|Yalda Moayedi et al. (2015), Scholarpedia, 10(3):7265.||doi:10.4249/scholarpedia.7265||revision #148580 [link to/cite this article]|
Mechanotransduction, the conversion of mechanical stimuli into biochemical or electrical signals within cells, is necessary for many aspects of development, homeostasis and sensation (Chalfie, 2009). For example, in vascular development, transduction of shear forces is needed for development and alignment of endothelial cells (Li et al., 2014; Ranade et al., 2014a; Tzima et al., 2005). In the vertebrate ear, movement of specialized stereocilia on mechanosensory hair cells transduces sound waves to initiate hearing (Kazmierczak and Muller, 2012). In mammalian skin, an array of somatosensory neurons transduces distinct components of cutaneous sensations, including pressure, stretch, flutter, vibration and pain.
In touch receptors and other mechanosensory cells, transduction is thought to be mediated by mechanically activated ion channels that are embedded in the cell’s plasma membrane. These ion channels open in response to cellular movement or plasma membrane deformation, allowing cations to enter or exit the cell, resulting in a change in membrane potential. This change in membrane voltage triggers a cascade of neural signaling that results in perception of discriminative, affective or painful touch. Here, we review current knowledge on mammalian touch receptors and mechanically activated ion channels in the skin.
Anatomy of touch receptors in mammalian skin
Skin, which is the largest sensory organ of the body, is equipped for many sensory functions. Non-hairy, or glabrous, skin that covers our palms and soles has distinctive receptors to facilitate high acuity (or discriminative) touch, allowing identification of shape and texture of objects. Hairy skin, which predominates on mammals, performs discriminative roles as well as encodes affective aspects of touch linked to “pleasant” emotional reactions. Classically, studies on discriminative touch reception have focused on the glabrous skin of non-human primates (Johnson, 2001). In recent years, there has been an expanded interest in the innervation of hairy skin in murine models (Lechner and Lewin, 2013). Somatosensory neurons and their anatomically specialized peripheral terminals, termed end organs, reside within different skin structures and facilitate the unique receptive abilities of each area (Figure 1). Four end-organ types reside in mammalian glabrous skin: Meissner corpuscles, Pacinian corpuscles, Merkel-cell neurite complexes and Ruffini endings. In the coat of hair that covers most of the mammalian body, called the pelage, four different types of hair follicles are richly innervated by neurons that help transduce different aspects of touch (Brown and Iggo, 1967; Li et al., 2011). In addition to these hair follicle types, mammals have vibrissae, or whiskers, that are organs of discriminative touch in some species. The anatomy and location of tactile afferents, specialized end organs and associated cells help to define their functional roles in touch reception.
Somatosensory neuronsSomatosensory neurons, with cell bodies in dorsal root ganglia (DRG) or trigeminal ganglia, innervate the skin and transmit mechanosensory information to the spinal cord and hindbrain. Anatomically, DRG neurons are pseudounipolar and are classified based on degree of myelination and conduction velocity. These include heavily myelinated Aβ afferents, lightly myelinated Aδ afferents, and unmyelinated C-fibers. Aβ neurons have the fastest conduction velocity and the largest axonal diameter. Aδ fibers have a slightly smaller diameter than Aβ fibers and a slower conduction velocity due to thinner myelination. C-fibers are the slowest and smallest diameter class of somatosensory neurons and account for the majority of neurons innervating the skin (Smith and Lewin, 2009). The stimulus thresholds of somatosensory neurons in the skin help to define their function: neurons underlying discriminative and affective touch have low-threshold responses to mechanical stimuli, and are thus called low threshold mechanoreceptors (LTMRs). Nociceptive stimuli tend to have much higher thresholds for mechanical activation than LTMRs. Many nociceptive neurons are also activated by thermal and chemical stimulation.
Pacinian CorpusclesPacinian corpuscles lie deep within the dermis of glabrous skin, as well as in other organs such as pancreas, gut, joints, tendons and interosseous membranes in different species (Bell et al., 1994). Pacinian corpuscles are large, oval shaped end organs that resemble onions in cross sections due to stacks of lamellar Schwann cells that surround the sensory afferents along a parallel axis. The end organ is further encased in layers of perineural cells. Within each Pacinian corpuscle, a single Aβ-LTMR axon follows a linear path through the center of the corpuscle. Interestingly, Pacinian corpuscles grow throughout life and are found to be up to 4 mm long in adult humans (Cauna and Mannan, 1958).
Meissner corpusclesMeissner corpuscles are situated in the dermis of glabrous skin directly below the epithelium of rete ridges. The Meissner corpuscle itself is an oval shaped structure of stacked lamellar Schwann cells encapsulated in a layer of fibroblasts. By contrast with the Pacinian corpuscle’s concentric layers, the Meissner corpuscle’s lamellae are stacked perpendicular to the neuron’s entrance site. Aβ-axons course through the corpuscle following a tortuous route through lamellae. An Aβ fiber can innervate many Meissner corpuscles, and a single corpuscle can be innervated by multiple axons (Abraira and Ginty, 2013; Cauna, 1956; Halata, 1975). Meissner corpuscles also receive C-fiber innervation (Pare et al., 2001) but the functional significance of this innervation is unclear.
Merkel cell-neurite complexesMerkel cells are derived from epithelial precursors and are positioned in the basal layer of the epidermis (Morrison et al., 2009; Van Keymeulen et al., 2009). Merkel cells associate with slowly adapting type I (SAI) afferents (described below) to form Merkel cell-neurite complexes. In glabrous skin, Merkel cells reside at the base of rete ridges. In hairy skin, Merkel cell-neurite complexes are found in touch domes, which are epidermal thickenings that form a crescent around guard hairs. SAI neurons form elaborate arborizations, innervating Merkel cells in one or more touch domes (Iggo and Muir, 1969; Lesniak et al., 2014; Tapper, 1965; Woodbury and Koerber, 2007). Merkel cells are mechanosensitive cells that are capable of exciting SAI afferents (Ikeda et al., 2014; Maksimovic et al., 2014); however the basis for synaptic transmission has not been identified. Although Merkel cells express synaptic machinery, they have not been shown to contain clear-core vesicles associated with fast synaptic transmission (Maksimovic et al., 2013). Interestingly, Merkel cells also express several biogenic amines and neuropeptides, leading them to also be classified as neuroendocrine cells of the skin (Halata et al., 2003), however, neuroendocrine functions have yet to be identified.
Ruffini endingsRuffini endings are structures of dense spindle shaped neurite networks in the deep layers of the dermis of both hairy and glabrous skin. Ruffini afferent endings are encased in layers of perineural cells and filled with Schwann cells and a network of endings from a single neuron. The presence and distribution of Ruffini endings in different species is debated, as they are elusive in histology (Johnson, 2001).
Hair types and innervationThe mammalian coat contains four hair follicle types that fall into three classes: guard, awl/auchene and zigzag hairs. Hair types are distinguished by size, number of columns of cells in the medulla, and the number of kinks in the hair shaft (Duverger and Morasso, 2009). Guard hairs, also called tylotrich hairs, are the largest hair type, have two medulla columns, no kinks and compose between 1-3% of the mouse coat. In rodent species, touch domes are found adjacent to guard hairs. Awl and auchene hairs are of medium size, have 2-4 columns in the medulla and make up about 25-30% of the mouse coat. Awl and auchene hairs are indistinguishable except for a single kink in the latter. Zigzag hairs are small, contain one row of medulla cells, have several kinks and comprise roughly 65-70% of the mouse coat (Duverger and Morasso, 2009; Li et al., 2011). Hair types are not only morphologically distinct, but are also innervated by a unique array of neuronal types.
Four types of somatosensory neurons with two distinct histological profiles innervate mammalian hair follicles. Circumferential neurons form rings while lanceolate endings form interdigitated, fence-like structures associated with terminal Schwann cells around the hair follicles. All hair follicles have circumferential endings and a unique cadre of lanceolate endings, which fall into Aβ, Aδ and C-LTMR classes (Abraira and Ginty, 2013; Li et al., 2011). Guard hairs receive Aβ-rapidly adapting (RA) LTMR innervation; awl/auchene receive Aβ-RA LTMR, Aδ-LTMR and C-LTMR; and zigzag hairs receive Aδ and C-LTMR innervation. The response properties of circumferential endings have yet to be identified (Li and Ginty, 2014; Li et al., 2011). As in other hair types, vibrissae are innervated by circumferential and lanceolate endings, but are also richly innervated with Merkel cells, Ruffini-like endings, encapsulated endings and other specialized endings (Ebara et al., 2002).
Functions of Cutaneous Mechanoreceptors
In addition to their end-organ structures, somatosensory neurons can be functionally classified based on physiological properties, including the stimulus modality to which they best respond, conduction velocity and adaptation properties (Figure 1). Aβ and Aδ LTMRs transmit information about gentle touch and are categorized based on physiological responses: rapidly adapting (RA) afferents fire phasically at the beginning and the end of a stimulus. RA afferents are particularly sensitive to vibrations and slip. By contrast, slowly adapting (SA) afferents display sustained firing during a prolonged stimulus, such as constant pressure. In addition to these classes, C-fibers that respond to innocuous touch have been identified in hairy skin. These are known as C-LTMRs in mice and C-tactile afferents in humans. The significance of and the relationship between C-LTMRs and C-tactile afferents are unclear at this time (Liu et al., 2007; Vrontou et al., 2013; Wessberg et al., 2003).
In glabrous skin, RA afferents are associated with Meissner corpuscles and Pacinian corpuscles. Meissner afferents respond best to stimuli moving across their receptive field, allowing them to encode texture. Meissner corpuscles have small receptive fields and respond well to moving and low frequency vibratory stimuli, triggering the sensation of flutter. Pacinian corpuscles respond best to sudden changes in skin pressure and high frequency vibrations, and are thought to contribute information about digit and joint positions. Pacinian corpuscles have the properties of having very low thresholds for activation and very little spatial resolution (Brisben et al., 1999; Johnson, 2001). Unlike Meissner corpuscles, Pacinian corpuscles respond to distant stimuli conducted through bone (Macefield, 2005). This feature is due to the exquisite sensitivity of Pacinian corpuscles and to their deep position within the dermis. These traits also cause Pacinian corpuscles to facilitate the transmission of information about attributes of distant objects during tool use, such as the texture of an object that is being manipulated with forceps or the soil below a shovel (Johnson, 2001). Meissner and Pacinian corpuscles also differ in their frequency response properties. Meissner corpuscles respond best to low frequency vibrations with optimal responses in the 40-60 Hz range whereas Pacinian corpuscles respond to higher frequency ranges with optimal responses at the frequency range of 200-300 Hz (Johnson et al., 2000).
In the hairy skin, RA afferents and C-LTMRs associate with hair follicles to detect hair movement. As described above, three distinct lanceolate types innervate hairs including Aβ-RA LTMRs, Aδ-LTMRs and C-LTMRs. While Aβ-RA LTMRs and C-LTMRs encircle the entire hair follicle, Aδ-LTMRS have recently been found to polarize around the caudal side of zizag and awl/auchene hairs. These afferents are exquisitely sensitive to hair movement in the rostral direction (Rutlin et al., 2014). C-LTMRs also form lanceolate endings around coat hairs (Abraira and Ginty, 2013; Li et al., 2011). Stimulation of these fibers is hypothesized to be associated with affective touch, such as in maternal grooming (Vrontou et al., 2013).
At least two types of SA afferents innervate mammalian skin. SAI afferents innervate Merkel cells in both hairy and glabrous skin. SAI afferents display the highest spatial acuity amongst mechanosensory afferents and are thought to encode information about object edges and curvature. SAII afferents respond to skin stretch, and are believed to provide information about finger positions and handgrip. SAII afferents are hypothesized to terminate in Ruffini endings. Microneurography studies in humans have identified SAII responses; however, the presence of SAII responses are contested in other species, causing this to be the least studied cutaneous mechanoreceptor type (Chambers et al., 1972; Johnson, 2001; Koltzenburg et al., 1997; Wellnitz et al., 2010).
Many nociceptors are polymodal sensory neurons that can respond to multiple modalities including mechanical, thermal and chemical stimuli (Cain et al., 2001). Nociceptors have high stimulus activation thresholds and slow inactivation kinetics. The majority of nociceptive neurons are unmyelinated C-fibers, however a subset of Aδ fibers, also known as a mechanonociceptor (AM) fibers, respond to noxious mechanical and thermal stimuli. The end organs of AM fibers are unknown.
Central projections of peripheral mechanosensitive neurons
How information about touch is transmitted to and integrated in the central nervous system is an intriguing open question. A labeled line code where sensory organs relay singular aspects of touch is likely too simplistic to account for the richness of cutaneous sensations. Much research has focused on single unit recordings of sensory fibers to determine response properties to stimuli, but it is unknown precisely how the central nervous system processes these inputs.
In the classical view of touch transduction, LTMR axons branch directly into the dorsal columns via the direct path and terminate in dorsal column nuclei in the hindbrain. From there, information feeds forward via second order neurons to the medial lemniscus of the thalamus where tertiary neurons send signals to the somatosensory cortex. LTMR axons also send collaterals to deep layers of the spinal cord dorsal horn. Little is known about the molecular identities of the spinal cord interneurons with which LTMRs synapse, or whether initial processing of touch information occurs within the spinal cord. Other projection pathways have been identified in the spinal cord, suggesting that the classic model may be too simplistic (Abraira and Ginty, 2013). The first is a “postsynaptic dorsal column pathway” where LTMRs first synapse in the dorsal horn of the spinal cord and second order neurons send projections to the hindbrain via the dorsal columns. The second pathway is the spinocervical tract, in which dorsal horn neurons send axons to the lateral cervical nuclei and then to the ventral posterior lateral nucleus of the thalamus via the medial lemniscus. The significance and relative contributions of these alternate pathways has yet to be determined, however, these open up the possibility of initial touch processing occurring within the spinal cord.
How are somatosensory afferents capable of detecting mechanical signals and converting these into action potentials? This question has been challenging since the discovery of mechanoreceptive neurons in the nineteen century. Recent advances in the molecular and biophysical study of touch reception has begun to address this long-standing mystery.
Mechanically activated ion channels can initiate the process of mechanical signal detection. Ion channels are macromolecular pores in the cell membrane. Mechanical stimulation of the plasma membrane opens mechanotransduction channels, leading to an increase in ion conductance and depolarizing the neuron’s membrane potential. This series of processes converts mechanical stimulation into electrical signals in the cell membrane.
Mechanotransduction channels in vertebrates have remained elusive for decades. In invertebrates, transient receptor potential (TRP) channels and degenerin and epithelial Na+ channel (DEG/ENaC) are bona fide mechanotransduction channels that are necessary and sufficient to confer mechanosensitivity in cells. The acid sensing ion channels (ASICs), which are DEG/ENaC homologues in vertebrates, also gathered attention as candidate mechanotransduction channels. ASIC and TRP channels have been examined extensively in mammalian touch receptors, but do not appear to be essential for mechanosensory transduction. However, recent work identified proteins of the Piezo family as mechanically activated ion channels (Coste et al., 2010). Piezo genes are broadly expressed in non-mammalian cells and in a variety of mechanosensitive tissues. Three lines of evidence illustrate that Piezo channels, particularly Piezo2, are important for mammalian touch reception.
First, Piezo2 channels are expressed in touch receptors, including Merkel cells and a subset of somatosensory neurons. In Merkel cell-neurite complexes, both the sensory terminals and Merkel cells express Piezo2 (Ranade et al., 2014b; Woo et al., 2014). The sensory terminal of Meissner corpuscles also expresses Piezo2. In hairy skin, Aβ-RA-LTMR lanceolate endings and circumferential fibers express this molecule (Ranade et al., 2014b).
Second, Piezo2 is necessary for the mechanosensitivity of touch receptors. Selective genetic deletion of Piezo2 in mouse Merkel cells abolishes mechanically activated currents in vitro (Woo et al., 2014), and blocking Piezo2 activity in Merkel cells of rat whisker follicles exhibited similar results in situ (Ikeda et al., 2014). Similarly, genetic deletion of Piezo2 in DRG neurons dramatically reduces the proportion of neurons that display rapidly inactivating mechanotransduction currents, a hallmark of LTMRs (Ranade et al., 2014b). By contrast, slowly and intermediately inactivating currents, which are found in nociceptors, are unchanged in conditional Piezo2 knockout mice. These findings suggest that Piezo2 is required for mechanotransduction in LTMRs but that Piezo2-independent mechanisms mediate mechanically activated currents in other DRG neurons.
Finally, Piezo2 is required in mechanosensory function. In Merkel cell-neurite complexes, SAI afferents whose Merkel cells lack Piezo2 still exhibit action potentials; however, they show intermediate adaptation characteristics compared with control genotypes (Maksimovic et al., 2014; Woo et al., 2014). Deletion of Piezo2 in both Merkel cells and LTMRs completely abolishes mechanically evoked responses in many LTMRs, and decreases the touch-evoked activity in those afferents that retain some mechanosensitivity (Ranade et al., 2014b). Moreover, mechanically evoked responses in Aδ nociceptors are also decreased by eliminating Piezo2 (Ranade et al., 2014b). By contrast, mechanically evoked firings are normal in C fibers of Piezo2 knockout mice. These findings support the notion that Piezo2 is particularly important for gentle touch reception rather than nociception.
The contribution of Piezo2 in touch sensation is also supported by behavioral experiment in rodents. Mice that selectively lack Piezo2 in epidermal Merkel cells display higher thresholds to gentle touch stimuli (1.0-1.5 g), but the sensitivity to suprathreshold mechanical stimuli remains intact (Woo et al., 2014). The disruption of Piezo2 in both sensory neurons and Merkel cells causes reduced mechanical sensitivity up to 3 g (Ranade et al., 2014b). In both cases, withdrawal responses to larger forces (>4 g) remain intact (Figure 2). Knocking down Piezo2 in rat whisker follicles by injecting shRNA lentiviral particles also decreases behavioral avoidance to mechanical stimulation (Ikeda et al., 2014).
Collectively, these studies indicate that Piezo2 plays a critical role in detecting touch in several types of mammalian touch receptors. A recent study also found a physical interaction between Piezo2 and a protein tether that amplifies mechanical displacement (Poole et al., 2014). Further studies are needed to understand how Piezo2 channels are gated in mammalian touch receptors.
Neural versus perceptual responses to touch stimuli
Although electrophysiological studies have been instrumental for analyzing the function of cell types and molecules in mammalian touch reception, behavioral assays are required to assess the importance of these cells and molecules to sensory signaling in the intact nervous system. Subjective perception is important for guiding appropriate behavioral outputs in response to environmental stimuli. For example, a painful stimulus causes a typical avoidance behavior like a flinch. Based on this notion, an experimenter quantifies the number of avoidance behaviors and uses it as an index to evaluate the intensity of pain. By modifying behavioral assays used in pain studies, researchers can examine subjective gentle touch perception. As described below, several behavioral assays have been developed to assess tactile responsiveness in rodents.
The Von Frey test is a widely utilized behavioral assay to measure perceptual mechanical thresholds. In this test, an experimenter uses a variety of filaments of specific diameters to mechanically stimulate test animals. Generally speaking, a fiber-like filament buckles at a mechanical load that is determined by its diameter. By using a variety of filaments with different diameters, an experimenter can exert different magnitudes of mechanical stimulation to body sites. In rodent models, the most frequently used region for testing touch sensitivity is the hind paw. An experimenter counts the number of withdrawals preceded by the mechanical stimulus. The magnitude of applied force that produces 50% paw withdrawal is a measure of perceptual threshold (Dixon, 1980). The Von Frey test is commonly used in recent literature (Garrison et al., 2012; Zheng et al., 2012).
A cotton swab test is an alternative method to measure the sensitivity to mechanical stimulus. The tip of cotton swab is puffed out until it has a light furry appearance that can uniformly stimulate the paw (Garrison et al., 2012). The experimenter gently touches or strokes the hind paw of animals and quantifies the number of withdrawals. This stimulus is more naturalistic rather than giving a localized stimulus as with the Von Frey filament. The cotton swab has been employed in human experiments to examine hypersensitivity to innocuous mechanical stimulations [known as mechanical allodynia (Treede and Cole, 1993)].
The adhesive tape removal test measures how quickly an animal can detect a continuous mechanical stimulus. The experimenter cuts adhesive tape into tiny pieces [for example, 30x40 mm for the paw (Bouet et al., 2009)] and attaches the tape strip onto the paw or the back (Ranade et al., 2014b). The experimenter then observes the animal for the presence of paw shakes (Bradbury et al., 2002) or counts the number of attempts to remove the tape (Ranade et al., 2014b).
The texture preference test examines the sensitivity to surface roughness. An experimenter prepares sandpaper of two different grits and carpets them onto the floor of the testing arena. Test animals are placed in the testing arena and the experimenter quantifies the duration spent on each texture. Based on the conditioned place preference paradigms, test subjects tend to spend more time in rewarding places [in this case, comfortable textures are assumed to be a reward (Wetzel et al., 2007)]. If test subjects cannot discriminate surface textures, they spend approximately equal time on both textures. In mouse models, it has been reported that female mice prefer rough textures, while male mice show no preference (Maricich et al., 2012).
A recently developed vibration test examines the perceptual sensitivity to vibratory stimulation. This test also employs a two-choice preference paradigm. An experimenter prepares two pairs of platforms and vibrators. The vibrator is attached to the bottom of the platform via a plate spring. In the experiment, one of the vibrators is actuated at a set frequency and the other one is left static. Recent studies showed that mice tend to avoid vibratory stimulus at 150 Hz (Ranade et al., 2014b), but mice that have Piezo2 deleted in sensory neurons do not show this avoidance behavior.
The advantage of behavioral assays to physiology experiments is that they can estimate the neural correlates of touch sensitivity and perceptual modalities. Recordings from sensory afferent responses by employing an ex vivo preparation [e.g., skin-nerve preparation (Zimmermann et al., 2009)] or in vivo preparation [in the dorsal root ganglion (Boada and Woodbury, 2007)] are capable of providing a better understanding of the relationship between the subtype of sensory afferents and characteristics of mechanical stimuli. By combining behavioral responses with neural responses from the same animals, we may answer whether touch coding is based on a labeled line theory or pattern theory.
The current disadvantage of behavioral assays in rodent models is that it is not possible to give a localized stimulus to a single receptive field. For example, the size of a receptive field in mice is generally less than < 0.3 mm2 (Wellnitz et al., 2010), which is one-thirtieth the size of receptive field of human SAI afferents in hairy skin [about 10 mm2 (Johansson, 1978)]. This makes it difficult to directly compare neural responses to focused stimulus with behavioral responses to blunt mechanical stimulus.
Recent findings have revealed details about the mechanisms underlying the sense of touch. Peripheral somatosensory neurons and their end organs have anatomically distinct morphology and responses to mechanical stimuli. They encode various kinds of mechanical modalities into distinct neural responses. The recent identification of Piezo2 as required for mechanically activated currents in touch receptors has propelled the field forward by promoting an understanding of the underlying encoding mechanisms of mechanoreceptors; however, the data indicate that additional mechanosensitive channels remain to be identified. Behavioral assays work as a window to clarify the causal relationship between neural responses and behaviors. Currently, we understand the detailed classification of mechanoreceptive cells and the response characteristics of associated sensory neurons. One of the next major questions is how somatosensory information is integrated and utilized in the spinal cord and the central nervous system for feeding, rearing, avoiding or emotionally bonding with others.
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