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Charcot-Marie-Tooth (CMT) is the most common inherited peripheral neuropathy, affecting approximately 2.8 million people. The CMT leads to distal neuropathy that is characterized by reduced motor nerve conduction velocity, ataxia, muscle atrophy and sensory loss. We generated a mouse model of CMT type 2E (CMT2E) expressing human neurofilament light E396K (hNF-LE396K ), which develops decreased motor nerve conduction velocity, ataxia and muscle atrophy by 4 months of age. Symptomatic hNF-LE396K mice developed phenotypes that were consistent with proprioceptive sensory defects as well as reduced sensitivity to mechanical stimulation, while thermal sensitivity and auditory brainstem responses were unaltered. Progression from presymptomatic to symptomatic included a 50% loss of large diameter sensory axons within the fifth lumbar dorsal root of hNF-LE396K mice. Owing to proprioceptive deficits and loss of large diameter sensory axons, we analyzed muscle spindle morphology in presymptomatic and symptomatic hNF-LE396K and hNF-L control mice. Muscle spindle cross-sectional area and volume were reduced in all hNF-LE396K mice analyzed, suggesting that alterations in muscle spindle morphology occurred prior to the onset of typical CMT pathology. These data suggested that CMT2E pathology initiated in the muscle spindles altering the proprioceptive sensory system. Early sensory pathology in CMT2E could provide a unifying hypothesis for the convergence of pathology observed in CMT.

Muscle spindles and Golgi tendon organs (GTOs) are two types of sensory receptors that respond to changes in length or tension of skeletal muscles. These mechanosensors have long been known to participate in both proprioception and stretch reflex. Here, we present recent findings implicating these organs in maintenance of spine alignment as well as in realignment of fractured bones. These discoveries have been made in several mouse lines lacking functional mechanosensors in part or completely. In both studies, the absence of functional spindles and GTOs produced a more severe phenotype than that of spindles alone. Interestingly, the spinal curve phenotype, which appeared during peripubertal development, bears resemblance to the human condition adolescent idiopathic scoliosis. This similarity may contribute to the study of the disease by offering both an animal model and a clue as to its aetiology. Moreover, it raises the possibility that impaired proprioceptive signalling may be involved in the aetiology of other conditions. Overall, these new findings expand considerably the scope of involvement of proprioception in musculoskeletal development and function. This article is part of the Theo Murphy meeting issue 'Mechanics of development'. [ABSTRACT FROM AUTHOR]

Highlights • Granular insula (dGIrvs2) receives proprioception from jaw muscle spindles (JCMS). • The dGIrvs2 projects to the thalamus and sensorimotor cortex. • The dGIrvs2 projects to some regions in the basal ganglia. • The dGIrvs2 projects to the central amygdaloid nucleus and extended amygdala. • JCMS proprioception may affect motor, sensory, emotional, and homeostatic functions. Abstract We have recently revealed that the proprioceptive signal from jaw-closing muscle spindles (JCMSs) is conveyed to the dorsal part of granular insular cortex rostroventrally adjacent to the rostralmost part of secondary somatosensory cortex (dGIrvs2) via the caudo-ventromedial edge (VPMcvm) of ventral posteromedial thalamic nucleus (VPM) in rats. However, it remains unclear to which cortical or subcortical structures the JCMS proprioceptive information is subsequently conveyed from the dGIrvs2. To test this issue, we injected an anterograde tracer, biotinylated dextranamine, into the electophysiologically identified dGIrvs2, and analyzed the resultant distribution profiles of labeled axon terminals in rats. Labeled terminals were distributed with an ipsilateral predominance. In the cerebral cortex, they were seen in the primary and secondary somatosensory cortices, lateral and medial agranular cortices and dorsolateral orbital cortex. In the basal ganglia, they were found in the caudate putamen, core part of accumbens nucleus, lateral globus pallidus, subthalamic nucleus, and substantia nigra pars compacta and pars reticulata. They were also observed in the central amygdaloid nucleus and extended amygdala (the interstitial nucleus of posterior limb of anterior commissure and the juxtacapsular part of lateral division of bed nucleus of stria terminalis). In the thalamus, they were seen in the reticular nucleus, ventromedial nucleus, core VPM, parvicellular part of ventral posterior nucleus, oval paracentral nucleus, medial and triangular parts of posterior nucleus, and zona incerta as well as the VPMcvm. These data suggest that the JCMS proprioceptive information through the dGIrvs2 is transmitted to the emotional ‘limbic’ regions as well as sensorimotor regions. [ABSTRACT FROM AUTHOR]

Little is known about how proprioceptive signals arising from muscles reach to higher brain regions such as the cerebral cortex. We have recently shown that a particular thalamic region, the caudo-ventromedial edge (VPMcvm) of ventral posteromedial thalamic nucleus (VPM), receives the proprioceptive signals from jaw-closing muscle spindles (JCMSs) in rats. In this study, we further addressed how the orofacial thalamic inputs from the JCMSs were transmitted from the thalamus (VPMcvm) to the cerebral cortex in rats. Injections of a retrograde and anterograde neuronal tracer, wheat-germ agglutinin-conjugated horseradish peroxidase (WGA-HRP), into the VPMcvm demonstrated that the thalamic pathway terminated mainly in a rostrocaudally narrow area in the dorsal part of granular insular cortex rostroventrally adjacent to the rostralmost part of the secondary somatosensory cortex (dGIrvs2). We also electrophysiologically confirmed that the dGIrvs2 received the proprioceptive inputs from JCMSs. To support the anatomical evidence of the VPMcvm–dGIrvs2 pathway, injections of a retrograde neuronal tracer Fluorogold into the dGIrvs2 demonstrated that the thalamic neurons projecting to the dGIrvs2 were confined in the VPMcvm and the parvicellular part of ventral posterior nucleus. In contrast, WGA-HRP injections into the lingual nerve area of core VPM demonstrated that axon terminals were mainly labeled in the core regions of the primary and secondary somatosensory cortices, which were far from the dGIrvs2. These results suggest that the dGIrvs2 is a specialized cortical region receiving the orofacial proprioceptive inputs. Functional contribution of the revealed JCMSs–VPMcvm–dGIrvs2 pathway to Tourette syndrome is also discussed. [ABSTRACT FROM AUTHOR]

Connecting biologically inspired neural simulations to physical or simulated embodiments can be useful both in robotics, for the development of a new kind of bio-inspired controllers, and in neuroscience, to test detailed brain models in complete action-perception loops. The aim of this work is to develop a fully spike-based, biologically inspired mechanism for the translation of proprioceptive feedback. The translation is achieved by implementing a computational model of neural activity of type Ia and type II afferent fibers of muscle spindles, the primary source of proprioceptive information, which, in mammals is regulated through fusimotor activation and provides necessary adjustments during voluntary muscle contractions. As such, both static and dynamic γ-motoneurons activities are taken into account in the proposed model. Information from the actual proprioceptive sensors (i.e., motor encoders) is then used to simulate the spindle contraction and relaxation, and therefore drive the neural activity. To assess the feasibility of this approach, the model is implemented on the NEST spiking neural network simulator and on the SpiNNaker neuromorphic hardware platform and tested on simulated and physical robotic platforms. The results demonstrate that the model can be used in both simulated and real-time robotic applications to translate encoder values into a biologically plausible neural activity. Thus, this model provides a completely spike-based building block, suitable for neuromorphic platforms, that will enable the development of sensory-motor closed loops which could include neural simulations of areas of the central nervous system or of low-level reflexes. [ABSTRACT FROM AUTHOR]

The impact of aging on proprioceptive sensory neurons and intrafusal muscle fibers (IMFs) remains largely unexplored despite the central function these cells play in modulating voluntary movements. Here, we show that proprioceptive sensory neurons undergo deleterious morphological changes in middle age (11- to 13-month-old) and old (15- to 21-month-old) mice. In the extensor digitorum longus and soleus muscles of middle age and old mice, there is a significant increase in the number of Ia afferents with large swellings that fail to properly wrap around IMFs compared with young adult (2- to 4-month-old) mice. Fewer II afferents were also found in the same muscles of middle age and old mice. Although these age-related changes in peripheral nerve endings were accompanied by degeneration of proprioceptive sensory neuron cell bodies in dorsal root ganglia (DRG), the morphology and number of IMFs remained unchanged. Our analysis also revealed normal levels of neurotrophin 3 (NT3) but dysregulated expression of the tyrosine kinase receptor C (TrkC) in aged muscles and DRGs, respectively. These results show that proprioceptive sensory neurons degenerate prior to atrophy of IMFs during aging, and in the presence of the NT3/TrkC signaling axis. [ABSTRACT FROM AUTHOR]

Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV1.6 isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV1.6 immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV1.6 IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV1.6 IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV1.1, predominantly in sensory terminals together with NaV1.6 and for NaV1.7, mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles. [ABSTRACT FROM AUTHOR]

This study examined the alterations in the number and size of motoneurons innervating the medial gastrocnemius (MG) and biceps femoris (BF) motor nuclei in diabetic rats (12 or 22 weeks after injection of streptozotocin) and age-matched controls using retrograde labeling technique. Additionally, morphological alterations of muscle spindles in BF and MG muscles were tested. Significantly fewer labeled MG motoneurons were found in 12- and 22-week diabetic rats as compared with age-matched control animals. In contrast, the number of BF motoneurons was preserved in each group. Compared to control animals, the ratio of larger motoneurons of MG and BF muscle were decreased at 12 weeks, and smaller MG motoneurons were drastically decreased at 22 weeks. Moreover, MG muscle spindle showed reduction of its number and increase of intrafusal muscle fibers; however, BF muscle spindles showed little or no difference from control animals. We conclude that there is an early loss of alpha motoneurons for both MG and BF muscles followed by a later loss of gamma motoneurons in MG muscle in diabetic animals. Moreover, loss of gamma motoneuron might induce atrophy of MG muscle spindles. [ABSTRACT FROM AUTHOR]

Position sense at the human elbow joint has traditionally been measured in blindfolded subjects using a forearm matching task. Here we compare position errors in a matching task with errors generated when the subject uses a pointer to indicate the position of a hidden arm. Evidence from muscle vibration during forearm matching supports a role for muscle spindles in position sense. We have recently shown using vibration, as well as muscle conditioning, which takes advantage of muscle's thixotropic property, that position errors generated in a forearm pointing task were not consistent with a role by muscle spindles. In the present study we have used a form of muscle conditioning, where elbow muscles are co-contracted at the test angle, to further explore differences in position sense measured by matching and pointing. For fourteen subjects, in a matching task where the reference arm had elbow flexor and extensor muscles contracted at the test angle and the indicator arm had its flexors conditioned at 90°, matching errors lay in the direction of flexion by 6.2°. After the same conditioning of the reference arm and extension conditioning of the indicator at 0°, matching errors lay in the direction of extension (5.7°). These errors were consistent with predictions based on a role by muscle spindles in determining forearm matching outcomes. In the pointing task subjects moved a pointer to align it with the perceived position of the hidden arm. After conditioning of the reference arm as before, pointing errors all lay in a more extended direction than the actual position of the arm by 2.9°-7.3°, a distribution not consistent with a role by muscle spindles. We propose that in pointing muscle spindles do not play the major role in signalling limb position that they do in matching, but that other sources of sensory input should be given consideration, including afferents from skin and joint. [ABSTRACT FROM AUTHOR]

In this study we have investigated the effect of whole body vibration (WBV) on the tendon reflex (T-reflex) amplitude. Fifteen young adult healthy volunteer males were included in this study. Records of surface EMG of the right soleus muscle and accelerometer taped onto the right Achilles tendon were obtained while participant stood upright with the knees in extension, on the vibration platform. Tendon reflex was elicited before and during WBV. Subjects completed a set of WBV. Each WBV set consisted of six vibration sessions using different frequencies (25, 30, 35, 40, 45, 50Hz) applied randomly. In each WBV session the Achilles tendon was tapped five times with a custom-made reflex hammer. The mean peak-to-peak (PP) amplitude of T-reflex was 1139.11±498.99µV before vibration. It decreased significantly during WBV (p<0.0001). The maximum PP amplitude of T-reflex was 1333±515μV before vibration. It decreased significantly during WBV (p<0.0001). No significant differences were obtained in the mean acceleration values of Achilles tendon with tapping between before and during vibration sessions. This study showed that T-reflex is suppressed during WBV. T-reflex suppression indicates that the spindle primary afferents must have been pre-synaptically inhibited during WBV similar to the findings in high frequency tendon vibration studies. [ABSTRACT FROM AUTHOR]

The supratrigeminal nucleus (Vsup), originally proposed as a premotoneuron pool in the trigeminal reflex arc, is a key structure of jaw movement control. Surprisingly, however, the location of the rat Vsup has not precisely been defined. In light of our previous cat studies, we made two hypotheses regarding the rat Vsup: (1) the Vsup is cytoarchitectonically distinguishable from its surrounding structures; (2) the Vsup receives central axon terminals of the trigeminal mesencephalic nucleus (Vmes) neurons which are primary afferents innervating muscle spindles of jaw-closing muscles and periodontal ligaments around the teeth. To test the first hypothesis, we examined the cytoarchitecture of the rat Vsup. The Vsup was identified as an area medially adjacent to the dorsomedial part of trigeminal principal sensory nucleus (Vp), and extended from the level just rostral to the caudal two-thirds of the trigeminal motor nucleus (Vmo) to the level approximately 150 μm caudal to the Vmo. Our rat Vsup was much smaller and its location was considerably different in comparison to the Vsup reported previously. To evaluate the second hypothesis, we tested the distribution patterns of Vmes primary afferent terminals in the cytoarchitectonically identified Vsup. After transganglionic tracer applications to the masseter, deep temporal, and medial pterygoid nerves, a large number of axon terminals were observed in all parts of Vsup (especially in its medial part). After applications to the inferior alveolar, infraorbital, and lingual nerves, a small number of axon terminals were labeled in the caudolateral Vsup. The Vsup could also be identified electrophysiologically. After electrical stimulation of the masseter nerve, evoked potentials with slow negative component were isolated only in the Vsup. The present findings suggest that the rat Vsup can be cytoarchitectonically and electrophysiologically identified, receives somatotopic termination of the trigeminal primary afferents, and principally receives strong termination of the spindle Vmes primary afferents. [ABSTRACT FROM AUTHOR]

Skeletal muscle force can be transmitted to the skeleton, not only via its tendons of origin and insertion but also through connective tissues linking the muscle belly to surrounding structures. Through such epimuscular myofascial connections, length changes of a muscle may cause length changes within an adjacent muscle and hence, affect muscle spindles. The aim of the present study was to investigate the effects of epimuscular myofascial forces on feedback from muscle spindles in triceps surae muscles of the rat. We hypothesized that within an intact muscle compartment, muscle spindles not only signal length changes of the muscle in which they are located but can also sense length changes that occur as a result of changing the length of synergistic muscles. Action potentials from single afferents were measured intra-axonally in response to ramp-hold release (RHR) stretches of an agonistic muscle at different lengths of its synergist, as well as in response to synergist RHRs. A decrease in force threshold was found for both soleus (SO) and lateral gastrocnemius afferents, along with an increase in length threshold for SO afferents. In addition, muscle spindle firing could be evoked by RHRs of the synergistic muscle. We conclude that muscle spindles not only signal length changes of the muscle in which they are located but also local length changes that occur as a result of changing the length and relative position of synergistic muscles. [ABSTRACT FROM AUTHOR]

Objective: Investigate the effects of shoulder elevation on repositioning errors in upright and supine body orientations, and examine these effects on anterior and posterior deltoid muscle activation. We hypothesized decreased errors, and altered anterior and posterior deltoid activation with increasing elevation, in both orientations.Design: Crossover trial.Setting: University laboratory.Participants: Thirty-five college-aged participants.Intervention: Subjects attempted to replicate target positions of various elevation angles in upright and supine body orientations. Also, anterior and posterior deltoid activation was recorded in each shoulder position and body orientation.Main Outcome Measures: Vector and variable repositioning errors, anterior and posterior deltoid percentage of maximal contraction.Results: Vector error was greater in supine compared to upright at 90° and 110°, but not at 70°. Variable error was larger in supine than upright, but was unaffected by elevation. Anterior deltoid activation increased with elevation in the upright posture only. Posterior deltoid activation increased with elevation across postures.Conclusions: Muscle activation, external torque, and cutaneous sensations may combine to provide afferent feedback, and be used with centrally-generated signals to interpret the state of the limb during movement. Clinicians may prescribe open kinetic chain exercises in the upright posture with the shoulder elevated approximately 90-100°. [ABSTRACT FROM AUTHOR]

I present a brief review of current understanding of the innervation of the mammalian muscle spindle, from a personal historical perspective. The review begins with comparative studies on the numbers of spindle afferents and considers how their relative abundance may best be assessed. This is followed by an examination of the distribution and some functional properties of the motor innervation. The primary ending is the subject of the final section, in particular, I look at what can be learned from serial sectioning and volumetric reconstruction, and present new results on a model and simulations concerning sensory terminal deformation during stretch. [ABSTRACT FROM AUTHOR]

The first descriptions of muscle spindles with intrafusal fibres containing striated myofibrils and nervous elements were given approximately 150 years ago. It took, however, another 100 years to establish the presence of two types of intrafusal muscle fibres: nuclear bag and nuclear chain fibres. The present paper highlights primarily the contribution of Robert Banks in fibre typing of intrafusal fibres: the confirmation of the principle of two types of nuclear bag fibres in mammalian spindles and the variation in occurrence of a dense M-band along the fibres. Furthermore, this paper summarizes how studies from the Umeå University group (Laboratory of Muscle Biology in the Department of Integrative Medical Biology) on fibre typing and the structure and composition of M-bands have contributed to the current understanding of muscle spindle complexity in adult humans as well as to muscle spindle development and effects of ageing. The variable molecular composition of the intrafusal sarcomeres with respect to myosin heavy chains and M-band proteins gives new perspectives on the role of the intrafusal myofibrils as stretch-activated sensors influencing tension/stiffness and signalling to nuclei. [ABSTRACT FROM AUTHOR]

Mammals may exhibit different forms of locomotion even within a species. A particular form of locomotion (e.g. walk, run, bound) appears to be selected by supraspinal commands, but the precise pattern, i.e. phasing of limbs and muscles, is generated within the spinal cord by so-called central pattern generators. Peripheral sense organs, particularly the muscle spindle, play a crucial role in modulating the central pattern generator output. In turn, the feedback from muscle spindles is itself modulated by static and dynamic fusimotor (gamma) neurons. The activity of muscle spindle afferents and fusimotor neurons during locomotion in the cat is reviewed here. There is evidence for some alpha-gamma co-activation during locomotion involving static gamma motoneurons. However, both static and dynamic gamma motoneurons show patterns of modulation that are distinct from alpha motoneuron activity. It has been proposed that static gamma activity may drive muscle spindle secondary endings to signal the intended movement to the central nervous system. Dynamic gamma motoneuron drive appears to prime muscle spindle primary endings to signal transitions in phase of the locomotor cycle. These findings come largely from reduced animal preparations (decerebrate) and require confirmation in freely moving intact animals. [ABSTRACT FROM AUTHOR]

The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch-reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch-evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX-treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na+ channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function. [ABSTRACT FROM AUTHOR]

This article summarises progress to date over an exciting and very enjoyable first 15 years of collaboration with Bob Banks. Our collaboration began when I contacted him with (to me) an unexpected observation that a dye used to mark recycling synaptic vesicle membrane at efferent terminals also labelled muscle spindle afferent terminals. This observation led to the re-discovery of a system of small clear vesicles present in all vertebrate primary mechanosensory nerve terminals. These synaptic-like vesicles ( SLVs) have been, and continue to be, the major focus of our work. This article describes our characterisation of the properties and functional significance of these SLVs, combining our complementary skills: Bob's technical expertise and encyclopaedic knowledge of mechanosensation with my experience of synaptic vesicles and the development of the styryl pyridinium dyes, of which the most widely used is FM1-43. On the way we have found that SLVs seem to be part of a constitutive glutamate secretory system necessary to maintain the stretch-sensitivity of spindle endings. The glutamate activates a highly unusual glutamate receptor linked to phospholipase D activation, which we have termed the PLD- mGluR. It has a totally distinct pharmacology first described in the hippocampus nearly 20 years ago but, like the SLVs that were first described over 50 years ago, has since been little researched. Yet, our evidence and literature searches suggest this glutamate/ SLV/ PLD- mGluR system is a ubiquitous feature of mechanosensory endings and, at least for spindles, is essential for maintaining mechanosensory function. This article summarises how this system integrates with the classical model of mechanosensitive channels in spindles and other mechanosensory nerve terminals, including hair follicle afferents and baroreceptors controlling blood pressure. Finally, in this time when there is an imperative to show translational relevance, I describe how this fascinating system might actually be a useful therapeutic drug target for clinical conditions such as hypertension and muscle spasticity. This has been a fascinating 15-year journey in collaboration with Bob who, as well as having an astute scientific mind, is also a great enthusiast, motivator and friend. I hope this exciting and enjoyable journey will continue well into the future. [ABSTRACT FROM AUTHOR]

Mechanotransduction by proprioceptive sensory organs is poorly understood. Evidence was recently shown that muscle spindle and hair follicle primary afferents (lanceolates) constantly release glutamate from synaptic-like vesicles ( SLVs) within the terminals. The secreted glutamate activates a highly unusual metabotropic glutamate receptor ( mGluR) to modulate the firing rate (spindles) and SLV recycling (lanceolates). This receptor has yet to be isolated and sequenced. To further investigate this receptor's pharmacology, ligands selective for classical mGluRs have been recently characterised for their ability to alter stretch-evoked spindle firing and SLV endocytosis in these different endings. Here, it is described how the results of these screens facilitated the development of novel compounds to be used in the process of isolating and sequencing of this non-canonical mGluR. This study shows how the compounds were tested for their ability to alter stretch-evoked afferent firing in muscle spindles and SLV endocytosis in the lanceolate endings of hair follicles to ensure they maintained their ability to bind to the receptor. For the development of novel compounds, kainate was chosen as the parent ligand due to its potency and ease of chemical modification. Novel kainate derivatives were then synthesised and tested to find potent analogues suitable for 'click-chemistry', an established technique for relatively quick, cheap, stereospecific and high-yield chemical modifications (Angewandte Chemie (International ed. in English), 40, 2001, pp2004). Of the novel kainate analogues developed, unfortunately ZCZ49 and ZCZ50 lost the ability to produce a significant change in spindle stretch-evoked firing. However, ZCZ90 was as potent as kainate, increasing firing by a similar margin at 1 μ m ( n = 8; P < 0.001). The addition of either a biotin or a fluorescein side group to ZCZ90, using the click-chemistry technique, did not affect the potency and hence these compounds will be used in further studies of the receptor. As well as the development of these compounds, the study found not only many similarities, but also some key differences between the two types of primary mechanosensory endings investigated. These differences must be taken into account in further study. However, they also present an intriguing opportunity for these receptors to be targeted selectively to modulate ending sensitivity as treatments for muscle spasm in multiple sclerosis and spinal cord injury, and possibly even baroreceptor firing to treat hypertension. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the presence of sympathetic innervation in human muscle spindles, using antibodies against neuropeptide Y ( NPY), NPY receptors and tyrosine hydroxylase ( TH). A total of 232 muscle spindles were immunohistochemically examined. NPY and NPY receptors were found on the intrafusal fibers, on the blood vessels supplying muscle spindles and on free nerve endings in the periaxial space. TH-immunoreactivity was present mainly in the spindle nerve and vessel. This is, to our knowledge, the first morphological study concerning the sympathetic innervation of the human muscle spindles. The results provide anatomical evidence for direct sympathetic innervation of the intrafusal fibers and show that sympathetic innervation is not restricted to the blood vessels supplying spindles. Knowledge about direct sympathetic innervation of the muscle spindle might expand our understanding of motor and proprioceptive dysfunction under stress conditions, for example, chronic muscle pain syndromes. [ABSTRACT FROM AUTHOR]

Muscle spindles from the hind limb muscles of adult Ryr1 I4895T/wt (IT/+) mice exhibit severe structural abnormalities. Up to 85% of the spindles are separated from skeletal muscle fascicles by a thick layer of connective tissue. Many intrafusal fibers exhibit degeneration, with Z-line streaming, compaction and collapse of myofibrillar bundles, mitochondrial clumping, nuclear shrinkage and pyknosis. The lesions resemble cores observed in the extrafusal myofibers of this animal model and of core myopathy patients. Spindle abnormalities precede those in extrafusal fibers, indicating that they are a primary pathological feature in this murine Ryr1- related core myopathy. Muscle spindle involvement, if confirmed for human core myopathy patients, would provide an explanation for an array of devastating clinical features characteristic of these diseases and provide novel insights into the pathology of RYR1 -related myopathies. [ABSTRACT FROM AUTHOR]

The focus of this review is on the principal sensory ending of the mammalian muscle spindle, known as the primary ending. The process of mechanosensory transduction in the primary ending is examined under five headings: (i) action potential responses to defined mechanical stimuli-representing the ending's input-output properties; (ii) the receptor potential-including the currents giving rise to it; (iii) sensory-terminal deformation-measurable changes in the shape of the primary-ending terminals correlated with intrafusal sarcomere length, and what may cause them; (iv) putative stretch-sensitive channels-pharmacological and immunocytochemical clues to their identity; and (v) synaptic-like vesicles-the physiology and pharmacology of an intrinsic glutamatergic system in the primary and other mechanosensory endings, with some thoughts on the possible role of the system. Thus, the review highlights spindle stretch-evoked output is the product of multi-ionic receptor currents plus complex and sophisticated regulatory gain controls, both positive and negative in nature, as befits its status as the most complex sensory organ after the special senses. [ABSTRACT FROM AUTHOR]

When a muscle relaxes after a contraction, cross-bridges between actin and myosin in sarcomeres detach, but about 1 % spontaneously form new, non-force-generating attachments. These bridges give muscle its thixotropic property. They remain in place for long periods if the muscle is left undisturbed and give the muscle a passive stiffness in response to a stretch. They are detached by stretch, but reform at the new length. If the muscle is then shortened, the presence of these bridges prevents muscle fibres from shortening and they fall slack. So, resting muscle can be in one of two states, where it presents in response to a stretch with a high stiffness, if no slack is present, or with a compliant response in the presence of slack. Intrafusal fibres of muscle spindles show thixotropic behaviour. For spindles, after a conditioning contraction, they are left stretch sensitive, with a high level of background discharge. Alternatively, if after the contraction the muscle is shortened, intrafusal fibres fall slack, leaving spindles with a low level of background activity and insensitivity to stretch. Muscle spindles are receptors involved in the senses of human limb position and movement. The technique of muscle conditioning can be used to help understand the contribution of muscle spindles to these senses and how the brain interprets signals arising in spindles. When, in a two-arm position-matching task, elbow muscles of the two arms are deliberately conditioned in opposite ways, the blindfolded subject makes large position errors of which they are unaware. The evidence suggests that the brain is concerned with the difference signal coming from the antagonists acting at the elbow and with the overall difference in signal from the two arms. Another way of measuring position sense is to use a single arm and indicate its perceived position with a pointer. Here, there is no access to a signal from the other limb, and position sense relies on referral to a central map of the body, the postural schema. [ABSTRACT FROM AUTHOR]

Muscle spindles are commonly considered as stretch receptors encoding movement, but the functional consequence of their efferent control has remained unclear. The " α - γ coactivation" hypothesis states that activity in a muscle is positively related to the output of its spindle afferents. However, in addition to the above, possible reciprocal inhibition of spindle controllers entails a negative relationship between contractile activity in one muscle and spindle afferent output from its antagonist. By recording spindle afferent responses from alert humans using microneurography, I show that spindle output does reflect antagonistic muscle balance. Specifically, regardless of identical kinematic profiles across active finger movements, stretch of the loaded antagonist muscle (i.e., extensor) was accompanied by increased afferent firing rates from this muscle compared with the baseline case of no constant external load. In contrast, spindle firing rates from the stretching antagonist were lowest when the agonist muscle powering movement (i.e., flexor) acted against an additional resistive load. Stepwise regressions confirmed that instantaneous velocity, extensor, and flexor muscle activity had a significant effect on spindle afferent responses, with flexor activity having a negative effect. Therefore, the results indicate that, as consequence of their efferent control, spindle sensitivity (gain) to muscle stretch reflects the balance of activity between antagonistic muscles rather than only the activity of the spindle-bearing muscle. [ABSTRACT FROM AUTHOR]

Muscle spindles are complex stretch-sensitive mechanoreceptors. They consist of specialized skeletal muscle fibers, called intrafusal fibers, which are innervated in the central (equatorial) region by afferent sensory axons and in both polar regions by efferent γ-motoneurons. We show that AChRs are concentrated at the γ-motoneuron endplate as well as in the equatorial region where they colocalize with the sensory nerve ending. In addition to the AChRs, the contact site between sensory nerve ending and intrafusal muscle fiber contains a high concentration of choline acetyltransferase, vesicular acetylcholine transporter and the AChR-associated protein rapsyn. Moreover, bassoon, a component of the presynaptic cytomatrix involved in synaptic vesicle exocytosis, is present in γ-motoneuron endplates but also in the sensory nerve terminal. Finally, we demonstrate that during postnatal development of the γ-motoneuron endplate, the AChR subunit stoichiometry changes from the γ-subunit-containing fetal AChRs to the ε-subunit-containing adult AChRs, similar and approximately in parallel to the postnatal subunit maturation at the neuromuscular junction. In contrast, despite the onset of ε-subunit expression during postnatal development the γ-subunit remains detectable in the equatorial region by subunit-specific antibodies as well as by analysis of muscle spindles from mice with genetically-labeled AChR γ-subunits. These results demonstrate an unusual maturation of the AChR subunit composition at the annulospiral endings and suggest that in addition to the recently described glutamatergic secretory system, the sensory nerve terminals are also specialized for cholinergic synaptic transmission, synaptic vesicle storage and exocytosis. [ABSTRACT FROM AUTHOR]