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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.

We review our approach for undertaking microelectrode recordings from the posterior tibial nerve at the ankle, which has allowed us to identify, for the first time, the firing properties of muscle spindle endings in the intrinsic muscles of the foot and of cutaneous mechanoreceptors in the sole during unsupported standing. The responsiveness of muscle spindles in the short muscles of the foot to stretch and related joint movements was similar to that of spindles located in the intrinsic muscles of the hand. Only 27% were spontaneously active in the unloaded condition, whereas 50% were active during unsupported free standing. Moreover, in the latter condition firing rates of 67% of the endings were correlated with changes of the centre of pressure (CoP), primarily (88%) along the anteroposterior axis. The firing of cutaneous afferents supplying the sole of the foot in unsupported free standing depended on the receptor type and location of the receptive field: fast‐adapting type I and slowly adapting type I afferents responded transiently during contact with the substrate on standing and to spontaneous postural adjustments, whereas the tonic firing of slowly adapting type II endings encoded fluctuations in the CoP. We conclude that muscle spindle endings in the intrinsic muscles of the foot are recruited or increase their spontaneous discharge on standing and can faithfully encode changes in CoP during spontaneous or evoked postural sway, a function shared by slowly adapting type II afferents in the sole. These data emphasize the important contributions of sensory sources in the foot to maintaining and responding to perturbations in upright posture. What is the central question of this study? We review our work on microelectrode recordings from muscle spindle afferents in the intrinsic muscles of the human foot and of tactile afferents in the sole. What is the main finding and its importance? Most spindle afferents were silent when the foot was unloaded but fired tonically during standing, their discharge covarying with centre of pressure. Most cutaneous afferents responded only during contact and incidental adjustments in posture. We conclude that spindle endings in the muscles of the foot, in addition to tactile afferents from the sole, provide useful proprioceptive information during standing.

Previous studies performed in jaw muscles of rabbits and rats have demonstrated that sympathetic outflow may affect the activity of muscle spindle afferents (MSAs). The resulting impairment of MSA information has been suggested to be involved in the genesis and spread of chronic muscle pain. The present study was designed to investigate sympathetic influences on muscle spindles in feline trapezius and splenius muscles (TrSp), as these muscles are commonly affected by chronic pain in humans. Experiments were carried out in cats anesthetized with alpha-chloralose. The effect of electrical stimulation (10 Hz for 90 s or 3 Hz for 5 min) of the peripheral stump of the cervical sympathetic nerve (CSN) was investigated on the discharge of TrSp MSAs (units classified as Ia-like and II-like) and on their responses to sinusoidal stretching of these muscles. In some of the experiments, the local microcirculation of the muscles was monitored by laser Doppler flowmetry. In total, 46 MSAs were recorded. Stimulation of the CSN at 10 Hz powerfully depressed the mean discharge rate of the majority of the tested MSAs (73%) and also affected the sensitivity of MSAs to sinusoidal changes of muscle length, which were evaluated in terms of amplitude and phase of the sinusoidal fitting of unitary activity. The amplitude was significantly reduced in Ia-like units and variably affected in II-like units, while in general the phase was affected little and not changed significantly in either group. The discharge of a smaller percentage of tested units was also modulated by 3-Hz CSN stimulation. Blockade of the neuromuscular junctions by pancuronium did not induce any changes in MSA responses to CSN stimulation, showing that these responses were not secondary to changes in extrafusal or fusimotor activity. Further data showed that the sympathetically induced modulation of MSA discharge was not secondary to the concomitant reduction of muscle blood flow induced by the stimulation. Hence, changes in sympathetic outflow can modulate the afferent signals from muscle spindles through an action exerted directly on the spindles, independent of changes in blood flow. It is suggested that such an action may be one of the mechanisms mediating the onset of chronic muscle pain in these muscles in humans.

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.

Muscle spindle proprioceptive receptors play a primary role in encoding the effects of external mechanical perturbations to the body. During externally-imposed stretches of passive, i.e. electrically-quiescent, muscles, the instantaneous firing rates (IFRs) of muscle spindles are associated with characteristics of stretch such as length and velocity. However, even in passive muscle, there are history-dependent transients of muscle spindle firing that are not uniquely related to muscle length and velocity, nor reproduced by current muscle spindle models. These include acceleration-dependent initial bursts, increased dynamic response to stretch velocity if a muscle has been isometric, and rate relaxation, i.e., a decrease in tonic IFR when a muscle is held at a constant length after being stretched. We collected muscle spindle spike trains across a variety of muscle stretch kinematic conditions, including systematic changes in peak length, velocity, and acceleration. We demonstrate that muscle spindle primary afferents in passive muscle fire in direct relationship to muscle force-related variables, rather than length-related variables. Linear combinations of whole muscle-tendon force and the first time derivative of force (dF/dt) predict the entire time course of transient IFRs in muscle spindle Ia afferents during stretch (i.e., lengthening) of passive muscle, including the initial burst, the dynamic response to lengthening, and rate relaxation following lengthening. Similar to acceleration scaling found previously in postural responses to perturbations, initial burst amplitude scaled equally well to initial stretch acceleration or dF/dt, though later transients were only described by dF/dt. The transient increase in dF/dt at the onset of lengthening reflects muscle short-range stiffness due to cross-bridge dynamics. Our work demonstrates a critical role of muscle cross-bridge dynamics in history-dependent muscle spindle IFRs in passive muscle lengthening conditions relevant to the detection and sensorimotor response to mechanical perturbations to the body, and to previously-described history-dependence in perception of limb position.

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.

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.

It is challenging to stimulate gamma motor neurons, which are important regulators of muscle spindle afferent function, without also recruiting alpha motor neurons. Here, we test the feasibility of stimulating gamma motor neuron axons using optogenetics in two transgenic mouse lines. We used an ex vivo muscle–nerve preparation in adult mice to monitor muscle spindle afferent firing, which should increase in response to gamma motor neuron‐induced lengthening of the sensory region of the muscle spindle. A force transducer measured alpha motor neuron‐mediated twitch contractions. Blue LED light (470 nm; 1–5 mW) was delivered via a light guide to the sciatic nerve. We confirmed that the more slowly conducting gamma motor neurons were recruited first in mice expressing channelrhodopsin 2 in choline acetyltransferase‐positive motor neurons, whereas alpha motor neurons required higher optical intensities, enabling co‐activation of alpha and gamma motor neurons depending on light intensity. However, this approach cannot isolate gamma motor neuron activity completely. Cre‐dependent channelrhodopsin 2 optoactivation using the putative gamma motor neuron marker neuronal PAS domain protein 1 (Npas1) also increased muscle spindle afferent firing rates and caused only small twitch contractions. This provides functional validation that Npas1 is present primarily in gamma motor neurons and can be used to manipulate gamma motor neurons independently. We propose optogenetic stimulation as a promising tool to manipulate gamma motor neuron activity. What is the central question of this study? Additional tools are needed to modulate gamma motor neuron function independently to gain a better understanding of the function of the fusimotor system. What is the main finding and its importance? Optogenetics tools can be used to stimulate gamma motor neurons independently of alpha motor neurons by expressing channelrhodopsin 2 in neuronal PAS domain protein 1‐expressing cells or using lower light intensities with channelrhodopsin 2 expressed in all choline acetyltransferase‐positive motor neurons. This technique could be used to study the role of gamma motor neurons in motor control and proprioception during normal behaviour and disease.

Acid-sensing ion channel 3 (ASIC3) is involved in acid nociception, but its possible role in neurosensory mechanotransduction is disputed. We report here the generation of Asic3-knockout/eGFPf-knockin mice and subsequent characterization of heterogeneous expression of ASIC3 in the dorsal root ganglion (DRG). ASIC3 is expressed in parvalbumin (Pv+) proprioceptor axons innervating muscle spindles. We further generate a floxed allele of Asic3 ( Asic3 f/f ) and probe the role of ASIC3 in mechanotransduction in neurite-bearing Pv+ DRG neurons through localized elastic matrix movements and electrophysiology. Targeted knockout of Asic3 disrupts spindle afferent sensitivity to dynamic stimuli and impairs mechanotransduction in Pv+ DRG neurons because of substrate deformation-induced neurite stretching, but not to direct neurite indentation. In behavioural tasks, global knockout ( Asic3 −/− ) and Pv-Cre::Asic3 f/f mice produce similar deficits in grid and balance beam walking tasks. We conclude that, at least in mouse, ASIC3 is a molecular determinant contributing to dynamic mechanosensitivity in proprioceptors. Acid-sensing ion channel 3 (ASIC3) is known to play a role in nociception, but its role in low threshold neurosensory mechanotransduction is unclear. Here, the authors target ASIC3 expression in dorsal root ganglion parvalbumin positive neurons and find ASIC3 contributes to dynamic proprioception responses.

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.