The masseter muscle participates in a wide variety of activities including mastication, swallowing and speech. The functional demands for accurate mandibular positioning and generation of forces during incising or a power stroke require a diverse set of forces that are determined by the innate muscle form. The complex internal tendon architecture subdivides the masseter into multiple partitions that can be further subdivided into neuromuscular compartments representing small motor unit territories. Individual masseter compartments have unique biomechanical properties that, when activated individually or in groups, can generate a wide range of sagittal and off-sagittal torques about the temporomandibular joint. The myosin heavy chain (MyHC) fiber-type distribution in the adult masseter is sexually dimorphic and is influenced by hormones such as testosterone. These testosterone-dependent changes cause a phenotype switch from slower to faster fiber-types in the male. The development of the complex organization of the masseter muscle, the MyHC fiber-type message and protein expression, and the formation of endplates appear to be pre-programmed and not under control of the muscle nerve. However, secondary myotube generation and endplate maturation are nerve dependent. The delayed development of the masseter muscle compared to the facial, tongue and jaw opening muscles may be related to the delayed functional requirements for chewing. In summary, masseter muscle form is pre-programmed prior to birth while muscle fiber contractile characteristics are refined postnatally in response to functional requirements. The motor control mechanisms that are required to coordinate the activation of discrete functional elements of this muscle remain to be determined.
masseter; masticatory muscle; tongue; compartments; development; myosin; endplate
Control of posture is a prerequisite for efficient motor performance. Posture depends on muscles capable of enduring contractions, whereas movements often require quick, forceful muscle actions. To serve these different goals, muscles contain fibers that meet these different tasks. Muscles with strong postural functions mainly consist of slow muscle fibers with a great resistance against fatigue. Flexor muscles in the leg and arm muscles are mainly composed of fast muscle fibers producing relatively large forces that are rapidly fatigable. Development of the neuromuscular system continues after birth. We discuss in the human baby and in animal experiments changes in muscle fiber properties, regression from polyneural into mononeural innervation, and developmental changes in the motoneurons of postural muscles during that period. The regression of poly-neural innervation in postural muscles and the development of dendrite bundles of their motoneurons seem to be linked to the transition from the immature into the adult-like patterns of moving and postural control.
Cell number in the spinal nucleus of the bulbocavernosus (SNB) of rats was the first neural sex difference shown to differentiate under the control of androgens, acting via classical intracellular androgen receptors. SNB motoneurons reside in the lumbar spinal cord and innervate striated muscles involved in copulation, including the bulbocavernosus (BC) and levator ani (LA). SNB cells are much larger and more numerous in males than in females, and the BC/LA target muscles are reduced or absent in females. The relative simplicity of this neuromuscular system has allowed for considerable progress in pinpointing sites of hormone action, and identifying the cellular bases for androgenic effects. It is now clear that androgens act at virtually every level of the SNB system, in development and throughout adult life. In this review we focus on effects of androgens on developmental cell death of SNB motoneurons and BC/LA muscles; the establishment and maintenance of SNB motoneuron soma size and dendritic length; BC/LA muscle morphology and physiology; and behaviors controlled by the SNB system. We also describe new data on neurotherapeutic effects of androgens on SNB motoneurons after injury in adulthood.
Motoneuron; Bulbocavernosus; Levator ani; Androgen; Neuromuscular; Dendrite; Sexual differentiation; Cell death; Testosterone; Dihydrotestosterone
Segregation of intramuscular motor nerves indicates distinct superior and inferior zones within the horizontal but not vertical rectus extraocular muscles in humans and monkeys, supporting a potential functional role for differential innervation that might mediate oculorotary actions.
It has been proposed that the lateral rectus (LR), like many skeletal and craniofacial muscles, comprises multiple neuromuscular compartments subserving different physiological functions. To explore the anatomic potential of compartmentalization in all four rectus extraocular muscles (EOMs), evidence was sought of possible regional selectivity in intramuscular innervation of all rectus EOMs.
Whole orbits of two humans and one macaque monkey were serially sectioned at 10 μm thickness and stained with Masson's trichrome. Three-dimensional reconstruction was performed of the intramuscular courses of motor nerves from the deep orbit to the anterior extents of their arborizations within all four rectus EOMs in each orbit.
Findings concorded in monkey and human orbits. Externally to the global surface of the lateral (LR) and medial rectus (MR) EOMs, motor nerve trunks bifurcated into approximately equal-sized branches before entering the global layer and observing a segregation of subsequent arborization into superior zones that exhibited minimal overlap along the length of the LR and only modest overlap for MR. In contrast, intramuscular branches of the superior and the nasal portion of the inferior rectus were highly mixed.
Consistent segregation of intramuscular motor nerve arborization suggests functionally distinct superior and inferior zones within the horizontal rectus EOMs in both humans and monkeys. Reduced or absent compartmentalization in vertical rectus EOMs supports a potential functional role for differential innervation in horizontal rectus zones that could mediate previously unrecognized vertical oculorotary actions.
Since connective tissue pulleys implement Listing's law by systematically changing rectus extraocular muscle (EOM) pulling directions, non-Listing's law gaze-dependence of the vestibulo-ocular reflex is currently inexplicable. Differential activation of compartments within rectus EOMs may endow the ocular motor system with more behavioral diversity than previously supposed. Innervation to horizontal, but not vertical, rectus EOMs of mammals is segregated into superior and inferior compartments. Magnetic resonance imaging in normal subjects demonstrates contractile changes in the lateral rectus (LR) inferior, but not superior, compartment during ocular counter-rolling (OCR) induced by head tilt. In human orbits ipsilesional to unilateral superior oblique palsy, neither LR compartment exhibits contractile change during head tilt, although the inferior compartment contracts normally in contralesional orbits. This suggests that differential compartmental LR contraction assists normal OCR. Computational simulation suggests that differential compartmental action in horizontal rectus EOMs could achieve more force than required by vertical fusional vergence.
extraocular muscles; magnetic resonance imaging; motor nerve; pulleys; vestibulo-ocular reflex
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.
steroids; neuroprotection; morphology; dendrites
Innervation to monkey and human lateral rectus muscles is segregated into well-defined superior and inferior zones, so that the lateral rectus may function as two parallel muscles under separate control. Differential activation of the two lateral rectus zones could impart previously unrecognized torsional and vertical actions to this nominally “horizontal” rectus muscle, potentially resolving an important paradox in ocular kinematics.
Skeletal and craniofacial muscles are frequently composed of multiple neuromuscular compartments that serve different physiological functions. Evidence of possible regional selectivity in LR intramuscular innervation was sought in a study of the anatomic potential of lateral rectus (LR) muscle compartmentalization.
Whole orbits of two humans and five macaque monkeys were serially sectioned at 10-μm thickness and stained with Masson trichrome. The abducens nerve (CN6) was traced anteriorly from the deep orbit as it branched to enter the LR and arborized among extraocular muscle (EOM) fibers. Three-dimensional reconstruction was performed in human and monkey orbits.
Findings were in concordance in the monkey and human orbits. External to the LR global surface, CN6 bifurcated into approximately equal-sized trunks before entering the global layer. Subsequent arborization showed a systematic topography, entering a well-defined inferior zone 0.4 to 2.5 mm more posteriorly than branches entering the largely nonoverlapping superior zone. Zonal innervation remained segregated anteriorly and laterally within the LR.
Consistent segregation of intramuscular CN6 arborization in humans and monkeys suggests functionally distinct superior and inferior zones for the LR. Since the LR is shaped as a broad vertical strap, segregated control of the two zones could activate them separately, potentially mediating previously unappreciated but substantial torsional and vertical oculorotary LR actions.
Recently, we described a new method for representing and analyzing the connectivity of a motoneuronal network. We used it to deduce a connectivity model for the neuromuscular network that generates locomotion in the nematode Caenorhabditis elegans. The network regulates muscle contraction and for this reason we used the location or function of body wall muscles to map every element (neuron or muscle cell) in a new framework, namely the peri-motor space. The previously published connectivity data for C. elegans locomotion network are incomplete; in particular, the connectivity of motoneurons in the posterior half of the animal is missing or partial. When we analyzed the connectivity data for motoneurons in the anterior half, we detected repeating patterns which we named iterativity. We analyzed the iterativity of each class of motoneuron and statistically validated that it is higher than expected by chance. We could then extrapolate the iteration into the posterior half. Here we will explain the new terms and elaborate on the process of analysis and the features of the new connectivity model.
Caenorhabditis elegans; locomotion; motoneurons; network connectivity; peri-motor
The biomechanical structure of the hand and its underlying neurophysiology contribute to the coordination of the kinematics and kinetics necessary for multidigit grasping. We recently examined the neural organization of inputs to different extrinsic finger flexors during multi‐digit object hold and found moderate to strong motor unit short‐term synchrony. This suggests a common neural input to the motoneurons innervating these different hand muscles/muscle compartments, which may in turn influence the coordination of grip forces.
To further characterize this common input to the hand muscles during multidigit grasping, we used the frequency‐based measure of coherence. Motor unit coherence provides information with regards to the oscillatory frequency of a common input, as well as the coupling of the discharges of a motor unit pair at both short and long latencies.
Preliminary results indicate that a large proportion of trials are characterized by significant coherence in the 1–12 Hz frequency range, which is more pronounced in the within‐ than between‐muscle/muscle compartment analysis. This indicates a differential organization of common oscillatory inputs to pairs of motoneurons innervating the same vs. different muscles/ muscle compartments. The functional role of the 1–12 Hz oscillatory modulation of motor unit behavior is currently being investigated.
EMG; grasping; hand
The lumbar spinal cord of rats contains the sexually dimorphic, steroid-sensitive spinal nucleus of the bulbocavernosus (SNB). Androgens are necessary for the development of the SNB neuromuscular system, and in adulthood, continue to influence the morphology and function of the motoneurons and their target musculature. However, estrogens are also involved in the development of the SNB system, and are capable of maintaining function in adulthood. In this experiment we assessed the ability of testosterone metabolites, estrogens and non-aromatizable androgens, to maintain neuromuscular morphology in adulthood. Motoneuron and muscle morphology was assessed in adult normal males, sham-castrated males, castrated males treated with testosterone, dihydrotestosterone, estradiol, or left untreated, and gonadally intact males treated with the 5α-reductase inhibitor finasteride or the aromatase inhibitor fadrozole. After 6 weeks of treatment, SNB motoneurons were retrogradely labeled with cholera toxin-HRP and reconstructed in three dimensions. Castration resulted in reductions in SNB target muscle size, soma size, and dendritic morphology. Testosterone treatment after castration maintained SNB soma size, dendritic morphology, and elevated target muscle size; dihydrotestosterone treatment also maintained SNB dendritic length, but was less effective than testosterone in maintaining both SNB soma size and target muscle weight. Treatment of intact males with finasteride or fadrozole did not alter the morphology of SNB motoneurons or their target muscles. In contrast, estradiol treatment was completely ineffective in preventing castration-induced atrophy of the SNB neuromuscular system. Together, these results suggest that the maintenance of adult motoneuron or muscle morphology is strictly mediated by androgens.
gonadal hormones; motoneurons; dendrites; spinal cord; rat
The glottis is composed of muscular, cartilaginous, and other viscoelastic tissues which perform some of our most important, complex, coordinated, and life-sustaining functions. Dominated by the thyroarytenoid muscles and associated glottic closure muscles, the larynx is involved in respiration, swallowing, voicing, coughing, valsalva, vomiting, laughing, and crying. With respiration continuing in the background, all other “secondary” laryngeal events seamlessly occur. When the delicate balance of coordinating these events is disrupted by disease or disorder, many of these tasks are compromised. Due to the complex innervation of these volitional and reflexive tasks with brainstem central pattern generators, primary sensorimotor areas and importantly, limbic areas, failure can occur due to disease, anatomic compromise, and even emotional state. Understanding the level of sensori-motor control and interaction among systems that share these laryngeal neuromuscular substrates will improve the diagnostic and therapeutic skill of the clinician when treating compromise of laryngeal function.
larynx; swallow; respiration; cough; thyroarytenoid
Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.
Spinal muscular atrophy (SMA) is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNΔ7). In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs) in hindlimb muscles of SMNΔ7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a ∼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3–5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1)-positive synapses onto SMNΔ7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNΔ7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNΔ7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy.
Androgens have a variety of protective and therapeutic effects in both the central and peripheral nervous systems. Here we review these effects as they related specifically to spinal and cranial motoneurons. Early in development, androgens are critical for the formation of important neuromuscular sex differences, decreasing the magnitude of normally occurring cell death in select motoneuron populations. Throughout the lifespan, androgens also protect against motoneuron death caused by axonal injury. Surviving motoneurons also display regressive changes to their neurites as a result of both direct axonal injury and loss of neighboring motoneurons. Androgen treatment enhances the ability of motoneurons to recover from these regressive changes and regenerate both axons and dendrites, restoring normal neuromuscular function. Androgens exert these protective effects by acting through a variety of molecular pathways. Recent work has begun to examine how androgen treatment can interact with other treatment strategies in promoting recovery from motoneuron injury.
motoneurons; androgens; axotomy; neuroprotection; cell death; sex differences; nerve regeneration; dendrites; testosterone; steroids
The study examines the role of the volume of the effect compartment in simulations of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants.
The molar amount of the postsynaptic receptors at the motor end plates in muscle was assumed constant; the apparent receptor concentration in the effect compartment is the ratio of this amount and the volume arbitrarily assigned to the effect compartment. The muscle relaxants were postulated to diffuse between the central and the effect compartment and to bind to the postsynaptic receptors. NMB was calculated from the free concentration of the muscle relaxant in the effect compartment.
The simulations suggest that the time profiles of NMB and the derived pharmacokinetic and pharmacodynamic variables are dependent on the apparent receptor concentration in the effect compartment. For small, but not for large, volumes, times to peak submaximal NMB are projected to depend on the magnitude of NMB and on the binding affinities.
An experimental design to estimate the volume of the effect compartment is suggested.
Skeletal muscle is the largest organ system in mammalian organisms providing postural control and movement patterns of varying intensity. Through evolution, skeletal muscle fibers have evolved into three phenotype clusters defined as a motor unit which consists of all muscle fibers innervated by a single motoneuron linking varying numbers of fibers of similar phenotype. This fundamental organization of the motor unit reflects the fact that there is a remarkable interdependence of gene regulation between the motoneurons and the muscle mainly via activity-dependent mechanisms. These fiber types can be classified via the primary type of myosin heavy chain (MHC) gene expressed in the motor unit. Four MHC gene encoded proteins have been identified in striated muscle: slow type I MHC and three fast MHC types, IIa, IIx, and IIb. These MHCs dictate the intrinsic contraction speed of the myofiber with the type I generating the slowest and IIb the fastest contractile speed. Over the last ~35 years, a large body of knowledge suggests that altered loading state cause both fiber atrophy/wasting and a slow to fast shift in the contractile phenotype in the target muscle(s). Hence, this review will examine findings from three different animal models of unloading: (1) space flight (SF), i.e., microgravity; (2) hindlimb suspension (HS), a procedure that chronically eliminates weight bearing of the lower limbs; and (3) spinal cord isolation (SI), a surgical procedure that eliminates neural activation of the motoneurons and associated muscles while maintaining neurotrophic motoneuron-muscle connectivity. The collective findings demonstrate: (1) all three models show a similar pattern of fiber atrophy with differences mainly in the magnitude and kinetics of alteration; (2) transcriptional/pretranslational processes play a major role in both the atrophy process and phenotype shifts; and (3) signaling pathways impacting these alterations appear to be similar in each of the models investigated.
spaceflight; hindlimb suspension (unloading); spinal cord isolation; myosin isoforms; non-coding RNAs
Aging can result in a loss of neuronal cell bodies and a decrease in neuronal size in some regions of the brain and spinal cord. Motoneuron loss in the spinal cord is thought to contribute to the progressive decline in muscle mass and strength that occurs with age (sarcopenia). Swallowing disorders represent a large clinical problem in elderly persons; however, age-related alterations in cranial motoneurons that innervate muscles involved in swallowing have been understudied. We aimed to determine if age-related alterations occurred in the hypoglossal nucleus in the brainstem. If present, these changes might help explain alterations at the neuromuscular junction and changes in the contractile properties of tongue muscle that have been reported in older rats. We hypothesized that with increasing age, there would be a loss of motoneurons and a reduction in neuronal size and the number of primary dendrites associated with each hypoglossal motoneuron. Neurons in the hypoglossal nucleus were visualized with the neuronal marker NeuN in young (9–10 months), middle-aged (24–25 months), and old (32–33 months) male F344/BN rats. Hypoglossal motoneurons were retrograde labeled with injections of Cholera Toxin β into the genioglossus muscle of the tongue and visualized using immunocytochemistry. Results indicated that the number of primary dendrites of hypoglossal motoneurons decreased significantly with age, while no age-associated changes were found in the number or size of hypoglossal motoneurons. Loss of primary dendrites could reduce the number of synaptic inputs and thereby impair function.
deglutition; deglutition disorders; Sarcopenia; cranial motoneurons; genioglossus muscle; tongue; aging
Phrenic motoneurons are located in the cervical spinal cord and innervate the diaphragm muscle, the main inspiratory muscle in mammals. Similar to other skeletal muscles, phrenic motoneurons and diaphragm muscle fibers form motor units which are the final element of neuromotor control. In addition to their role in sustaining ventilation, phrenic motor units are active in other non-ventilatory behaviors important for airway clearance such as coughing or sneezing. Diaphragm muscle fibers comprise all fiber types and are commonly classified based on expression of contractile proteins including myosin heavy chain isoforms. Although there are differences in contractile and fatigue properties across motor units, there is a matching of properties for the motor neuron and muscle fibers within a motor unit. Motor units are generally recruited in order such that fatigue-resistant motor units are recruited earlier and more often than more fatigable motor units. Thus, in sustaining ventilation, fatigue-resistant motor units are likely required. Based on a series of studies in cats, hamsters and rats, an orderly model of motor unit recruitment was proposed that takes into consideration the maximum forces generated by single type-identified diaphragm muscle fibers as well as the proportion of the different motor unit types. Using this model, eupnea can be accomplished by activation of only slow-twitch diaphragm motor units and only a subset of fast-twitch, fatigue-resistant units. Activation of fast-twitch fatigable motor units only becomes necessary when accomplishing tasks that require greater force generation by the diaphragm muscle, e.g., sneezing and coughing.
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.
motoneuron; H-reflex; F-wave; tendon jerk; V-wave; CMEP; MEP
The sensory circuit of the stretch reflex arc is composed of intrafusal muscle fibers and their innervating proprioceptive neurons that convert mechanical information regarding muscle length and tension into action potentials that synapse onto the homonymous motoneurons in the ventral spinal cord which innervate the extrafusal fibers of the same muscle. To date, the in vitro synaptic connection between proprioceptive sensory neurons and spinal motoneurons has not been demonstrated. A functional in vitro system demonstrating this connection would enable the understanding of feedback by the integration of sensory input into the spinal reflex arc. Here we report a co-culture of rat embryonic motoneurons and proprioceptive sensory neurons from dorsal root ganglia (DRG) in a defined serum-free medium on a synthetic silane substrate (DETA). Furthermore, we have demonstrated functional synapse formation in the co-culture by immunocytochemistry and electrophysiological analysis. This work will be valuable for enabling in vitro model systems for the study of spinal motor control and related pathologies such as spinal cord injury, muscular dystrophy and spasticity by improving our understanding of the integration of the mechanosensitive feedback mechanism.
Proprioceptive sensory neurons; Dorsal root ganglion; Stretch reflex arc; Motoneurons; DETA; Serum free
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.
steroids; neuroprotection; morphology; dendrites
The neuromuscular junctions are the specialized synapses whereby spinal motor neurons control the contraction of skeletal muscles. The formation of the neuromuscular junctions is controlled by a complex interplay of multiple mechanisms coordinately activated in motor nerve terminals and in their target myotubes. However, the transcriptional regulators that control in motor neurons the genetic programs involved in neuromuscular junction development remain unknown. Here, we provide evidence that the Onecut transcription factor HNF-6 regulates in motor neurons the formation of the neuromuscular junctions. Indeed, adult Hnf6 mutant mice exhibit hindlimb muscle weakness and abnormal locomotion. This results from defects of hindlimb neuromuscular junctions characterized by an abnormal morphology and defective localization of the synaptic vesicle protein synaptophysin at the motor nerve terminals. These defects are consequences of altered and delayed formation of the neuromuscular junctions in newborn mutant animals. Furthermore, we show that the expression level of numerous regulators of neuromuscular junction formation, namely agrin, neuregulin-2 and TGF-ß receptor II, is downregulated in the spinal motor neurons of Hnf6 mutant newborn animals. Finally, altered formation of neuromuscular junction-like structures in a co-culture model of wildtype myotubes with mutant embryonic spinal cord slices is rescued by recombinant agrin and neuregulin, indicating that depletion in these factors contributes to defective neuromuscular junction development in the absence of HNF-6. Thus, HNF-6 controls in spinal motor neurons a genetic program that coordinates the formation of hindlimb neuromuscular junctions.
Piano performance involves a large repertoire of highly skilled movements. The acquisition of these exceptional skills despite innate neural and biomechanical constraints requires a sophisticated interaction between plasticity of the neural system and organization of a redundant number of degrees of freedom (DOF) in the motor system. Neuroplasticity subserving virtuosity of pianists has been documented in neuroimaging studies investigating effects of long-term piano training on structure and function of the cortical and subcortical regions. By contrast, recent behavioral studies have advanced the understanding of neuromuscular strategies and biomechanical principles behind the movement organization that enables skilled piano performance. Here we review the motor control and biomechanics literature, introducing the importance of describing motor behaviors not only for understanding mechanisms responsible for skillful motor actions in piano playing, but also for advancing diagnosis and rehabilitation of movement disorders caused by extensive piano practice.
degrees of freedom; fine motor control; redundancy; optimal control; focal dystonia
The organisational principles of locomotor networks are less well understood than those of many sensory systems, where in-growing axon terminals form a central map of peripheral characteristics. Using the neuromuscular system of the Drosophila embryo as a model and retrograde tracing and genetic methods, we have uncovered principles underlying the organisation of the motor system. We find that dendritic arbors of motor neurons, rather than their cell bodies, are partitioned into domains to form a myotopic map, which represents centrally the distribution of body wall muscles peripherally. While muscles are segmental, the myotopic map is parasegmental in organisation. It forms by an active process of dendritic growth independent of the presence of target muscles, proper differentiation of glial cells, or (in its initial partitioning) competitive interactions between adjacent dendritic domains. The arrangement of motor neuron dendrites into a myotopic map represents a first layer of organisation in the motor system. This is likely to be mirrored, at least in part, by endings of higher-order neurons from central pattern-generating circuits, which converge onto the motor neuron dendrites. These findings will greatly simplify the task of understanding how a locomotor system is assembled. Our results suggest that the cues that organise the myotopic map may be laid down early in development as the embryo subdivides into parasegmental units.
Tracing neuronal processes in normal and mutant fruit fly embryos indicates new principles of motor neuron organization
Reasons for the progressive age-related loss of skeletal muscle mass and function, namely sarcopenia, are complex. Few studies describe sarcopenia in mice, although this species is the mammalian model of choice for genetic intervention and development of pharmaceutical interventions for muscle degeneration. One factor, important to sarcopenia-associated neuromuscular change, is myofibre denervation. Here we describe the morphology of the neuromuscular compartment in young (3 month) compared to geriatric (29 month) old female C57Bl/6J mice. There was no significant difference in the size or number of motoneuron cell bodies at the lumbar level (L1–L5) of the spinal cord at 3 and 29 months. However, in geriatric mice, there was a striking increase (by ∼2.5 fold) in the percentage of fully denervated neuromuscular junctions (NMJs) and associated deterioration of Schwann cells in fast extensor digitorum longus (EDL), but not in slow soleus muscles. There were also distinct changes in myofibre composition of lower limb muscles (tibialis anterior (TA) and soleus) with a shift at 29 months to a faster phenotype in fast TA muscle and to a slower phenotype in slow soleus muscle. Overall, we demonstrate complex changes at the NMJ and muscle levels in geriatric mice that occur despite the maintenance of motoneuron cell bodies in the spinal cord. The challenge is to identify which components of the neuromuscular system are primarily responsible for the marked changes within the NMJ and muscle, in order to selectively target future interventions to reduce sarcopenia.