhibition. Glycine is suggested to be the probable transmitter released by commissural interneurones and mediating mid-cycle inhibition during fictive swimming, acting to increase conductance of Cl-. PMID:3625556

  18. Head Injuries

    MedlinePlus

    ... of head injuries include bicycle or motorcycle wrecks, sports injuries, falls from windows (especially among children who live ... to watch for? When can I start playing sports again after a head injury? How can brain damage from a head injury ...

  19. Head Injuries

    MedlinePlus

    ... before. Often, the injury is minor because your skull is hard and it protects your brain. But ... injuries can be more severe, such as a skull fracture, concussion, or traumatic brain injury. Head injuries ...

  20. Back Injuries

    MedlinePlus

    ... extending from your neck to your pelvis. Back injuries can result from sports injuries, work around the house or in the garden, ... back is the most common site of back injuries and back pain. Common back injuries include Sprains ...

  1. Head Injuries

    MedlinePlus

    ... before. Usually, the injury is minor because your skull is hard and it protects your brain. But ... injuries can be more severe, such as a skull fracture, concussion, or traumatic brain injury. Head injuries ...

  2. Cell size and geometry of spinal cord motoneurons in the adult cat following the intramuscular injection of adriamycin: comparison with data from aged cats.

    PubMed

    Liu, R H; Yamuy, J; Engelhardt, J K; Xi, M C; Morales, F R; Chase, M H

    1996-10-28

    Adriamycin (ADM), an antineoplastic antibiotic, when injected intramuscularly, is taken up by motoneuron axonal terminals and retrogradely transported to the motoneuron soma where it exerts its neurotoxic effect. In the present study, ADM was injected into the hindlimb muscles of five adult cats. Measurements of the electrophysiological properties of the lumbar motoneurons innervating these muscles were obtained using intracellular techniques. Based upon these data the equivalent cylinder model of motoneurons was employed to evaluate ADM-induced changes in cell size and cell geometry. The size of cell somas in the ventral horn was also measured using light microscopy and computer imaging software. There were significant increases in the membrane time constant (25%) and input resistance (50%) in motoneurons whose muscles were treated with ADM (ADM-MNs) compared with data from control motoneurons (control-MNs). The increase in membrane time constant is attributed to an increase in membrane resistance; the increase in input resistance appears to depend upon both an increase in membrane resistance and a decrease in total cell surface area. Cell capacitance, which is proportional to the total cell surface area, was significantly reduced (15%) in ADM-MNs. Calculations based on cable theory indicate that while there was no significant change in the length of the equivalent cylinder for ADM-MNs, there was a significant decrease (17%) in the diameter of the equivalent cylinder. These data indicate that there is a decrease in total cell surface area which can be attributed to the shrinkage of branches throughout the dendritic tree. There was also a small (7%) but statistically significant decrease in the electrotonic length of ADM-MNs. Morphological analysis also revealed that the mean cross-sectional area of the somas of those ventral horn neurons which are likely to correspond to the motoneuron population was significantly reduced on the ADM-treated side compared to that

  3. A Caged Ret Kinase Inhibitor and its Effect on Motoneuron Development in Zebrafish Embryos

    PubMed Central

    Bliman, David; Nilsson, Jesper R.; Kettunen, Petronella; Andréasson, Joakim; Grøtli, Morten

    2015-01-01

    Proto-oncogene tyrosine-protein kinase receptor RET is implicated in the development and maintenance of neurons of the central and peripheral nervous systems. Attaching activity-compromising photocleavable groups (caging) to inhibitors could allow for external spatiotemporally controlled inhibition using light, potentially providing novel information on how these kinase receptors are involved in cellular processes. Here, caged RET inhibitors were obtained from 3-substituted pyrazolopyrimidine-based compounds by attaching photolabile groups to the exocyclic amino function. The most promising compound displayed excellent inhibitory effect in cell-free, as well as live-cell assays upon decaging. Furthermore, inhibition could be efficiently activated with light in vivo in zebrafish embryos and was shown to effect motoneuron development. PMID:26300345

  4. Descending pathways to the cutaneus trunci muscle motoneuronal cell group in the cat

    NASA Technical Reports Server (NTRS)

    Holstege, Gert; Blok, Bertil F.

    1989-01-01

    Pathways involved in the cutaneous trunci muscle (CTM) reflex in the cat were investigated. Experimental animals were injected with tritium-labeled L-leucine into their spinal cord, brain stem, or diencephalon and, after six weeks, perfused with 10-percent formalin. The brains and spinal cords were postfixed in formalin and were cut into transverse 25-micron-thick frozen sections for autoradiography. Results based on injections in the C1, C2, C6, and C8 segments suggest that propriospinal pathways to the CTM motor nucleus originating in the cervical cord do no exist, although these propriospinal projections are very strong to all other motoneuronal cell groups surrounding the CTM motor nucleus. The results also demonstrate presence of specific supraspinal projections to the CTM motor nucleus, originating in the contralateral nucleus retroambiguous and the ipsilateral dorsolateral pontine tegmentum.

  5. Signaling mechanism underlying the histamine-modulated action of hypoglossal motoneurons.

    PubMed

    Liu, Zi-Long; Wu, Xu; Luo, Yan-Jia; Wang, Lu; Qu, Wei-Min; Li, Shan-Qun; Huang, Zhi-Li

    2016-04-01

    Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea. However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms have remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H1 receptors (H1 Rs). The phospholipase C inhibitor U-73122 blocked H1 Rs-mediated excitatory effects, but protein kinase A inhibitor and protein kinase C inhibitor did not, indicating that the signal transduction cascades underlying the excitatory action of histamine on HMNs were H1 R/Gq/11 /phospholipase C/inositol-1,4,5-trisphosphate (IP3 ). The effects of histamine were also dependent on extracellular Na(+) and intracellular Ca(2+) , which took place via activation of Na(+) -Ca(2+) exchangers. These results identify the signaling molecules associated with the regulatory effect of histamine on HMNs. The findings of this study may provide new insights into therapeutic approaches in obstructive sleep apnea. We proposed the post-synaptic mechanisms underlying the modulation effect of histamine on hypoglossal motoneuron. Histamine activates the H1 Rs via PLC and IP3 , increases Ca(2+) releases from intracellular stores, promotes Na(+) influx and Ca(2+) efflux via the NCXs, and then produces an inward current and depolarizes the neurons. Histamine modulates the excitability of HMNs with other neuromodulators, such as noradrenaline, serotonin and orexin. We think that these findings should provide an important new direction for drug development for the treatment of obstructive sleep apnea. PMID:26811198

  6. Differences in Dysfunction of Thenar and Hypothenar Motoneurons in Amyotrophic Lateral Sclerosis

    PubMed Central

    Fang, Jia; Cui, Liying; Liu, Mingsheng; Guan, Yuzhou; Li, Xiaoguang; Li, Dawei; Cui, Bo; Shen, Dongchao; Ding, Qingyun

    2016-01-01

    This study aimed to determine differences in spinal motoneuron dysfunction between the abductor pollicis brevis (APB) and the abductor digiti minimi (ADM) in amyotrophic lateral sclerosis (ALS) patients based on studying F-waves. Forty ALS patients and 20 normal controls (NCs) underwent motor nerve conduction studies on both median and ulnar nerves, including F-waves elicited by 100 electrical stimuli. The F-wave persistence (P < 0.05), index repeating neuron (RN; P < 0.001), and index repeater F-waves (Freps; P < 0.001) significantly differed between the APB and the ADM in the NC participants. For the hands of the ALS patients that lacked detectable wasting or weakness and exhibited either no or mild impairment of discrete finger movements, significantly reduced F-wave persistence (P < 0.001), increased index RN (P < 0.001), and increased index Freps (P < 0.001) were observed in APB in comparison with the normal participants, with relatively normal ADM F-wave parameters. For the hands of ALS patients that exhibited wasting and weakness, the mean F-wave amplitude (P < 0.05), the F/M amplitude ratio (P < 0.05), F-wave persistence (P < 0.001), index RN (P < 0.05), and index Freps (P < 0.05) significantly differed between APB and ADM. The differences in the dysfunction of motoneurons innervating APB and ADM are unique manifestations in ALS patients. The F-wave persistence (P = 0.002), index RN (P < 0.001), and index Freps (P < 0.001) in the APB seemed to differentiate ALS from the NCs more robustly than the ADM/APB Compound muscle action potential (CMAP) amplitude ratio. Thus, F-waves may reveal subclinical alterations in anterior horn cells, and may potentially help to distinguish ALS from mimic disorders. PMID:27014030

  7. Differences in Dysfunction of Thenar and Hypothenar Motoneurons in Amyotrophic Lateral Sclerosis.

    PubMed

    Fang, Jia; Cui, Liying; Liu, Mingsheng; Guan, Yuzhou; Li, Xiaoguang; Li, Dawei; Cui, Bo; Shen, Dongchao; Ding, Qingyun

    2016-01-01

    This study aimed to determine differences in spinal motoneuron dysfunction between the abductor pollicis brevis (APB) and the abductor digiti minimi (ADM) in amyotrophic lateral sclerosis (ALS) patients based on studying F-waves. Forty ALS patients and 20 normal controls (NCs) underwent motor nerve conduction studies on both median and ulnar nerves, including F-waves elicited by 100 electrical stimuli. The F-wave persistence (P < 0.05), index repeating neuron (RN; P < 0.001), and index repeater F-waves (Freps; P < 0.001) significantly differed between the APB and the ADM in the NC participants. For the hands of the ALS patients that lacked detectable wasting or weakness and exhibited either no or mild impairment of discrete finger movements, significantly reduced F-wave persistence (P < 0.001), increased index RN (P < 0.001), and increased index Freps (P < 0.001) were observed in APB in comparison with the normal participants, with relatively normal ADM F-wave parameters. For the hands of ALS patients that exhibited wasting and weakness, the mean F-wave amplitude (P < 0.05), the F/M amplitude ratio (P < 0.05), F-wave persistence (P < 0.001), index RN (P < 0.05), and index Freps (P < 0.05) significantly differed between APB and ADM. The differences in the dysfunction of motoneurons innervating APB and ADM are unique manifestations in ALS patients. The F-wave persistence (P = 0.002), index RN (P < 0.001), and index Freps (P < 0.001) in the APB seemed to differentiate ALS from the NCs more robustly than the ADM/APB Compound muscle action potential (CMAP) amplitude ratio. Thus, F-waves may reveal subclinical alterations in anterior horn cells, and may potentially help to distinguish ALS from mimic disorders. PMID:27014030

  8. Putative Excitatory and Putative Inhibitory Inputs Localize to Different Dendritic Domains in a Drosophila Flight Motoneuron

    PubMed Central

    Kuehn, Claudia; Duch, Carsten

    2012-01-01

    Input-output computations of individual neurons may be affected by the three-dimensional structure of their dendrites and by the targeting of input synapses to specific parts of their dendrites. However, only few examples exist where dendritic architecture can be related to behaviorally relevant computations of a neuron. By combining genetic, immunohistochemical, and confocal laser scanning methods this study estimates the location of the spike initiating zone and the dendritic distribution patterns of putative synaptic inputs on an individually identified Drosophila flight motorneuron, MN5. MN5 is a monopolar neuron with more than 4000 dendritic branches. The site of spike initiation was estimated by mapping sodium channel immunolabel onto geometric reconstructions of MN5. Maps of putative excitatory cholinergic and of putative inhibitory GABAergic inputs on MN5 dendrites were created by charting tagged Dα7 nicotinic acetylcholine receptors and Rdl GABAA receptors onto MN5 dendritic surface reconstructions. Although these methods provided only an estimate of putative input synapse distributions, the data indicated that inhibitory and excitatory synapses were targeted preferentially to different dendritic domains of MN5, and thus, computed mostly separately. Most putative inhibitory inputs were close to spike initiation, which was consistent with sharp inhibition, as predicted previously based on recordings of motoneuron firing patterns during flight. By contrast, highest densities of putative excitatory inputs at more distant dendritic regions were consistent with the prediction that in response to different power demands during flight, tonic excitatory drive to flight motoneuron dendrites must be smoothly translated into different tonic firing frequencies. PMID:23279094

  9. SUCCESSFUL TRANSPLANTATION OF MOTONEURONS INTO THE PERIPHERAL NERVE DEPENDS ON THE NUMBER OF TRANSPLANTED CELLS

    PubMed Central

    KATO, SHUICHI; KURIMOTO, SHIGERU; NAKANO, TOMONORI; YONEDA, HIDEMASA; ISHII, HISAO; MITA-SUGIURA, SATOKA; HIRATA, HITOSHI

    2015-01-01

    ABSTRACT Transplantation of motoneurons (MN) into the peripheral nerve to provide a source of neurons for muscle reinnervation, termed motoneuron integrated striated muscle (MISM), may provide the potential to restore functional muscle activity, when combined with computer-programmed functional electrical stimulation (FES). The number of MNs required to restore innervation to denervated muscles in adult Fischer 344 rats was investigated by comparing two groups, one transplanted with 2 × 105 cells (group A) and the other with 1 × 106 cells (group B). Twelve weeks after transplantation, electrophysiological analysis, muscle function analysis, and tissue analysis were performed. The mean motor nerve conduction velocity was faster (12.4 ± 1.0 m/s vs. 8.5 ± 0.7 m/s, P = 0.011) and the mean amplitude of compound muscle action potential was larger (1.6 ± 0.4 mV vs. 0.7 ± 0.2 mV, P = 0.034) in group B. The dorsiflexed ankle angle was larger in group B (27 ± 5° vs. 75 ± 8°, P = 0.02). The mean myelinated axon number in the peroneal nerve and the proportion of reinnervated motor end plates were also greater in group B (317 ± 33 vs. 104 ± 17, 87.5 ± 3.4% vs. 40.6 ± 7.7%; P < 0.01, respectively). When sufficient MNs are transplanted into the peripheral nerve, MISM forms functional motor units. MISM, in conjunction with FES, provides a new treatment strategy for paralyzed muscles. PMID:25797991

  10. Mechanisms of disease: motoneuron disease aggravated by transgenic expression of a functionally modified AMPA receptor subunit.

    PubMed

    Kuner, Rohini; Groom, Anthony J; Müller, Gerald; Kornau, Hans-Christian; Stefovska, Vanya; Bresink, Iris; Hartmann, Bettina; Tschauner, Karsten; Waibel, Stefan; Ludolph, Albert C; Ikonomidou, Chrysanthy; Seeburg, Peter H; Turski, Lechoslaw

    2005-08-01

    To reveal whether increased Ca2+ permeability of glutamate AMPA channels triggered by the transgene for GluR-B(N) induces decline in motor functions and neurodegeneration in the spinal cord, we evaluated growth, motor coordination, and spinal reflexes in transgenic GluR-B(N) and wild-type (wt) mice. To reveal whether the transgenic GluR-B(N) expression aggravates the course of motoneuron disease in SOD1 mice, we mated heterozygous GluR-B(N) and SOD1 [C57BL6Ico-TgN(hSOD1-G93A)1Gur] mice to generate double-transgenic progeny. The phenotypic sequelae in mice carrying mutations were evaluated by monitoring growth, motor coordination, and survival. Neuronal degeneration was assessed by morphological and stereological analysis of spinal cord and brain. We found that transgenic expression in mice of GluR-B(N)-containing glutamate AMPA receptors with increased Ca2+ permeability leads to a late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progressed over the entire life span, but manifested clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerated disease progression, aggravated severity of motor decline, and decreased survival. These observations reveal that moderate, but persistently elevated Ca2+ influx via glutamate AMPA channels causes degeneration of spinal motoneurons and motor decline over the span of life. These features resemble the course of sporadic amyotrophic lateral sclerosis (ALS) in humans and suggest that modified function of glutamate AMPA channels may be causally linked to pathogenesis of ALS. PMID:16179532