scholarly journals Neuromuscular connectomes across development reveal synaptic ordering rules

2021 ◽  
Author(s):  
Yaron Meirovitch ◽  
Kai Kang ◽  
Ryan W Draft ◽  
Elisa C Pavarino ◽  
Maria Fernanda Henao Echeverri ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Muscle Fibers ◽  
Motor Units ◽  
Postnatal Life ◽  
Size Principle ◽  
Mouse Muscle ◽  
Action At A Distance ◽  
Activity Dependent ◽  
Insight Into

The connections between motor neurons and muscle fibers are dramatically reorganized in early postnatal life. This work attempts to better understand this synaptic rewiring by using a connectomic approach, i.e., tracing out all the connections between motor neurons and muscle fibers, at successive ages in a small mouse muscle. We reconstructed 31 partial-complete neuromuscular connectomes, using serial section scanning electron microscopy in a neonatal mouse and Brainbow-based and XFP-based fluorescent reconstructions in older animals. Our data included a total of more than 6000 neuromuscular junctions (NMJs), including complete connectomes from one newborn, seven developmental ages (P6-P9), and two adults. Analysis confirmed the massive rewiring that takes place as axons prune their motor units but add more synaptic areas at the NMJs with which they remain in contact. Interestingly, we found synaptic ordering rules that likely underlie this circuit maturation and yield the resulting adult neuromuscular pattern, as manifest in Henneman's size principle. In particular, by analyzing both the identities of axons sharing NMJs at developing ages and muscle fibers with multiple endplates, we found evidence suggesting an activity-based linear ranking of motor neurons such that neurons co-innervated the same endplates and same muscle fibers (if there were more than one endplate) when the axons were similar in activity and hence rank. In addition, this ranking provided a means for understanding action at a distance in which the activity at one neuromuscular junction can impact the fate of the axons at another junction at a different site on the same muscle fiber. These activity-dependent mechanisms provide insight into the means by which timing of activity among different axons innervating the same population of cells, that start out with nearly all-to-all connectivity, can produce a well-organized system of axons, a system that is necessary for the recruitment order of neurons during a graded behavior like muscle contraction.

scholarly journals Breathing: Motor Control of Diaphragm Muscle

Physiology ◽  
2018 ◽  
Vol 33 (2) ◽  
pp. 113-126 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Neural Network ◽  
Motor Control ◽  
Motor Unit ◽  
Motor Neurons ◽  
Muscle Fibers ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Final Output ◽  
Unit Organization

Breathing occurs without thought but is controlled by a complex neural network with a final output of phrenic motor neurons activating diaphragm muscle fibers (i.e., motor units). This review considers diaphragm motor unit organization and how they are controlled during breathing as well as during expulsive behaviors.

scholarly journals Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Éric Martineau ◽  
Adriana Di Polo ◽  
Christine Vande Velde ◽  
Richard Robitaille
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Axonal Degeneration ◽  
Synapse Formation ◽  
Neuromuscular Junctions ◽  
Motor Units ◽  
Early Event ◽  
Motor Neuron Degeneration ◽  
Single Motor Units

Despite being an early event in ALS, it remains unclear whether the denervation of neuromuscular junctions (NMJ) is simply the first manifestation of a globally degenerating motor neuron. Using in vivo imaging of single axons and their NMJs over a three-month period, we identify that single motor-units are dismantled asynchronously in SOD1G37R mice. We reveal that weeks prior to complete axonal degeneration, the dismantling of axonal branches is accompanied by contemporaneous new axonal sprouting resulting in synapse formation onto nearby NMJs. Denervation events tend to propagate from the first lost NMJ, consistent with a contribution of neuromuscular factors extrinsic to motor neurons, with distal branches being more susceptible. These results show that NMJ denervation in ALS is a complex and dynamic process of continuous denervation and new innervation rather than a manifestation of sudden global motor neuron degeneration.

scholarly journals Central and peripheral innervation patterns of defined axial motor units in larval zebrafish

2019 ◽  
Author(s):  
Saul Bello-Rojas ◽  
Ana E. Istrate ◽  
Sandeep Kishore ◽  
David L. McLean
Keyword(s):  
Motor Neurons ◽  
Muscle Fibers ◽  
Motor Units ◽  
Spinal Motor Neurons ◽  
Larval Zebrafish ◽  
Spinal Motor ◽  
Axon Collaterals ◽  
Peripheral Innervation ◽  
Innervation Patterns ◽  
Fast Twitch

AbstractSpinal motor neurons and the peripheral muscle fibers they innervate form discrete motor units that execute movements of varying force and speed. Subsets of spinal motor neurons also exhibit axon collaterals that influence motor output centrally. Here, we have used in vivo imaging to anatomically characterize the central and peripheral innervation patterns of axial motor units in larval zebrafish. Using early born ‘primary’ motor neurons and their division of epaxial and hypaxial muscle into four distinct quadrants as a reference, we define three distinct types of later born ‘secondary’ motor units. The largest are ‘m-type’ units, which innervate deeper fast-twitch muscle fibers via medial nerves. Next in size are ‘ms-type’ secondaries, which innervate superficial fast-twitch and slow fibers via medial and septal nerves, followed by ‘s-type’ units, which exclusively innervate superficial slow muscle fibers via septal nerves. All types of secondaries innervate up to four axial quadrants. Central axon collaterals are found in subsets of primaries based on soma position and predominantly in secondary fast-twitch units (m, ms) with increasing likelihood based on number of quadrants innervated. Collaterals are labeled by synaptophysin-tagged fluorescent proteins, but not PSD95, consistent with their output function. Also, PSD95 dendrite labeling reveals that larger motor units receive more excitatory synaptic input. Collaterals are largely restricted to the neuropil, however perisomatic connections are observed between motor units. These observations suggest that recurrent interactions are dominated by motor neurons recruited during stronger movements and set the stage for functional investigations of recurrent motor circuitry in larval zebrafish.

scholarly journals Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition

2020 ◽  
Author(s):  
Katarina Stoklund Dittlau ◽  
Emily N. Krasnow ◽  
Laura Fumagalli ◽  
Tijs Vandoorne ◽  
Pieter Baatsen ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Neurite Outgrowth ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Induced Pluripotent Stem Cell ◽  
Microfluidic Devices ◽  
Motor Units ◽  
Human Motor ◽  
Induced Pluripotent

AbstractNeuromuscular junctions (NMJs) ensure proper communication between motor neurons and muscle through the release of neurotransmitters. In motor neuron disorders, such as amyotrophic lateral sclerosis (ALS), NMJs degenerate resulting in muscle atrophy, paralysis and respiratory failure. The aim of this study was to establish a versatile and reproducible in vitro model of a human motor unit to study the effect of ALS-causing mutations. Therefore, we generated a co-culture of human induced pluripotent stem cell-derived motor neurons and human primary mesoangioblast-derived myotubes in microfluidic devices. A chemotactic and volumetric gradient facilitated the growth of motor neuron neurites through microgrooves resulting in the interaction with myotubes and the formation of NMJs. We observed that ALS-causing FUS mutations resulted in a reduced neurite outgrowth and in a decreased NMJ number. Interestingly, the selective HDAC6 inhibitor, Tubastatin A, improved the neurite outgrowth and the NMJ morphology of FUS-ALS co-cultures, further prompting HDAC6 inhibition as a potential therapeutic strategy for ALS.

Power Savings of a Variable Recruitment Hydraulic Artificial Muscle Actuation Scheme

2014 ◽  
Author(s):  
Michael Meller ◽  
Ephrahim Garcia
Keyword(s):  
Pressure Drop ◽  
Motor Neurons ◽  
Muscle Fibers ◽  
Artificial Muscle ◽  
Motor Units ◽  
Hydraulic Control ◽  
Hydraulic Systems ◽  
Muscle Bundle ◽  
Variable Recruitment ◽  
Actuation Scheme

We investigate utilizing inelastic bladder hydraulic artificial muscle actuators as muscle fibers. These muscle fibers are then grouped together to form a variable recruitment artificial muscle bundle. This muscle bundle configuration is biologically inspired, where in skeletal muscle, different numbers of motor units are recruited to match the load by increasing the number of motor neurons firing. This results in extremely efficient locomotion in nature. It is desired to use a similar methodology to increase the actuation efficiency of valve-controlled hydraulic systems. Such hydraulic control systems induce a pressure drop in the valves to throttle the flow to the cylinder actuators. Using the valves in this manner is simple but very inefficient. Hence, this paper presents selectively recruiting different numbers of the hydraulic artificial muscle fibers to match a required loading scenario similar to our bipedal robot. By using fewer of the muscle fibers to match a smaller load, less power is consumed from the hydraulic power unit because instead of inducing a pressure drop, the volume of fluid delivered is decreased. The potential efficiency improvements associated with this actuation scheme is compared to a traditional hydraulic system with differential cylinders.

The resilience of the size principle in the organization of motor unit properties in normal and reinnervated adult skeletal muscles

2004 ◽  
Vol 82 (8-9) ◽  
pp. 645-661 ◽  
Author(s):  
Tessa Gordon ◽  
Christine K Thomas ◽  
John B Munson ◽  
Richard B Stein
Keyword(s):  
Motor Unit ◽  
Action Potentials ◽  
Muscle Fibers ◽  
Motor Units ◽  
Unit Size ◽  
Size Principle ◽  
Cross Sectional ◽  
Size Dependent ◽  
Rate Coding ◽  
The Relationship

Henneman's size principle relates the input and output properties of motoneurons and their muscle fibers to size and is the basis for size-ordered activation or recruitment of motor units during movement. After nerve injury and surgical repair, the relationship between motoneuron size and the number and size of the muscle fibers that the motoneuron reinnervates is initially lost but returns with time, irrespective of whether the muscles are self- or cross-reinnervated by the regenerated axons. Although the return of the size relationships was initially attributed to the recovery of the cross-sectional area of the reinnervated muscle fibers and their force per fiber, direct enumeration of the innervation ratio and the number of muscle fibers per motoneuron demonstrated that a size-dependent branching of axons accounts for the size relationships in normal muscle, as suggested by Henneman and his colleagues. This same size-dependent branching accounts for the rematching of motoneuron size and muscle unit size in reinnervated muscles. Experiments were carried out to determine whether the daily amount of neuromuscular activation of motor units accounts for the size-dependent organization and reorganization of motor unit properties. The normal size-dependent matching of motoneurons and their muscle units with respect to the numbers of muscle fibers per motoneuron was unaltered by synchronous activation of all of the motor units with the same daily activity. Hence, the restored size relationships and rematching of motoneuron and muscle unit properties after nerve injuries and muscle reinnervation sustain the normal gradation of muscle force during movement by size-ordered recruitment of motor units and the process of rate coding of action potentials. Dynamic modulation of size of muscle fibers and their contractile speed and endurance by neuromuscular activity allows for neuromuscular adaptation in the context of the sustained organization of the neuromuscular system according to the size principle.Key words: motor unit size, motor unit recruitment, innervation ratio, reinnervation.

scholarly journals Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units

2016 ◽  
Vol 2 (8) ◽  
pp. e1501429 ◽  
Author(s):  
Sebastien G. M. Uzel ◽  
Randall J. Platt ◽  
Vidya Subramanian ◽  
Taylor M. Pearl ◽  
Christopher J. Rowlands ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Motor Units ◽  
Cell Types ◽  
In Vitro Assays ◽  
Traumatic Injuries ◽  
Muscle Innervation

Motor units are the fundamental elements responsible for muscle movement. They are formed by lower motor neurons and their muscle targets, synapsed via neuromuscular junctions (NMJs). The loss of NMJs in neurodegenerative disorders (such as amyotrophic lateral sclerosis or spinal muscle atrophy) or as a result of traumatic injuries affects millions of lives each year. Developing in vitro assays that closely recapitulate the physiology of neuromuscular tissues is crucial to understand the formation and maturation of NMJs, as well as to help unravel the mechanisms leading to their degeneration and repair. We present a microfluidic platform designed to coculture myoblast-derived muscle strips and motor neurons differentiated from mouse embryonic stem cells (ESCs) within a three-dimensional (3D) hydrogel. The device geometry mimics the spinal cord–limb physical separation by compartmentalizing the two cell types, which also facilitates the observation of 3D neurite outgrowth and remote muscle innervation. Moreover, the use of compliant pillars as anchors for muscle strips provides a quantitative functional readout of force generation. Finally, photosensitizing the ESC provides a pool of source cells that can be differentiated into optically excitable motor neurons, allowing for spatiodynamic, versatile, and noninvasive in vitro control of the motor units.

scholarly journals Use it or lose it: tonic activity of slow motoneurons promotes their survival and preferentially increases slow fiber-type groupings in muscles of old lifelong recreational sportsmen

2016 ◽  
Vol 26 (4) ◽  
Author(s):  
Simone Mosole ◽  
Ugo Carraro ◽  
Helmut Kern ◽  
Stefan Loefler ◽  
Sandra Zampieri
Keyword(s):  
Motor Neurons ◽  
Fiber Type ◽  
Functional Decline ◽  
Muscle Fibers ◽  
Motor Units ◽  
The Body ◽  
Age Related ◽  
Immuno Histochemistry ◽  
High Level ◽  
And Function

Histochemistry, immuno-histochemistry, gel electrophoresis of single muscle fibers and electromyography of aging muscles and nerves suggest that: i) denervation contributes to muscle atrophy, ii) impaired mobility accelerates the process, and iii) lifelong running protects against loss of motor units. Recent corroborating results on the muscle effects of Functional Electrical Stimulation (FES) of aged muscles will be also mentioned, but we will in particular discuss how and why a lifelong increased physical activity sustains reinnervation of muscle fibers. By analyzing distribution and density of muscle fibers co-expressing fast and slow Myosin Heavy Chains (MHC) we are able to distinguish the transforming muscle fibers due to activity related plasticity, to those that adapt muscle fiber properties to denervation and reinnervation. In muscle biopsies from septuagenarians with a history of lifelong high-level recreational activity we recently observed in comparison to sedentary seniors: 1. decreased proportion of small-size angular myofibers (denervated muscle fibers); 2. considerable increase of fiber-type groupings of the slow type (reinnervated muscle fibers); 3. sparse presence of muscle fibers co-expressing fast and slow MHC. Immuno-histochemical characteristics fluctuate from those with scarce fiber-type modulation and groupings to almost complete transformed muscles, going through a process in which isolated fibers co-expressing fast and slow MHC fill the gaps among fiber groupings. Data suggest that lifelong high-level exercise allows the body to adapt to the consequences of the age-related denervation and that it preserves muscle structure and function by saving otherwise lost muscle fibers through recruitment to different slow motor units. This is an opposite behavior of that described in long term denervated or resting muscles. These effects of lifelong high level activity seems to act primarily on motor neurons, in particular on those always more active, i.e., on the slow motoneurons. The preferential reinnervation that follows along decades of increased activity maintains neuron and myofibers. All together the results open interesting perspectives for applications of FES and electroceuticals for rejuvenation of aged muscles to delay functional decline and loss of independence that are unavoidable burdens of advanced aging. Trial Registration: ClinicalTrials.gov: NCT01679977.

Morphological Adaptations of Neuromuscular Junctions Depend on Fiber Type

1997 ◽  
Vol 22 (3) ◽  
pp. 197-230 ◽  
Author(s):  
Gary C. Sieck ◽  
Y. S. Prakash
Keyword(s):  
Neuromuscular Junctions ◽  
Fiber Type ◽  
Muscle Fibers ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Dimensional Structure ◽  
Type I ◽  
Fiber Types ◽  
Structural And Functional Properties ◽  
Fast Twitch

The neuromuscular junction (NMJ) forms the communicative types of motor units, which are recruited selectively to accomplish various link between motoneurons and muscle fibers. The properties of motoneurons and muscle fibers are matched in different motor behaviors. Motor units and muscle fibers can be classified based upon structural and functional properties, reflecting the essential match between motoneuron and muscle fiber. Using a three-color immunofluorescence technique combined with confocal microscopy, we examined the three-dimensional structure of pre- and postsynaptic elements of NMJs on different fiber types in the rat diaphragm muscle. On type I and IIa fibers, comprising slow-twitch and fast-twitch fatigue-resistant motor units, the structure of NMJs is far less complex than on type IIx and IIb fibers comprising fast-twitch fatigue-intermediate and fast-twitch fatigable motor units. We also found a greater extent of overlap between pre- and postsynaptic elements of NMJs on type I and IIa fibers. This review focuses on these normal phenotypic differences in NMJ properties and on the adaptations that occur under various conditions of altered use. Key words: nerve terminal, motor endplate, morphology, neuromuscular transmission, fatigue, plasticity

Invited Review: Mechanisms underlying motor unit plasticity in the respiratory system

2003 ◽  
Vol 94 (3) ◽  
pp. 1230-1241 ◽  
Author(s):  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Motor Unit ◽  
Skeletal Muscles ◽  
Neuromuscular Junctions ◽  
Muscle Fibers ◽  
Respiratory Muscles ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Neuromotor Control ◽  
Phrenic Motoneurons

Neuromotor control of skeletal muscles, including respiratory muscles, is ultimately dependent on the function of the motor unit (comprising an individual motoneuron and the muscle fibers it innervates). Considerable diversity exists across diaphragm motor units, yet remarkable homogeneity is present (and maintained) within motor units. In recent years, the mechanisms underlying the development and adaptability of respiratory motor units have received great attention, leading to significant advances in our understanding of diaphragm motor unit plasticity. For example, following imposed inactivity of the diaphragm muscle, there are changes at phrenic motoneurons, neuromuscular junctions, and muscle fibers that tend to restore the ability of the diaphragm to sustain ventilation. The role of activity, neurotrophins, and other growth factors in modulating this adaptability is discussed.

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