“It is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is most adaptable to change”. Charles Darwin.
Animals must detect and respond to changes in external and internal environments in order to survive and reproduce. The sensory and motor systems of an animal exhibit remarkable sensitivity and plasticity in their structures and functions as needed to adjust to ever-changing environmental conditions. For example, when animals encounter predators or hazardous conditions, their sensory systems detect spatiotemporal patterns of these harmful stimuli, which are then transduced, integrated, and processed in central nervous systems to control motor systems, leading to change in behavioral programs, including locomotive maneuvers (1). Moreover, this behavioral modification is further modulated by previous experience and internal status.
Humans have a multitude of senses, including vision, audition, olfaction, gustation, and somatosensation, which are traditionally described as five senses. In the 19th century, Scottish anatomist Sir Charles Bell first characterized “muscle sense” and referred to it as the sixth sense (2-4). In the early 20th century, Charles Scott Sherrington studied the peripheral source of sensory afferents and their control on muscle contraction, and introduced the terms “
Motor control via the proprioceptive sensory system is well conserved in many motile animals, from vertebrates to invertebrates. In mammals, proprioceptive systems are well described anatomically and functionally (12-14). Invertebrate proprioceptive organs have also been well described in several species such as worms, flies and cockroaches (15, 16). Despite previous studies, the molecular mechanisms underlying proprioceptive feedback in motor control are still unclear. Here, we review recent findings about molecular and neuronal mechanisms underlying proprioception and its motor control in representative model systems, including
The DVA interneuron has been shown to mediate mechanical sensory integration (23, 24). Xu and coworkers identified the DVA interneuron as a type of proprioceptive neuron that regulates body bending angle (Fig. 1A) (25). This group found that
The next candidates as proprioceptive neurons are the PVD and FLP sensory neurons (Fig. 1A). These neurons appear to sense noxious signals in a way similar to how mammalian nociceptive receptor neurons do so (28, 29). Albeg and coworkers identified new roles of the PVD and FLP neurons in modulating crawling (30). The PVD and FLP neurons have characteristic structures that directly detect body stretch (Fig. 1A) (17, 30). The dendritic branches of the PVD and FLP neurons encompass the whole body; PVD branches cover the body region from the pharynx to the tail, whereas FLP branches surround the head region (Fig. 1A) (29, 30). Moreover, their terminal branches are positioned between the body-wall muscle and hypodermis (30, 31). This group found that PVD-ablated mutants exhibit a decreased bending angle and a more extended waveform (Fig. 1B). Also, mutants lacking functional PVD and FLP neurons exhibited locomotive defects, including reduced speed, increased reversal, and pauses (30). The PVD and FLP neurons express the MEC-10 degenerin/epithelial sodium channel (DEG/ENaC), which has been identified in mechanosensation (Fig. 1B) (29, 32). The group found that mec-10 mutants exhibit a decreased bending angle (Fig. 1B) and that during locomotion, the PVD neurons are activated through the MEC-10 channel (30). Thus, these results indicate that the MEC-10 channel can function as a proprioceptor in the PVD and FLP neurons, and that proprioceptive feedback from the PVD and FLP neurons may modulate proper crawling. However, direct activation of the PVD and FLP by muscle contraction and their downstream targets needs to be further verified in order to conclude that the PVD and FLP neurons and MEC-10 are bona fide proprioceptive neurons and receptors, respectively.
During forward movement,
The fruit fly
Proprioception of the adult legs is in part mediated by the mechanosensory apparatus such as chordotonal organs (COs) (Fig. 2A). Insect legs harbor multiple classes of exteroceptive and interoceptive mechanoreceptors (45). COs house internal mechanoreceptor neurons typically located at and between joints residing in individual limbs and body segments. The fundamental unit of COs is called the scolopidium, consisting of one to three bipolar sensory neurons and two types of accessory cells (neuron-enveloping scolopale and neuron-anchoring cap cells). The femoral chordotonal organ (FeCO) is a well- known proprioceptor in insects and is widely located in the legs (Fig. 2A). In
Despite functional studies of proprioceptive organs, the molecular mechanisms of leg proprioception are still unclear. For leg proprioception, Akitake
In summary, three different studies of leg proprioception indicate that the
The generation of precise motor control is mediated by multisensory integrations, such as vision, hearing, and touching. In
As in adults, sensory feedback is essential for larval crawling, but the specific roles of neurons and muscles in crawling remain to be fully understood (54, 55). Genetic manipulations on two classes of multidendritic (md) neurons, bipolar dendrites (bd), and the class I mds showed that they are essential in normal larval crawling as proprioceptors (Fig. 2A) (56). Further studies revealed morphologies and positions of the diverse multipledendritc (md) neurons (57, 58), suggesting that each of six md cell types may show functional differences in proprioceptive feedback circuits. To identify the functional difference of each md cell type, Vaadia
Mechanosensitive ion channels have been associated with the coordination of larval crawling. Cheng
There are two types of major proprioceptive organs in mammals: muscle spindles (MS) and Golgi tendon organs (GTO) (Fig. 3A) (8, 65). The MS is located in the middle of the muscle fibers, with its sensory afferent ending innervating the intrafusal muscle fiber. In contrast to extrafusal muscle fibers that contract upon an alpha motor-neuron impulse to produce major muscular power, intrafusal fibers are located inside the fusiform (spindle-like) capsule and are innervated by surrounding type Ia or II proprioceptive sensory afferents. When intrafusal fibers are stretched by movement, the type Ia afferent triggers an action potential corresponding to the change in muscle length, whereas the firing rate of the type II afferent encodes the length of muscle (8, 65). The GTO is located in the junction between tendon and muscle. Type Ib sensory nerve endings innervate the distal ending of the tendon, which is ensheathed in the capsule. The contraction of the muscle elicits a stretch of the tendon linked to the muscle, thereby triggering the action potential of the GTO afferents. The GTO also detects the force imposed upon the tendon, allowing the sensation of isometric exercise. The cell bodies of both MS and GTO reside in the dorsal root ganglion, which contains a cluster of cell bodies enriched with mechanosensitive, chemosensitive, and temperaturesensitive peripheral sensory neurons and bilaterally neighbors the spinal cord (8, 65).
Mammalian joints also contain sensory organs of low-threshold mechanosensitivity, such as Ruffini endings and Pacinian corpuscles (65). However, in contrast to chordotonal neurons in insects, the joint sensation does not seem to play a critical role except in detecting a movement threshold, because joint replacement surgery can spare the proprioceptive control of fine movement (8).
The soma of both MS and GTO resides in the dorsal root ganglion (DRG) with other peripheral sensory neurons, such as mechanosensitive touch-sensing neurons and thermosensory neurons (65, 66). In the DRG, peripheral sensory neurons are not topographically segregated according to their function but are distributed in a salt-and-pepper pattern. It is the molecular composition and projection pattern that distinguish proprioceptors from other peripheral sensory neurons (67-69). These proprioceptive DRG neurons are derived from neural crest progenitors and characterized by the expression of parvalbumin (PV), TrkC, and Runx3 (67, 68). However, either PV or Runx3 expression does not exclusively coincide with proprioceptors, even among DRG sensory neurons, because their expression is also found in the cutaneous mechanosensitive receptors (67, 69).
Recent progress in single-cell RNA sequencing offers unprecedently detailed genetic insight into the molecular signatures of the proprioceptors. Usoskin
In line with these molecular signatures, Cre drive lines that specifically expressed Cre DNA recombinase in either PV+ or Runx3+ cells provided efficient genetic accessibility to proprioceptors (72-74). However, these marker genes are expressed not only in proprioceptors but also in certain types of cutaneous mechanosensory neurons, raising cell-type validation issues for Cre driver-based studies. To genetically label proprioceptive neurons exclusively and efficiently, advanced genetic techniques are required in addition to proprioceptive-specific genetic-profile information. For example, an intersectional double genetic switch using both Cre and Flp driven by PV and Runx3, respectively, is reportedly efficient and exclusive in specifically labeling proprioceptors (72). Since the genetic toolbox controlled by Flp is rather limited compared to Cre-based toolbox, further development of intersectional switches would facilitate the specific genetic manipulation of proprioceptors. Because the proprioceptive identity is postnatally established (71), inducible systems such as CreERT2 would be required to finely delineate the cell-type specificity of proprioceptive neurons (75).
Proprioceptors respond to mechanical deformation of afferent endings by eliciting action potentials with notably high fidelity and low adaptation. This property makes proprioceptors exceptionally well adapted to ceaselessly monitor the position and movement of our body, where the cognate sensory stimuli are constantly present within a relatively limited range, in contrast to the evanescent sensory stimuli that stimulate our “five senses”. Accordingly, the physiological response of the proprioceptive system provides classic evidence supporting a fundamental concept of neuroscience, that the sensory stimuli generate the action potential of a fixed intensity in the sensory neuron and that the frequency of the generated action potential correlates with the strength of given stimuli (76).
Recent experimental approaches have used the fact that the DRG proprioceptors can also be excited by mechanical stimulation of the proprioceptor soma by micrometer-level indentation by a blunt-end glass needle (72-74, 77). Although the subcellular distribution of molecular receptors that transduce mechanical stimuli into a change in membrane potential is not clearly understood, the membrane-potential changes of proprioceptors in response to mechanical force imposed upon the soma of these neurons suggest that the distribution of the mechanosensitive proprioceptive channels is not limited to the sensory afferent endings. As we will explore later, although proprioception provides important information in feedback control of motor regulation, defective motor control is not necessarily attributable to the deficit of proprioception. Therefore, electrophysiological analyses of proprioceptors in response to mechanical stimuli are vital in identifying proprioceptive ion channels. A recent key discovery of mammalian proprioceptors is firmly rooted in the defective mechanosensitive current response in the DRG neurons. For example, electrophysiological properties of DRG PV neurons that genetically lack
The most well-known and most widely exercised example of a motor program that depends on proprioception is the spinal monosynaptic stretch reflex, also known as a knee-jerk reflex. Brief hitting of the patellar ligament stretches the quadricep muscle and the muscle spindle therein. The stretch of the muscle spindle, in turn, induces the firing of the proprioceptive neurons, which then communicate with downstream spinal motor neurons to extend the leg. Normal proprioception is a crucial component in successful knee jerk reflexes, whereas the deficit in the reflex indicates not only abnormal proprioception but also damage in the reflex arc, either interneuron or motor neuron or muscle function. Specific examination of proprioception requires a more explicit experimental design.
More than 30 different tests have been suggested to exam the proprioceptive functions of humans (78). There is no single gold-standard test to evaluate all the proprioceptive functions of the subject. Instead, each test evaluates a specific proprioceptive function of each location: perception of the static position of a body part or of a body movement. The degradation of proprioception results in the loss of acuity in movement control, which is worsened by the deprivation of complementary sensory modality, and poor novel motor learning. In the human genetic studies, genome sequence analysis identified PIEZO2 as a molecular cause that leads to proprioception deficits (79, 80). The patients carrying mutant PIEZO2 suffered from lack of proprioception, impaired motor coordination, electrophysiological phenotypes, and various degrees of joint malformation, without any compromised cognitive functions. Retarded initiation of walking is reported in infants (79, 80).
Mouse models have been a preferred mammalian model for studying proprioceptive functions in mammals because of their genetic accessibility. Early studies investigating the development of proprioceptive neurons from their progenitors produced several mutants with developmentally abnormal proprioceptors that later lacked proper proprioceptive functions as adults. Genetic models with problems in synaptic connection between proprioceptive neurons and motor neurons or in the functional development of the muscle spindle further validate that proprioception crucially coordinates posture as well as walking and swimming in mice (Fig. 3B) (81, 82).
Another line of evidence about how proprioception contributes to motor coordination in mice originates from mutants that lack the mechanosensitive ion channels responsible for proprioception.
Thus, locomotion in model animals requires further studies for us to gain a more wholistic understanding of how proprioceptive computation accurately accommodates mechanosensory inputs from components of locomotion, as we start to glimpse a mechanistic insight into the molecular and neuronal substrates for the sensory levels of proprioception (Table 1). Con-sidering that human proprioception contributes to both con-scious and unconscious perception of limb and trunk position and movement, the current behavioral assays in model animals are limited, in that they do not require conscious processing of proprioceptive information. Whereas most behavioral assays focus on motor coordination, the engagement of proprioception in motor learning and rehabilitation may provide an additional layer of insight (83). Recent progress in machine-vision technologies, such as DeepLabCut and MoSeq, will aid a better understanding of proprioception in motor control by facilitating machine-vision-based kinesthetic analysis (84, 85). Furthermore, there is currently no study investigating the causal relationships of proprioceptive neurons in motor control at millisecond precision with reversibility, warranting an optogenetic study to understand the dynamic contribution of proprioception to motor control.
This study was supported by the National Research Foundation of Korea (NRF-2020R1A4A1019436).
The authors have no conflicting interests.
Proprioceptors and their function
|DVA neuron||Mechanical sensory integration, control body bending angle||Dorsorectal ganglion||TRP-4||23, 24, 25, 26, 27|
|PVD & FLP neurons||Sensing noxious signals, control crawling behavior||Lumbar ganglion (Tail) / head||MEC-10||17, 28, 29, 30, 31, 32|
|SMDD neurons||Regulation of omega turn, control head steering||Ventral ganglion in the head||TRP-1, TRP-2||17, 26, 33, 34|
|B type cholinergic motor neurons||Undulatory locomotion, control wave propagation||Ventral nerve cord||-||17, 41|
|dbd, ddaE, ddaD neuron (larvae)||Peristaltic muscle contraction, control stride size and crawling speed||Chordotonal organ||NompC||49, 56, 59|
|ddaE, ddaD neuron (larvae)||Peristaltic muscle contraction, control forward / backward locomotion||Chordotonal organ||TMC||56, 59, 62, 63|
|FeCO (femoral chordotonal organ) (adult fly)||Membrane stretch sensing, control walking speed and leg replacement||Neurons, scolopale cells, macrochaetes, dorsal thorax and leg||TRPγ||46, 47, 48|
|FeCO (femoral chordotonal organ) (adult fly)||Mechanosensing, control walking speed and leg / wing twisting movements||Neurons, leg joints and ciliary tips of COs||NompC||46, 47, 49, 50, 51|
|Mouse||Type Ia and II sensory afferents||Sensing movement stretching, control muscle length||Muscle spindle and soma reside in dorsal root ganglion||PIEZO2||8, 65, 72, 73, 80, 81|
|Type Ib sensory afferent||Sensing muscle contraction, sense isometric exercise||Golgi tendon organ and soma reside in dorsal root ganglion||PIEZO2||8, 65, 72, 73, 80, 81|