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Extracellular calcium is crucial for the normal function of muscle spindle sensory afferents. They express multiple calcium buffering proteins. Extracellular calcium is essential for recycling of synaptic‐like vesicles (SLVs) in the terminals and for the stretch‐evoked inward calcium current of the receptor potential. Conversely, removal of calcium from the extracellular medium abolishes stretch‐evoked action potentials (APs). However, the calcium channel(s) involved and mechanism(s) of action are unknown. This study begins identifying the channels involved and their actions. Specific calcium channel toxins, agonists and antagonists were examined for effects on stretch‐evoked muscle spindle afferent discharge, and live spindle sensory terminal labelling with FM1‐43 was used to monitor SLV recycling in adult rat lumbrical muscle. Voltage‐gated calcium channels, particularly P/Q‐type (Cav2.1) and L‐type (Cav1.1–1.4), strongly regulated the firing frequency of APs in response to a standard stretch, probably by regulating the opening of ‘big’, ‘intermediate’ and ‘small’ calcium‐activated potassium channels (KCa), with direct evidence for BK (KCa1.1), SK (most likely KCa2.2) and IK (KCa3.1) involvement. Moreover, calcium from two different sources regulated separate aspects of SLV recycling. Thus, L‐type channel blockers inhibited FM1‐43 release, while TRPV4 (transient receptor potential, vanilloid, type 4) channel blockers entirely inhibited FM1‐43 uptake. No role in SLV recycling was found for P/Q type channels, and no role at all was found for N‐type (Cav2.3) channels. Overall, these studies pinpoint multiple different aspects of calcium signalling, through different channel families, and produce the first evidence of a role for a mechanosensory TRPV4 channel in muscle spindle sensory terminal function. What is the central question of this study? External calcium is essential for muscle spindle stretch‐evoked nerve firing and sensory nerve terminals express multiple calcium‐buffering proteins, yet calcium hardly contributes to stimulus‐evoked potentials: so what is calcium's role? What is the main finding and its importance? Muscle spindles of ex vivo rat muscles revealed multiple roles for calcium. Stretch (TRPV4) and voltage‐activated (L‐type) calcium channels control endo‐ and exocytosis of glutamate, respectively, essential for terminal stretch‐sensitivity. Multiple calcium‐activated potassium channels gated by voltage‐activated (L‐ and P/Q‐type) calcium channels regulate afferent discharge rates encoding muscle length to the CNS.

This is an account of experiments carried out in my laboratory over more than 20 years, exploring the influence of exercise on human limb position sense. It is known that after intense exercise we are clumsy in the execution of skilled movements. The first question we posed concerned eccentric exercise, where the contracting muscle is forcibly lengthened. Such exercise produces muscle damage, and the damage might extend to the muscle’s proprioceptors, the muscle spindles, producing a disturbance of limb position sense. However, provided the exercise was sufficiently severe (20–30% fall in muscle force), comparing eccentric exercise with concentric exercise, where no damage ensues, there was no difference in the effects on position sense. After exercise of elbow muscles, the forearm was always perceived as more extended than its actual position. It led to a new hypothesis: after exercise, did the extra effort required to lift the fatigued arm provide a position signal? Findings based on spindles’ thixotropic behaviour did not support such a proposition for the elbow joint, although at the wrist an effort signal may contribute. Spindle thixotropy has also been proposed to explain the poor proprioception experienced under conditions of weightlessness. After exercise of elbow extensors or flexors, the position errors were always in the direction of forearm extension. At the knee, after exercise the lower leg was always perceived as more flexed. These findings led to the conclusion that disturbances to position sense, post-exercise, did not involve peripheral receptors, and that the effect arose within the brain.

Muscle spindles sense changes in muscle length and transmit them to the central nervous system. Proprioception is essential for gait and postural maintenance, the abnormality of which has been linked to gait disorders and the risk of falling in older adults. However, the effects of aging on the muscle spindle structure remain nebulous. This study investigated age-related structural changes in the muscle spindles (from the equator to the polar) in the soleus and extensor digitorum longus (EDL) muscles of young, middle-aged, and aged mice. The findings indicated that the shape of the annulospiral endings of the sensory neurons began to deteriorate in middle-aged compared with young mice and was further exacerbated in aged mice. These changes were particularly pronounced in the nuclear bag fibers, whereas no significant age-related changes were observed in the intrafusal fibers or capsules. A decline in gait function due to changes in weight-bearing and weight-shifting in aged mice was also observed, suggesting that the deterioration of proprioceptive sensory neurons that innervate the nuclear bag fiber responsible for dynamic sensitivity prevents proper coordinated movement and contributes to movement disorders in aged animals including humans, together with the functional decline of extrafusal fibers.

The stretch reflex is a fundamental component of the motor system that orchestrates the coordinated muscle contractions underlying movement. At the heart of this process lie the muscle spindles (MS), specialized receptors finely attuned to fluctuations in tension within intrafusal muscle fibres. The tension variation in the MS triggers a series of neuronal events including an initial depolarization of sensory type Ia afferents that subsequently causes the activation of motoneurons within the spinal cord 1 , 2 . This neuronal cascade culminates in the execution of muscle contraction, underscoring a presumed closed-loop mechanism between the musculoskeletal and nervous systems. By contrast, here we report the discovery of a new population of macrophages with exclusive molecular and functional signatures within the MS that express the machinery for synthesizing and releasing glutamate. Using mouse intersectional genetics with optogenetics and electrophysiology, we show that activation of MS macrophages (MSMP) drives proprioceptive sensory neuron firing on a millisecond timescale. MSMP activate spinal circuits, motor neurons and muscles by means of a glutamate-dependent mechanism that excites the MS. Furthermore, MSMP respond to neural and muscle activation by increasing the expression of glutaminase, enabling them to convert the uptaken glutamine released by myocytes during muscle contraction into glutamate. Selective silencing or depletion of MSMP in hindlimb muscles disrupted the modulation of the stretch reflex for force generation and sensory feedback correction, impairing locomotor strategies in mice. Our results have identified a new cellular component, the MSMP, that directly regulates neural activity and muscle contraction. The glutamate-mediated signalling of MSMP and their dynamic response to sensory cues introduce a new dimension to our understanding of sensation and motor action, potentially offering innovative therapeutic approaches in conditions that affect sensorimotor function. A population of macrophages with exclusive molecular and functional signatures in the muscle spindles express machinery for synthesizing and releasing glutamate, and a cellular component, the muscle spindle macrophages, directly regulates neural activity and muscle contraction.

Muscle spindles are encapsulated sensory organs found in most of our muscles. Prevalent models of sensorimotor control assume the role of spindles is to reliably encode limb posture and movement. Here, I argue that the traditional view of spindles is outdated. Spindle organs can be tuned by spinal γ motor neurons that receive top-down and peripheral input, including from cutaneous afferents. A new model is presented, viewing γ motor activity as an intermediate coordinate transformation that allows multimodal information to converge on spindles, creating flexible coordinate representations at the level of the peripheral nervous system. That is, I propose that spindles play a unique overarching role in the nervous system: that of a peripheral signal-processing device that flexibly facilitates sensorimotor performance, according to task characteristics. This role is compatible with previous findings and supported by recent studies with naturalistically active humans. Such studies have so far shown that spindle tuning enables the independent preparatory control of reflex muscle stiffness, the selective extraction of information during implicit motor adaptation, and for segmental stretch reflexes to operate in joint space. Incorporation of advanced signal-processing at the periphery may well prove a critical step in the evolution of sensorimotor control theories.

Position sense is arguably more important than any of the other proprioceptive senses, because it provides us with information about the position of our body and limbs in relationship to one another and to our surroundings; it has been considered to contribute to our self‐awareness. There is currently no consensus over the best method of measuring position sense. We have recently measured position sense with three commonly used methods. These were two‐arm matching, one‐arm pointing and one‐arm repositioning, all carried out by blindfolded subjects with their lightly loaded forearms moving in the sagittal plane. It is currently believed that muscle spindles are the principal position sensors. We posed the question, was there evidence for spindles participating in the generation of position sense with each method? The indicator of spindle activity we used was the presence of thixotropic errors in the position signal, in response to conditioning voluntary contractions of forearm muscles. Based on this criterion, there was evidence of spindles contributing to position sense with all three methods. It was concluded that the spindle contribution to the position signal and the extent to which this was processed centrally was different with each method. It is argued that a case could be made for the existence of more than one position sense. Differences between the methods have implications for their meaning in a clinical setting. What is the topic of this review? This mini‐review discusses methods of measuring position sense at the human forearm. What advances does it highlight? Three classes of methods were considered: position sense by two‐arm matching, one‐arm pointing and one‐arm repositioning. A contribution from muscle spindles to generation of the position sense signal could be detected by means of voluntary conditioning contractions of elbow muscles. For all three methods, evidence was obtained of spindles contributing to the generation of position sense, but to different extents. These differences in the processing of the spindle signals have led to the suggestion of the existence of more than one position sense.

Proprioception is essential for perception and action. Like any other sense, proprioception is also subject to illusions. In this study, we model classic proprioceptive illusions in which tendon vibrations lead to biases in estimating the state of the body. We investigate these illusions with task‐driven models that have been trained to infer the state of the body from distributed sensory muscle spindle inputs (primary and secondary afferents). Recent work has shown that such models exhibit representations similar to the neural code along the ascending proprioceptive pathway. Importantly, we did not train the models on illusion experiments and simulated muscle–tendon vibrations by considering their effect on primary afferents. Our results demonstrate that task‐driven models are indeed susceptible to proprioceptive illusions, with the magnitude of the illusion depending on the vibration frequency. This work illustrates that primary afferents alone are sufficient to account for these classic illusions and provides a foundation for future theory‐driven experiments. What is the central question of this study? Are deep‐learning models of the ascending proprioceptive pathway subject to illusions like those induced by muscle tendon vibrations? What is the main finding and its importance? Task‐driven models trained on arm localization from proprioceptive input exhibit vibration‐induced illusory behaviour. This finding implies the sufficiency of simple feedforward processing of Ia afferents in explaining classic kinaesthetic illusions and enables future theory‐driven experiments.

In the past, the peripheral sense organs responsible for generating human position sense were thought to be the slowly adapting receptors in joints. More recently, our views have changed and the principal position sensor is now believed to be the muscle spindle. Joint receptors have been relegated to the lesser role of acting as limit detectors when movements approach the anatomical limit of a joint. In a recent experiment concerned with position sense at the elbow joint, measured in a pointing task over a range of forearm angles, we have observed falls in position errors as the forearm was moved closer to the limit of extension. We considered the possibility that as the arm approached full extension, a population of joint receptors became engaged and that they were responsible for the changes in position errors. Muscle vibration selectively engages signals of muscle spindles. Vibration of elbow muscles undergoing stretch has been reported to lead to perception of elbow angles beyond the anatomical limit of the joint. The result suggests that spindles, by themselves, cannot signal the limit of joint movement. We hypothesise that over the portion of the elbow angle range where joint receptors become active, their signals are combined with those of spindles to produce a composite that contains joint limit information. As the arm is extended, the growing influence of the joint receptor signal is evidenced by the fall in position errors.

Orthosis immobilisations are routinely used in orthopaedic procedures. This intervention is applicable in bone fractures, ligament injuries, and tendonitis, among other disorders of the musculoskeletal system. We aimed to evaluate the effects of ankle joint functional immobilisation on muscle fibre morphology, connective tissue, muscle spindle and fibre typification triggered by a novel metallic orthosis. We developed a rodent-proof experimental orthosis able to hold the tibiotalar joint in a functional position for short and long terms. The tibialis anterior muscles of free and immobilised legs were collected and stained by histology and histochemistry techniques to investigate general muscle morphology, connective tissue and muscle fibre typification. Morphometric analysis of muscle cross-section area, fibre type cross-section area, fibre type density, percentage of intramuscular connective tissue, and thickness of the muscle spindle capsule were obtained to gain insights into the experimental protocol. We found that short- and long-term immobilisation decreased the cross-section area of the muscles and induced centralisation of myonuclei. The connective tissue of immobilised muscle increased after 2 and 4 weeks mainly by deposition of type III and type I collagen fibres in the perimysium and endomysium, respectively, in addition to muscle spindle capsule thickening. Type IIB muscle fibre was severely affected in our study; the profile assumed odd shapes, and our data suggest interconversion of these fibre types within long-term immobilisation. In conclusion, our protocol has produced structural and histochemical changes in muscle biology. This method might be applied to various rodent models that enable genetic manipulation for the investigation of muscle degeneration/regeneration processes.

Proprioceptive sensory feedback is crucial for the control of movement. In many ways, sensorimotor control loops in the neuromuscular system act as state feedback controllers. These controllers combine input commands and sensory feedback regarding the mechanical state of the muscle, joint or limb to modulate the mechanical output of the muscles. To understand how these control circuits function, it is necessary to understand fully the mechanical state variables that are signalled by proprioceptive sensory (propriosensory) afferents. Using new computational approaches, we demonstrate how combinations of group Ia and II muscle spindle afferent feedback can allow for tuned responses to force and the rate of force (or length and velocity) and how combinations of muscle spindle and Golgi tendon organ feedback can parse external and internal (self‐generated) force. These models suggest that muscle spindle feedback might be used to monitor and control muscle forces in addition to length and velocity and, when combined with tendon organ feedback, can distinguish self‐generated from externally imposed forces. Given that these models combine feedback from different sensory afferent types, they emphasize the utility of analysing muscle propriosensors as an integrated population, rather than independently, to gain a better understanding of propriosensory–motor control. Furthermore, these models propose a framework that links neural connectivity in the spinal cord with neuromechanical control. Although considerable work has been done on propriosensory–motor pathways in the CNS, our aim is to build upon this work by emphasizing the mechanical context. What is the central question of this study? How can combinations of feedback from multiple propriosensor types signal muscle mechanical state variables for control? What is the main finding and its importance? Combined feedback from muscle spindle afferents can parse static and dynamic components of muscle stretch, and combined feedback from muscle spindle and tendon organ afferents can dissociate external forces from forces generated internally by contraction. We propose these mechanical state variables as potential control variables in sensorimotor circuits.