scholarly journals Neuromodulatory selection of motor neuron recruitment patterns in a visuomotor behavior increases speed

2019 ◽  
Author(s):  
Urvashi Jha ◽  
Vatsala Thirumalai
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Prey Capture ◽  
Receptor Activation ◽  
Motor Drive ◽  
List Type ◽  
Optomotor Response ◽  
Visuomotor Behavior ◽  
Larval Zebrafish ◽  
Selection Of

SummaryAnimals generate locomotion at different speeds to suit their behavioral needs. Spinal circuits generate locomotion at these varying speeds by sequential activation of different spinal interneurons and motor neurons. Larval zebrafish can generate slow swims for prey capture and exploration by activation of secondary motor neurons and much faster and vigorous swims during escapes and struggles via the additional activation of primary motor neurons. Neuromodulators are known to alter motor output of spinal circuits yet their precise role in speed regulation is not understood well. Here, in the context of optomotor response (OMR), an innate, evoked locomotor behavior, we show that dopamine (DA) provides an additional layer to regulation of swim speed in larval zebrafish. Activation of D1-like receptors increases swim speed during OMR in free-swimming larvae. By analysing tail bend kinematics in head-restrained larvae, we show that the increase in speed is actuated by larger tail bends. Whole cell patch clamp recordings from motor neurons reveal that during OMR, typically only secondary motor neurons are active while primary motor neurons are quiescent. Activation of D1-like receptors increases motor drive from secondary motor neurons by decreasing spike threshold and latency. In addition, D1-like receptor activation enhances excitability and recruits quiescent primary motor neurons. Our findings provide an example of neuromodulatory reconfiguration of spinal motor neuron speed modules such that members are selectively recruited and motor drive is increased to effect changes in locomotor speed.HighlightsZebrafish larvae generate swims of increased speed during optomotor response when D1-like receptors are activated.D1-like receptor activation increases the extent of tail bending during forward swims and turns resulting in increased swim speed.Neuromodulation via D1-like receptors increases motor drive by enhancing excitability of ‘slow’ motor neurons. In addition, D1-like receptor activation recruits quiescent ‘fast’ motor neurons to increase swim speed.This demonstrates neuromodulatory selection of motor neurons belonging to different ‘speed’ modules to alter swimming behavior.Graphical abstract

Regulation of motor neuron dendrite growth by NMDA receptor activation

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3063-3071 ◽  
Author(s):  
R.G. Kalb
Keyword(s):  
Nmda Receptor ◽  
Motor Neuron ◽  
Cell Body ◽  
Motor Neurons ◽  
Receptor Activation ◽  
Dendrite Growth ◽  
Postnatal Life ◽  
Receptor Antagonism ◽  
Neuron Cell Body ◽  
Early Postnatal Life

Spinal motor neurons undergo great changes in morphology, electrophysiology and molecular composition during development. Some of this maturation occurs postnatally when limbs are employed for locomotion, suggesting that neuronal activity may influence motor neuron development. To identify features of motor neurons that might be regulated by activity we first examined the structural development of the rat motor neuron cell body and dendritic tree labeled with cholera toxin-conjugated horseradish peroxidase. The motor neuron cell body and dendrites in the radial and rostrocaudal axes grew progressively over the first month of life. In contrast, the growth of the dendritic arbor/cell and number of dendritic branches was biphasic with overabundant growth followed by regression until the adult pattern was achieved. We next examined the influence of neurotransmission on the development of these motor neuron features. We found that antagonism of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor inhibited cell body growth and dendritic branching in early postnatal life but had no effect on the maximal extent of dendrite growth in the radial and rostrocaudal axes. The effects of NMDA receptor antagonism on motor neurons and their dendrites was temporally restricted; all of our anatomic measures of dendrite structure were resistant to NMDA receptor antagonism in adults. These results suggest that the establishment of mature motor neuron dendritic architecture results in part from dendrite growth in response to afferent input during a sensitive period in early postnatal life.

scholarly journals Groucho/TLE opposes axial to hypaxial motor neuron development

2020 ◽  
Author(s):  
Adèle Salin-Cantegrel ◽  
Rola Dali ◽  
Jae Woong Wang ◽  
Marielle Beaulieu ◽  
Mira Deshmukh ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
List Type ◽  
Neuron Development ◽  
In Ovo ◽  
Motor Circuits ◽  
Axial Muscles ◽  
Muscle Innervation

ABSTRACTSpinal cord motor neuron diversity and the ensuing variety of motor circuits allow for the processing of elaborate muscular behaviours such as body posture and breathing. Little is known, however, about the molecular mechanisms behind the specification of axial and hypaxial motor neurons controlling postural and respiratory functions respectively. Here we show that the Groucho/TLE (TLE) transcriptional corepressor is a multi-step regulator of axial and hypaxial motor neuron diversification in the developing spinal cord. TLE first promotes axial motor neuron specification at the expense of hypaxial identity by cooperating with non-canonical WNT5A signalling within the motor neuron progenitor domain. TLE further acts during post-mitotic motor neuron diversification to promote axial motor neuron topology and axonal connectivity whilst suppressing hypaxial traits. These findings provide evidence for essential and sequential roles of TLE in the spatial and temporal coordination of events regulating the development of motor neurons influencing posture and controlling respiration.HIGHLIGHTSGroucho/TLE mediates non-canonical WNT signalling in developing motor neuronsNon canonical WNT:TLE pathway regulates thoracic motor neuron diversificationTLE promotes axial while inhibiting hypaxial motor neuron developmentTLE influences developing motor neuron topology and muscle innervationIN BRIEFSalin-Cantegrel et al use in ovo engineered approaches to show that a non-canonical WNT:TLE pathway coordinates temporally and spatially separated elements of motor neuron diversification, repressing hypaxial motor neuron development to promote the axial fate.GRAPHICAL ABSTRACTTLE contribution to the development of thoracic somatic motor columnsProgenitor cells in the ventral pMN domain are exposed to higher concentrations of non-canonical WNTs and express more TLE. Cooperation of non-canonical WNTs and TLE renders ventral pMN progenitors refractory to a respiratory MN fate, thereby contributing to the separation of MMC and RMC MN lineages. Differentiating MNs that maintain high TLE expression also maintain LHX3 expression, adopt axial motor neuron topology and connect to axial muscles. TLE activity in differentiating MMC MNs prevents the acquisition of respiratory MN topology and innervation traits.

scholarly journals A cerebellar internal model calibrates a feedback controller involved in sensorimotor control

2020 ◽  
Author(s):  
Daniil A. Markov ◽  
Luigi Petrucco ◽  
Andreas M. Kist ◽  
Ruben Portugues
Keyword(s):  
Feedback Control ◽  
Visual Feedback ◽  
Internal Model ◽  
Control Mechanism ◽  
Internal Models ◽  
List Type ◽  
Optomotor Response ◽  
Larval Zebrafish ◽  
Sensory State ◽  
Control Feedback

AbstractAnimals must adapt their behavior to survive in a changing environment. Behavioral adaptations can be evoked by two mechanisms: feedback control and internal-model-based control. Feedback controllers can maintain the sensory state of the animal at a desired level under different environmental conditions. In turn, internal models learn the relationship between behavior and resulting sensory consequences in order to modify the behavior when this relationship changes. Here, we present multiple perturbations in visual feedback to larval zebrafish performing the optomotor response and show that they react to these perturbations through a feedback control mechanism. In contrast, if a perturbation is long-lasting, fish adapt their behavior by updating a cerebellum-dependent internal model. We use modelling and functional imaging to show that neuronal requirements for these mechanisms are met in the larval zebrafish brain. Our results illustrate the role of the cerebellum in encoding internal models and how these can calibrate neuronal circuits involved in reactive behaviors depending on the interactions between animal and environment.HighlightsBehavioral reactions to unexpected changes in visual feedback are implemented by a feedback control mechanismA long-lasting change in visual feedback updates the state of the neuronal controllerThe cerebellar internal model mediates this recalibration

scholarly journals Ligand-independent activation of the P2X7 receptor by Hsp90 inhibition stimulates motor neuron apoptosis

2019 ◽  
Vol 244 (11) ◽  
pp. 901-914
Author(s):  
Amy L Strayer ◽  
Cassandra N Dennys-Rivers ◽  
Karina C Ricart ◽  
Narae Bae ◽  
Joseph S Beckman ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
P2x7 Receptor ◽  
Receptor Activation ◽  
Neuron Death ◽  
Hsp90 Inhibition ◽  
Highly Sensitive ◽  
Motor Neuron Death ◽  
Lateral Sclerosis ◽  
Neuron Apoptosis

Activation of the extracellular ATP ionotropic receptor P2X7 stimulates motor neuron apoptosis, whereas its inhibition in cell and animal models of amyotrophic lateral sclerosis can be protective. These observations suggest that P2X7 receptor activation is relevant to motor neuron disease and that it could be targeted for therapeutic development. Heat shock protein 90 (Hsp90) is an integral regulatory component of the P2X7 receptor complex, antagonizing ligand-induced receptor activation. Here, we show that the repressive activity of Hsp90 on P2X7 receptor activation in primary motor neurons is highly sensitive to inhibition. Primary motor neurons in culture are 100-fold more sensitive to Hsp90 inhibition by geldanamycin than other neuronal populations. Pharmacological inhibition and down-regulation of the P2X7 receptor prevented motor neuron apoptosis triggered by Hsp90 inhibition, which occurred in the absence of extracellular ATP. These observations suggest that inhibition of a seemingly motor neuron specific pool of Hsp90 leads to ligand independent activation of P2X7 receptor and motor neuron death. Downstream of Hsp90 inhibition, P2X7 receptor activated the phosphatase and tensin homolog (TPEN), which in turn suppressed the pro-survival phosphatidyl inositol 3 kinase (PI3K)/Akt pathway, leading to Fas-dependent motor neuron apoptosis. Conditions altering the interaction between P2X7 receptor and Hsp90, such as recruitment of Hsp90 to other subcellular compartments under stress conditions, or nitration following oxidative stress can induce motor neuron death. These findings may have broad implications in neurodegenerative disorders, including amyotrophic lateral sclerosis, in which activation of P2X7 receptor may be involved in both autonomous and non-autonomous motor neurons death. Impact statement Here we show that a motor neuron specific pool of Hsp90 that is highly sensitive to geldanamycin inhibition represses ligand-independent activation of P2X7 receptor and is critical to motor neuron survival. Activation of P2X7 receptor by Hsp90 inhibition triggers motor neuron apoptosis through the activation of PTEN, which in turn inhibits the PI3 kinase/Akt survival pathway. Thus, inhibition of Hsp90 for therapeutic applications may have the unexpected negative consequence of decreasing the activity of trophic pathways in motor neurons. The inhibition of Hsp90 as a therapeutic approach may require the identification of the Hsp90 complexes involved in pathogenic processes and the development of inhibitors selective for these complexes.

scholarly journals Global transcriptome profile of the developmental principles of in vitro iPSC-to-motor neuron differentiation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Emilia Solomon ◽  
Katie Davis-Anderson ◽  
Blake Hovde ◽  
Sofiya Micheva-Viteva ◽  
Jennifer Foster Harris ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Acetylcholine Receptors ◽  
Gene Networks ◽  
Spinal Cord Injuries ◽  
Regulatory Gene ◽  
Transcriptome Profile

Abstract Background Human induced pluripotent stem cells (iPSC) have opened new avenues for regenerative medicine. Consequently, iPSC-derived motor neurons have emerged as potentially viable therapies for spinal cord injuries and neurodegenerative disorders including Amyotrophic Lateral Sclerosis. However, direct clinical application of iPSC bears in itself the risk of tumorigenesis and other unforeseeable genetic or epigenetic abnormalities. Results Employing RNA-seq technology, we identified and characterized gene regulatory networks triggered by in vitro chemical reprogramming of iPSC into cells with the molecular features of motor neurons (MNs) whose function in vivo is to innervate effector organs. We present meta-transcriptome signatures of 5 cell types: iPSCs, neural stem cells, motor neuron progenitors, early motor neurons, and mature motor neurons. In strict response to the chemical stimuli, along the MN differentiation axis we observed temporal downregulation of tumor growth factor-β signaling pathway and consistent activation of sonic hedgehog, Wnt/β-catenin, and Notch signaling. Together with gene networks defining neuronal differentiation (neurogenin 2, microtubule-associated protein 2, Pax6, and neuropilin-1), we observed steady accumulation of motor neuron-specific regulatory genes, including Islet-1 and homeobox protein HB9. Interestingly, transcriptome profiling of the differentiation process showed that Ca2+ signaling through cAMP and LPC was downregulated during the conversion of the iPSC to neural stem cells and key regulatory gene activity of the pathway remained inhibited until later stages of motor neuron formation. Pathways shaping the neuronal development and function were well-represented in the early motor neuron cells including, neuroactive ligand-receptor interactions, axon guidance, and the cholinergic synapse formation. A notable hallmark of our in vitro motor neuron maturation in monoculture was the activation of genes encoding G-coupled muscarinic acetylcholine receptors and downregulation of the ionotropic nicotinic acetylcholine receptors expression. We observed the formation of functional neuronal networks as spontaneous oscillations in the extracellular action potentials recorded on multi-electrode array chip after 20 days of differentiation. Conclusions Detailed transcriptome profile of each developmental step from iPSC to motor neuron driven by chemical induction provides the guidelines to novel therapeutic approaches in the re-construction efforts of muscle innervation.

scholarly journals Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Estela Area-Gomez ◽  
D. Larrea ◽  
T. Yun ◽  
Y. Xu ◽  
J. Hupf ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Cell Structure ◽  
Disease Onset ◽  
Point Of View ◽  
Motor Dysfunction ◽  
Cellular Processes ◽  
Progressive Muscle Weakness ◽  
Human Pathology ◽  
Lateral Sclerosis

AbstractMotor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.

scholarly journals Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents

2021 ◽  
Vol 11 (2) ◽  
pp. 160
Author(s):  
Mor R. Alkaslasi ◽  
Noell E. Cho ◽  
Navpreet K. Dhillon ◽  
Oksana Shelest ◽  
Patricia S. Haro-Lopez ◽  
...  
Keyword(s):  
Risk Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Disease Onset ◽  
Poor Health ◽  
Disease Symptoms ◽  
Established Risk Factor ◽  
Early Injury ◽  
Corticospinal Motor Neurons ◽  
Lateral Sclerosis

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.

scholarly journals Sensory and motor neuron-derived factor. A novel heregulin variant highly expressed in sensory and motor neurons.

1995 ◽  
Vol 270 (44) ◽  
pp. 26722
Author(s):  
Wei-Hsien Ho ◽  
Mark P. Armanini ◽  
Andrew Nuijens ◽  
Heidi S. Phillips ◽  
Phyllis L. Osheroff
Keyword(s):  
Motor Neuron ◽  
Motor Neurons

scholarly journals ALS-Like Disorder in Three HIV-Positive Patients: Case Series

2021 ◽  
pp. 59-64
Author(s):  
Zachary Aaron Satin ◽  
Elham Bayat
Keyword(s):  
Antiretroviral Therapy ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Case Series ◽  
Retrospective Chart Review ◽  
Effective Control ◽  
Hiv Positive ◽  
Disease Course ◽  
Retroviral Infection

There appears to be a relationship between retroviruses such as HIV and the development of an ALS-like syndrome. Few cases have been reported; however, there exists evidence of a higher frequency of motor neuron disease in HIV-infected patients, as well as potential slowing and reversibility of disease course with combination antiretroviral therapy. We conducted a retrospective chart review of patients presenting to the George Washington University ALS Clinic from September 2006 to June 2018 to identify patients with HIV receiving HAART who were subsequently diagnosed with ALS or an ALS-like disorder. Our goals were to describe our patients’ disease course and compare them to general characteristics of ALS. We report three cases of HIV-positive individuals, all male, who were subsequently diagnosed with ALS. Each presented with symptoms of limb onset ALS with involvement of upper and lower motor neurons and whose disease originated at the cervical level. All three had been diagnosed with HIV prior to presentation and were presumably compliant with antiretroviral therapy throughout. Our patients demonstrated effective control of their HIV infection. Each experienced relatively slow progression of motor impairment compared to general ALS characteristics. Our study offers a distinct profile of HIV-positive patients compliant with HAART subsequently diagnosed with an ALS-like disorder. Further study should aim to uncover pathophysiological similarities between motor neuron disease both in the presence and absence of retroviral infection and to develop effective medical therapy for each.

Sign in / Sign up

Export Citation Format

Share Document