Slowly Adapting Type I Research Articles

Modeling Long-term Spike Frequency Adaptation in SA-I Afferent Neurons Using an Izhikevich-based Biological Neuron Model.

To develop a biomimetic artificial tactile sensing system capable of detecting sustained mechanical touch, we propose a novel biological neuron model (BNM) for slowly adapting type I (SA-I) afferent neurons. The proposed BNM is designed by modifying the Izhikevich model to incorporate long-term spike frequency adaptation. Adjusting the parameters renders the Izhikevich model describing various neuronal firing patterns. We also search for optimal parameter values for the proposed BNM to describe firing patterns of biological SA-I afferent neurons in response to sustained pressure longer than 1-second. We obtain the firing data of SA-I afferent neurons for six different mechanical pressure ranging from 0.1 mN to 300 mN from the ex-vivo experiment on SA-I afferent neurons in rodents. Upon finding the optimal parameters, we generate spike trains using the proposed BNM and compare the resulting spike trains to those of biological SA-I afferent neurons using the spike distance metrics. We verify that the proposed BNM can generate spike trains showing long-term adaptation, which is not achievable by other conventional models. Our new model may offer an essential function to artificial tactile sensing technology to perceive sustained mechanical touch.

How Tactile Afferents in the Human Fingerpad Encode Tangential Torques Associated with Manipulation: Are Monkeys Better than Us?

Dexterous object manipulation depends critically on information about forces normal and tangential to the fingerpads, and also on torque associated with object orientation at grip surfaces. We investigated how torque information is encoded by human tactile afferents in the fingerpads and compared them to 97 afferents recorded in monkeys (n = 3; 2 females) in our previous study. Human data included slowly-adapting Type-II (SA-II) afferents, which are absent in the glabrous skin of monkeys. Torques of different magnitudes (3.5-7.5 mNm) were applied in clockwise and anticlockwise directions to a standard central site on the fingerpads of 34 human subjects (19 females). Torques were superimposed on a 2, 3, or 4 N background normal force. Unitary recordings were made from fast-adapting Type-I (FA-I, n = 39), and slowly-adapting Type-I (SA-I, n = 31) and Type-II (SA-II, n = 13) afferents supplying the fingerpads via microelectrodes inserted into the median nerve. All three afferent types encoded torque magnitude and direction, with torque sensitivity being higher with smaller normal forces. SA-I afferent responses to static torque were inferior to dynamic stimuli in humans, while in monkeys the opposite was true. In humans this might be compensated by the addition of sustained SA-II afferent input, and their capacity to increase or decrease firing rates with direction of rotation. We conclude that the discrimination capacity of individual afferents of each type was inferior in humans than monkeys which could be because of differences in fingertip tissue compliance and skin friction.SIGNIFICANCE STATEMENT We investigated how individual human tactile nerve fibers encode rotational forces (torques) and compared them to their monkey counterparts. Human hands, but not monkey hands, are innervated by a tactile neuron type (SA-II afferents) specialized to encode directional skin strain yet, so far, torque encoding has only been studied in monkeys. We find that human SA-I afferents were generally less sensitive and less able to discriminate torque magnitude and direction than their monkey counterparts, especially during the static phase of torque loading. However, this shortfall in humans could be compensated by SA-II afferent input. This indicates that variation in afferent types might complement each other signaling different stimulus features possibly providing computational advantage to discriminate stimuli.

From Skin Mechanics to Tactile Neural Coding: Predicting Afferent Neural Dynamics During Active Touch and Perception.

First order cutaneous neurons allow object recognition, texture discrimination, and sensorimotor feedback. Their function is well-investigated under passive stimulation while their role during active touch or sensorimotor control is understudied. To understand how human perception and sensorimotor controlling strategy depend on cutaneous neural signals under active tactile exploration, the finite element (FE) hand and Izhikevich neural dynamic model were combined to predict the cutaneous neural dynamics and the resulting perception during a discrimination test. Using in-vivo microneurography generated single afferent recordings, 75% of the data was applied for the model optimization and another 25% was used for validation. By using this integrated numerical model, the predicted tactile neural signals of the single afferent fibers agreed well with the microneurography test results, achieving the out-of-sample values of 0.94 and 0.82 for slowly adapting type I (SAI) and fast adapting type I unit (FAI) respectively. Similar discriminating capability with the human subject was achieved based on this computational model. Comparable performance with the published numerical model on predicting the cutaneous neural response under passive stimuli was also presented, ensuring the potential applicability of this multi-level numerical model in studying the human tactile sensing mechanisms during active touch. The predicted population-level 1st order afferent neural signals under active touch suggest that different coding strategies might be applied to the afferent neural signals elicited from different cutaneous neurons simultaneously.

Sex-Dependent Reduction in Mechanical Allodynia in the Sural-Sparing Nerve Injury Model in Mice Lacking Merkel Cells.

Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Aβ slowly adapting type I (SAI) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Aβ SAI LTMR action potentials that are transmitted to the CNS, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch of plantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory but are relatively preserved in nearby hairy skin innervated by the spared sural nerve. Using a genetic Merkel cell KO mouse model, we subsequently examined the importance of intact Merkel cell-Aβ complexes to SNI-associated mechanical hypersensitivity in skin innervated by the spared neurons. We found that, in the absence of Merkel cells, mechanical allodynia was partially reduced in male mice, but not female mice, under sural-sparing SNI conditions. Our results suggest that Merkel cell-Aβ afferent complexes partially contribute to mechanical allodynia produced by peripheral nerve injury, and that they do so in a sex-dependent manner.SIGNIFICANCE STATEMENT Merkel discs or Merkel cell-Aβ afferent complexes are mechanosensory end organs in mammalian skin. Yet, it remains unknown whether Merkel cells or their associated sensory neurons play a role in the mechanical hypersensitivity caused by peripheral nerve injury. We found that male mice genetically lacking Merkel cell-Aβ afferent complexes exhibited a reduction in mechanical allodynia after nerve injury. Interestingly, this behavioral phenotype was not observed in mutant female mice. Our study will facilitate understanding of mechanisms underlying neuropathic pain.

Neurodynamic analysis of Merkel cell-neurite complex transduction mechanism during tactile sensing.

The present study aimed to identify the mechanism of tactile sensation by analyzing the regularity of the firing pattern of Merkel cell-neurite complex (MCNC) under the stimulation of different compression depths. The fingertips were exposed to the contact pressure of a spherical object to sense external stimuli in this study. The distribution structure of slowly adapting type I (SAI) mechanoreceptors was considered for analyzing the neural coding of tactile stimuli, especially the firing pattern of SAI neural network for perceiving the external stimulation. The numerical simulation results showed that (1) when the skin was pressed by the same sphere and the depth of the pressing finger skin and position of the force application point remained unchanged, the firing rate of the neuron depended on the synergistic effect of the number of receptors connected with the neuron and the distance between the neuron and the force application point. (2) When the fingertip was pressed by the same sphere at a constant depth and the different contact position, the overall firing rate of the MCNC neural network increased with the number of SAI mechanoreceptors in the area where the force application point was located.

Computation predicts rapidly adapting mechanotransduction currents cannot account for tactile encoding in Merkel cell-neurite complexes.

Distinct firing properties among touch receptors are influenced by multiple, interworking anatomical structures. Our understanding of the functions and crosstalk of Merkel cells and their associated neurites—the end organs of slowly adapting type I (SAI) afferents—remains incomplete. Piezo2 mechanically activated channels are required both in Merkel cells and in sensory neurons for canonical SAI responses in rodents; however, a central unanswered question is how rapidly inactivating currents give rise to sustained action potential volleys in SAI afferents. The computational model herein synthesizes mechanotransduction currents originating from Merkel cells and neurites, in context of skin mechanics and neural dynamics. Its goal is to mimic distinct spike firing patterns from wildtype animals, as well as Atoh1 knockout animals that completely lack Merkel cells. The developed generator function includes a Merkel cell mechanism that represents its mechanotransduction currents and downstream voltage-activated conductances (slower decay of current) and a neurite mechanism that represents its mechanotransduction currents (faster decay of current). To mimic sustained firing in wildtype animals, a longer time constant was needed than the 200 ms observed for mechanically activated membrane depolarizations in rodent Merkel cells. One mechanism that suffices is to introduce an ultra-slowly inactivating current, with a time constant on the order of 1.7 s. This mechanism may drive the slow adaptation of the sustained response, for which the skin’s viscoelastic relaxation cannot account. Positioned within the sensory neuron, this source of current reconciles the physiology and anatomical characteristics of Atoh1 knockout animals.

A Digital Hardware Realization for Spiking Model of Cutaneous Mechanoreceptor.

Inspired by the biology of human tactile perception, a hardware neuromorphic approach is proposed for spiking model of mechanoreceptors to encode the input force. In this way, a digital circuit is designed for a slowly adapting type I (SA-I) and fast adapting type I (FA-I) mechanoreceptors to be implemented on a low-cost digital hardware, such as field-programmable gate array (FPGA). This system computationally replicates the neural firing responses of both afferents. Then, comparative simulations are shown. The spiking models of mechanoreceptors are first simulated in MATLAB and next the digital neuromorphic circuits simulated in VIVADO are also compared to show that obtained results are in good agreement both quantitatively and qualitatively. Finally, we test the performance of the proposed digital mechanoreceptors in hardware using a prepared experimental set up. Hardware synthesis and physical realization on FPGA indicate that the digital mechanoreceptors are able to replicate essential characteristics of different firing patterns including bursting and spiking responses of the SA-I and FA-I mechanoreceptors. In addition to parallel computation, a main advantage of this method is that the mechanoreceptor digital circuits can be implemented in real-time through low-power neuromorphic hardware. This novel engineering framework is generally suitable for use in robotic and hand-prosthetic applications, so progressing the state of the art for tactile sensing.

Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes.

Peripheral sensory neurons show incredible phenotypic and functional diversity that is initiated early by cell-autonomous and local environmental factors found within the DRG. However, the contribution of target tissues to subsequent sensory neuron development remains unknown. We show that Merkel cells are required for the molecular and functional maturation of the SAI neurons that innervate them. We also show that this process is controlled by BDNF signaling. These findings provide new insights into the regulation of somatosensory neuron development and reveal a novel way in which Merkel cells participate in mechanosensation.

Effects of changing skin mechanics on the differential sensitivity to surface compliance by tactile afferents in the human finger pad.

It is not known how changes in skin mechanics affect the responses of cutaneous mechanoreceptors in the finger pads to compression forces. We used venous occlusion to change the stiffness of the fingers and investigated whether this influenced the firing of low-threshold mechanoreceptors to surfaces of differing stiffness. Unitary recordings were made from 10 slowly adapting type I (SAI), 10 fast adapting type I (FAI) and 9 slowly adapting type II (SAII) units via tungsten microelectrodes inserted into the median nerve at the wrist. A servo-controlled stimulator applied ramp-and-hold forces (1, 2, and 4 N) at a constant loading and unloading rate (2 N/s) via a flat 2.5-cm-diameter silicone disk over the center of the finger pad. Nine silicone disks (objects), varying in compliance, were used. Venous occlusion, produced by inflating a sphygmomanometer cuff around the upper arm to 40 ± 5 mmHg, was used to induce swelling of the fingers and increase the compliance of the finger pulp. Venous occlusion had no effect on the firing rates of the SAI afferents, nor on the slopes of the relationship between mean firing rate and object compliance at each amplitude, but did significantly reduce the slopes for the FAI afferents. Although the SAII afferents possess a poor capacity to encode changes in object compliance, mean firing rates were significantly lower during venous occlusion. The finding that venous occlusion had no effect on the firing properties of SAI afferents indicates that these afferents preserve their capacity to encode changes in object compliance, despite changes in skin mechanics.

Mechanotransduction in epidermal Merkel cells.

The cellular and molecular basis of vertebrate touch reception remains least understood among the traditional five senses. Somatosensory afferents that innervate the skin encode distinct tactile qualities, such as flutter, slip, and pressure. Gentle touch is thought to be transduced by somatosensory afferents whose tactile end organs selectively filter mechanical stimuli. These tactile end organs comprise afferent terminals in association with non-neuronal cell types such as Merkel cells, keratinocytes, and Schwann cells. An open question is whether these non-neuronal cells serve primarily as passive mechanical filters or whether they actively participate in mechanosensory transduction. This question has been most extensively studied in Merkel cells, which are epidermal cells that complex with sensory afferents in regions of high tactile acuity such as fingertips, whisker follicles, and touch domes. Merkel cell-neurite complexes mediate slowly adapting type I (SAI) responses, which encode sustained pressure and represent object features with high fidelity. How Merkel cells contribute to unique SAI firing patterns has been debated for decades; however, three recent studies in rodent models provide some direct answers. First, whole-cell recordings demonstrate that Merkel cells are touch-sensitive cells with fast, mechanically activated currents that require Piezo2. Second, optogenetics and intact recordings show that Merkel cells mediate sustained SAI firing. Finally, loss-of-function studies in transgenic mouse models reveal that SAI afferents are also touch sensitive. Together, these studies identify molecular mechanisms of mechanotransduction in Merkel cells, reveal unexpected functions for these cells in touch, and support a revised, two-receptor site model of mechanosensory transduction.

Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors.

Touch submodalities, such as flutter and pressure, are mediated by somatosensory afferents whose terminal specializations extract tactile features and encode them as action potential trains with unique activity patterns1. Whether non-neuronal cells tune touch receptors through active or passive mechanisms is debated. Terminal specializations are thought to function as passive mechanical filters analogous to the cochlea’s basilar membrane, which deconstructs complex sounds into tones that are transduced by mechanosensory hair cells. The model that cutaneous specializations are merely passive has been recently challenged because epidermal cells express sensory ion channels and neurotransmitters2,3; however, direct evidence that epidermal cells excite tactile afferents is lacking. Epidermal Merkel cells display features of sensory receptor cells4,5 and make “synapse-like” contacts5,6 with slowly adapting type I (SAI) afferents7–9. These complexes, which encode spatial features such as edges and texture1, localize to skin regions with high tactile acuity, including whisker follicles, fingertips and touch domes. Here, we show that Merkel cells actively participate in touch reception in mice. First, Merkel cells display fast, touch-evoked mechanotransduction currents. Second, optogenetic approaches in intact skin show that Merkel cells are both necessary and sufficient for sustained action-potential firing in tactile afferents. Third, recordings from touch-dome afferents lacking Merkel cells demonstrate that Merkel cells confer high-frequency responses to dynamic stimuli and enable sustained firing. These data are the first to directly demonstrate a functional, excitatory connection between epidermal cells and sensory neurons. Together, these findings indicate that Merkel cells actively tune mechanosensory responses to facilitate high spatio-temporal acuity. Moreover, our results suggest a division of labour in the Merkel cell-neurite complex: Merkel cells signal static stimuli, such as pressure, whereas sensory afferents transduce dynamic stimuli, such as moving gratings. Thus, the Merkel-cell neurite complex is unique sensory structure with two receptor cell types specialized for distinct elements of discriminative touch.

Computation identifies structural features that govern neuronal firing properties in slowly adapting touch receptors

Touch is encoded by cutaneous sensory neurons with diverse morphologies and physiological outputs. How neuronal architecture influences response properties is unknown. To elucidate the origin of firing patterns in branched mechanoreceptors, we combined neuroanatomy, electrophysiology and computation to analyze mouse slowly adapting type I (SAI) afferents. These vertebrate touch receptors, which innervate Merkel cells, encode shape and texture. SAI afferents displayed a high degree of variability in touch-evoked firing and peripheral anatomy. The functional consequence of differences in anatomical architecture was tested by constructing network models representing sequential steps of mechanosensory encoding: skin displacement at touch receptors, mechanotransduction and action-potential initiation. A systematic survey of arbor configurations predicted that the arrangement of mechanotransduction sites at heminodes is a key structural feature that accounts in part for an afferent's firing properties. These findings identify an anatomical correlate and plausible mechanism to explain the driver effect first described by Adrian and Zotterman. DOI: http://dx.doi.org/10.7554/eLife.01488.001.

Touch Activates Mechanosensitive Ion Channels in Merkel Cells In Vitro

Merkel cell-neurite complexes are gentle touch receptors that mediate slowly adapting type I (SAI) responses. Since their description in 1875, Merkel cells have been proposed to be mechanosensory cells that transduce mechanical stimuli into electrical signals that activate somatosensory neurons. Consistent with this model, conditional knockout mice that lack Merkel cells show the loss of touch-evoked SAI responses. Moreover, in vitro studies on cultured Merkel cells report calcium elevation in Merkel cells in response to swelling or membrane stretch. Previous studies support the contribution of Merkel cells to touch sensation, however, the central question of whether Merkel cells are intrinsically touch sensitive is unanswered. To tackle this problem, we performed live-cell imaging and electrophysiological recordings from mouse Merkel cells. Merkel cells were dissociated from the epidermal skin of transgenic Atoh1/nGFP mice, whose Merkel cells selectively express green fluorescent protein. GFP-positive cells were purified using fluorescence-activated cell sorting and cultured for 1-5 days. Individual Merkel cells were stimulated by families of displacements (≦0.3-μm steps) with a glass probe driven by a piezoelectric actuator. Touch-evoked responses were monitored with either ratiometric calcium imaging or tight-seal, whole-cell recordings. Merkel cells displayed reversible calcium responses to focal displacements applied to somata. Moreover, electrophysiological recordings demonstrated mechanically activated inward currents at a negative holding potential. Peak inward currents ranged from 107.3-431.3 pA. The 10-90% operating range of these mechanically activated currents was 1.7±0.1 μm (N=10 cells, mean±SE). Like mechanosensitive currents in hair cells and somatosensory neurons, Merkel-cell currents adapted exponentially to sustained stimuli. Quantitative PCR indicated that Merkel cells expressed both Piezo1 and Piezo2 genes. Together, these data demonstrate that Merkel cells are intrinsically mechanosensitive in the absence of other skin cells or somatosensory neurons.

Two sensory channels mediate perception of fingertip force.

In two experiments we examined the ability of humans to exert forces accurately with the fingertips, and to perceive those forces. In experiment 1 participants used visual feedback to apply a range of fingertip forces with the distal pad of the thumb. Participants made magnitude discriminations regarding these forces, and their just noticeable differences were calculated at a series of standards by means of a two-interval, forced-choice tracking paradigm. As the standard increased, participants demonstrated a relative improvement in force discrimination; and the presence of a possible inflection point, at approximately 400 g, suggested that two sensory channels may contribute to performance. If this is the case, the operative channel at low forces is almost certainly the slowly adapting type I (SA-I) channel, while another mechanoreceptor class, the SA-II nail unit, is a plausible mediator of the more accurate performance seen at high force levels. To test this two-channel hypothesis in experiment 2, we hydrated participants' thumbnails in order to reduce nail rigidity and thus prevent stimulation of underlying SA-II mechanoreceptors. This technique was found to reduce sensory accuracy in a force-matching task at high forces (1000 g) while leaving low force matching (100 g) unimpaired. Taken together, these results suggest that two sensory channels mediate the perception of fingertip forces in humans: one channel predominating at low forces (below approximately 400 g) and another responsible for perceiving high forces which is likely mediated by the SA-II nail unit.

Differential sensitivity to surface compliance by tactile afferents in the human finger pad

We undertook a neurophysiological investigation of the responses of low-threshold mechanoreceptors in the human finger pad to surfaces of differing softness. Unitary recordings were made from 26 slowly adapting type I (SAI), 17 fast-adapting type I (FAI), and 9 slowly adapting type II (SAII) afferents via tungsten microelectrodes inserted into the median nerve at the wrist. A servo-controlled stimulator applied ramp-and-hold forces (1, 2, 4 N) at a constant loading and unloading rate (2 N/s) via a flat silicone disc over the center of the finger pad. Nine discs were used, which linearly increased in stiffness across the range. Population responses of the SAI afferents showed the greatest sensitivity to compliance, with a steep monotonic increase in mean firing rate with increasing stiffness (decreasing compliance) of the surface during the loading and plateau (but not unloading) phases. FAI afferents also showed a linear increase in firing during the loading but not unloading phase, although the slope was significantly lower than that of the SAI afferents at all amplitudes. Conversely, SAII afferents were influenced by object compliance only in certain conditions. Given their high density in the finger pads and their linear relationship between firing rate and object compliance during the loading and plateau phases, SAI afferents (together with FAI afferents during the loading phase) are ideally suited to contributing information on surface compliance to the overall estimation of softness, but the SAII afferents appear to play only a minor role.

Responses of cutaneous mechanoreceptors within fingerpad to stimulus information for tactile softness sensation of materials

Softness sensation is one of primitive tactile textures. While the psychophysical characteristics of softness sensation have been thoroughly studied, it is lack of a deep understanding of the underlying neuromechanical principles. On the stimulus-response processes of human fingerpad touching fabrics and the physiological properties of slowly adapting type I (SAIs) cutaneous mechanoreceptors within fingerpad, a fabric-skin-receptor coupling model was built and validated. By the fabric-skin-receptor model a series of numerical experiments was conducted, and how the evoked neural responses of cutaneous mechanoreceptors change with the composite compliance of both fingerpad skin and the materials in contact was investigated. The results indicated that the evoked neural responses of populations of cutaneous mechanoreceptors by the physical stimulus from fabrics were nearly proportional to the perceived softness magnitude, and nonlinearly increased and then decreased with the effective elastic modulus of fabrics or the relative elastic modulus of fabrics to soft tissues within fingerpad, where the nonlinear inflection point depended on the touching force level. Therefore, it concluded that the tactile judgment of the physical information for softness sensation of objects was an encoding of neural responses of populations of SAIs cutaneous mechanoreceptors, and the physical information depended on the mechanical interaction of fingerpad and objects in contact.

Force sensor in simulated skin and neural model mimic tactile SAI afferent spiking response to ramp and hold stimuli

BackgroundThe next generation of prosthetic limbs will restore sensory feedback to the nervous system by mimicking how skin mechanoreceptors, innervated by afferents, produce trains of action potentials in response to compressive stimuli. Prior work has addressed building sensors within skin substitutes for robotics, modeling skin mechanics and neural dynamics of mechanotransduction, and predicting response timing of action potentials for vibration. The effort here is unique because it accounts for skin elasticity by measuring force within simulated skin, utilizes few free model parameters for parsimony, and separates parameter fitting and model validation. Additionally, the ramp-and-hold, sustained stimuli used in this work capture the essential features of the everyday task of contacting and holding an object.MethodsThis systems integration effort computationally replicates the neural firing behavior for a slowly adapting type I (SAI) afferent in its temporally varying response to both intensity and rate of indentation force by combining a physical force sensor, housed in a skin-like substrate, with a mathematical model of neuronal spiking, the leaky integrate-and-fire. Comparison experiments were then conducted using ramp-and-hold stimuli on both the spiking-sensor model and mouse SAI afferents. The model parameters were iteratively fit against recorded SAI interspike intervals (ISI) before validating the model to assess its performance.ResultsModel-predicted spike firing compares favorably with that observed for single SAI afferents. As indentation magnitude increases (1.2, 1.3, to 1.4 mm), mean ISI decreases from 98.81 ± 24.73, 54.52 ± 6.94, to 41.11 ± 6.11 ms. Moreover, as rate of ramp-up increases, ISI during ramp-up decreases from 21.85 ± 5.33, 19.98 ± 3.10, to 15.42 ± 2.41 ms. Considering first spikes, the predicted latencies exhibited a decreasing trend as stimulus rate increased, as is observed in afferent recordings. Finally, the SAI afferent’s characteristic response of producing irregular ISIs is shown to be controllable via manipulating the output filtering from the sensor or adding stochastic noise.ConclusionsThis integrated engineering approach extends prior works focused upon neural dynamics and vibration. Future efforts will perfect measures of performance, such as first spike latency and irregular ISIs, and link the generation of characteristic features within trains of action potentials with current pulse waveforms that stimulate single action potentials at the peripheral afferent.

Sensory Mechanisms in Mammalian Touch Receptor Cells

The sense of touch is critical for hand dexterity that allows mammals to recognize and grasp objects. Different qualities of touch are encoded by sensory neurons with distinct properties. Shapes and curvature are encoded by Merkel cell-neurite complexes, which mediate slowly adapting type I (SAI) responses. Merkel cells, which cluster in fingertips and other highly touch-sensitive skin areas, are enigmatic epidermal cells first described in 1875. The role that these cells play in SAI responses has been debated for 40 years.Based on morphology, Merkel cells are proposed to be mechanosensory cells. If so, Merkel cells should 1) transduce force into membrane-potential changes that gate voltage-activated ion channels and 2) signal afferent neurons through synaptic transmission. Functional studies testing these predictions in intact skin have produced conflicting results. To tackle these questions, my laboratory uses a combination of mouse genetics, in vitro systems and intact electrophysiological recordings. Our in vitro studies have demonstrated that Merkel cells are intrinsically force-sensitive and that voltage-activated channels open downstream of mechanical stimuli. Moreover, Merkel cells express numerous ion channels and presynaptic proteins. Collectively, these results suggest that Merkel cells are capable of serving as touch receptor cells and pave the way to discover transduction mechanisms.To determine whether Merkel cells are necessary for touch responses, we used Cre-loxP technology to generate mice that completely lack Merkel cells in the body skin. We then used an ex vivo skin-nerve preparation to survey the classes of touch-sensitive afferents in the saphenous nerve. Although we found no significant differences in nociceptive sensory fibers, we observed a complete loss of SAI responses among light-touch receptors in mice lacking Merkel cells compared with wild-type mice. These results demonstrate that Merkel cells are required for appropriate sensory coding of light touch.

The Regularity of Sustained Firing Reveals Two Populations of Slowly Adapting Touch Receptors in Mouse Hairy Skin

Touch is initiated by diverse somatosensory afferents that innervate the skin. The ability to manipulate and classify receptor subtypes is prerequisite for elucidating sensory mechanisms. Merkel cell-neurite complexes, which distinguish shapes and textures, are experimentally tractable mammalian touch receptors that mediate slowly adapting type I (SAI) responses. The assessment of SAI function in mutant mice has been hindered because previous studies did not distinguish SAI responses from slowly adapting type II (SAII) responses, which are thought to arise from different end organs, such as Ruffini endings. Thus we sought methods to discriminate these afferent types. We developed an epidermis-up ex vivo skin-nerve chamber to record action potentials from afferents while imaging Merkel cells in intact receptive fields. Using model-based cluster analysis, we found that two types of slowly adapting receptors were readily distinguished based on the regularity of touch-evoked firing patterns. We identified these clusters as SAI (coefficient of variation = 0.78 +/- 0.09) and SAII responses (0.21 +/- 0.09). The identity of SAI afferents was confirmed by recording from transgenic mice with green fluorescent protein-expressing Merkel cells. SAI receptive fields always contained fluorescent Merkel cells (n = 10), whereas SAII receptive fields lacked these cells (n = 5). Consistent with reports from other vertebrates, mouse SAI and SAII responses arise from afferents exhibiting similar conduction velocities, receptive field sizes, mechanical thresholds, and firing rates. These results demonstrate that mice, like other vertebrates, have two classes of slowly adapting light-touch receptors, identify a simple method to distinguish these populations, and extend the utility of skin-nerve recordings for genetic dissection of touch receptor mechanisms.

Encoding of tangential torque in responses of tactile afferent fibres innervating the fingerpad of the monkey

Torsional loads are ubiquitous during everyday dextrous manipulations. We examined how information about torque is provided to the sensorimotor control system by populations of tactile afferents. Torsional loads of different magnitudes were applied in clockwise and anticlockwise directions to a standard central site on the fingertip. Three different background levels of contact (grip) force were used. The median nerve was exposed in anaesthetized monkeys and single unit responses recorded from 66 slowly adapting type-I (SA-I) and 31 fast adapting type-I (FA-I) afferents innervating the distal segments of the fingertips. Most afferents were excited by torque but some were suppressed. Responses of the majority of both afferent types were scaled by torque magnitude applied in one or other direction, with the majority of FA-I afferent responses and about half of SA-I afferent responses scaled in both directions. Torque direction affected responses in both afferent types, but more so for the SA-I afferents. Latencies of the first spike in FA-I afferent responses depended on the parameters of the torque. We used a Parzen window classifier to assess the capacity of the SA-I and FA-I afferent populations to discriminate, concurrently and in real-time, the three stimulus parameters, namely background normal force, torque magnitude and direction. Despite the potentially confounding interactions between stimulus parameters, both the SA-I and the FA-I populations could extract torque magnitude accurately. The FA-I afferents signalled torque magnitude earlier than did the SA-I afferents, but torque direction was extracted more rapidly and more accurately by the SA-I afferent population.