Slowly Adapting Type I Afferents Research Articles

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.

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.

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.

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.

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.

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.

Cutaneous Afferents From the Monkeys Fingers: Responses to Tangential and Normal Forces

Control of tangential force plays a key role in everyday manipulations. In anesthetized monkeys, forces tangential to the skin were applied at a range of magnitudes comparable to those used in routine manipulations and in eight different directions. The paradigm used enabled separation of responses to tangential force from responses to the background normal force. For slowly adapting type I (SAI) afferents, tangential force responses ranged from excitatory through no response to suppression, with both a static and dynamic component. For fast adapting type I (FAI) afferents, responses were dynamic and excitatory only. Responses of both afferent types were scaled by tangential force magnitude, elucidating the neural basis for previous human psychophysical scaling data. Most afferents were direction selective with a range of preferred directions and a range in sharpness of tuning. Both the preferred direction and the degree of tuning were independent of the background normal force. Preferred directions were distributed uniformly over 360 degrees for SAI afferents, but for FAI afferents they were biased toward the proximo-ulnar direction. Afferents from all over the glabrous skin of the distal segment of the finger responded; there was no evident relationship between the position of an afferent's receptive field on the finger and its preferred direction or its degree of tuning. Nor were preferred directions biased either toward or away from the receptive field center. In response to the relatively large normal forces, some afferents saturated and others did not, regardless of the positions of their receptive fields. Total afferent response matched human psychophysical scaling functions for normal force.

Monkey cutaneous SAI and RA responses to raised and depressed scanned patterns: effects of width, height, orientation, and a raised surround.

Monkey cutaneous SAI and RA responses to raised and depressed scanned patterns: effects of width, height, orientation, and a raised surround. J. Neurophysiol. 78: 2503-2517, 1997. The aim of this study was to examine the slowly adapting type I (SAI) and rapidly adapting (RA) primary afferent representation of raised and depressed surface features. Isolated, raised, and depressed squares and small raised squares with a circular surround were scanned across the receptive fields of SAI and RA mechanoreceptive afferents innervating the distal fingerpads of the rhesus monkey. Pattern height ranged from -620 to +620 micron and width ranged from 0.2 to 7.0 mm. The surround radii ranged from 3.0 to 7.0 mm. Previous combined psychophysical and neurophysiological studies have provided evidence that SAI afferent responses are responsible for the perception of spatial form and texture and that RA afferents are responsible for the detection of stimuli that produce minute skin motion (flutter, slip, microgeometric surface features). Our results strengthen these hypotheses. Response properties shared by both SAI and RA afferent types were that both responded only to the edges of the larger raised and depressed patterns, both responded to falling edges half as vigorously as to rising edges, both responded to rising and falling edges with impulse rates that were proportional to the sine of the angle between the edge and the scanning direction, and both had suppressed responses to a small raised surface feature when a raised surround was closer than 6 mm. Response differences consistent with the hypothesis that SAI afferents are specialized for the representation of form were that SAI responses were confined to areas around the features that evoked them in areas that were 40-50% smaller than the comparable RA response areas, SAI responses were more than four times more sensitive to stimulus height than were RA afferents over the range from 280 to 620 micron, and SAI (but not RA) afferents responded 20-50% more vigorously to corners than to edges. Response differences consistent with the hypothesis that RA afferents are specialized for the detection of minute surfaces features were that only RA afferents responded to very small surface depressions, depressed squares 0.8 mm wide, that were detectable by palpation. Mechanisms underlying the many differences in SAI and RA response properties are discussed.

Neural Coding Mechanisms in Tactile Pattern Recognition: The Relative Contributions of Slowly and Rapidly Adapting Mechanoreceptors to Perceived Roughness

Tactile pattern recognition depends on form and texture perception. A principal dimension of texture perception is roughness, the neural coding of which was the focus of this study. Previous studies have shown that perceived roughness is not based on neural activity in the Pacinian or cutaneous slowly adapting type II (SAII) neural responses or on mean impulse rate or temporal patterning in the cutaneous slowly adapting type I (SAI) or rapidly adapting (RA) discharge evoked by a textured surface. However, those studies found very high correlations between roughness scaling by humans and measures of spatial variation in SAI and RA firing rates. The present study used textured surfaces composed of dots of varying height (280-620 micron) and diameter (0.25-2.5 mm) in psychophysical and neurophysiological experiments. RA responses were affected least by the range of dot diameters and heights that produced the widest variation in perceived roughness, and these responses could not account for the psychophysical data. In contrast, spatial variation in SAI impulse rate was correlated closely with perceived roughness over the whole stimulus range, and a single measure of SAI spatial variation accounts for the psychophysical data in this (0.974 correlation) and two previous studies. Analyses based on the possibility that perceived roughness depends on both afferent types suggest that if the RA response plays a role in roughness perception, it is one of mild inhibition. These data reinforce the hypothesis that SAI afferents are mainly responsible for information about form and texture whereas RA afferents are mainly responsible for information about flutter, slip, and motion across the skin surface.

II. Identification of afferents contributing to sympathetically evoked activity in wide-dynamic-range neurons

The purpose of this study was to determine which types of mechanoreceptor afferents contribute to sympathetically evoked activity in wide-dynamic-range (WDR) neurons — the spinal neurons thought to mediate sympathetically maintained pain. The experimental approach was to record and compare activity evoked in single WDR neurons, hair afferents, and slowly adapting type I (SAI) afferents in anesthetized cats. During electrical stimulation of the sympathetic trunk, WDR neurons responded with either an early transient burst of activity, sustained activity, or both. The early transient response was observed only in neurons with piloerection in the receptive field; this response had a similar time course to sympathetically evoked activity in hair afferents with piloerection in the receptive field. The sustained response that occurred in some WDR neurons was independent of piloerection and was similar in time course to the response evoked in SAI afferents by sympathetic stimulation. We conclude that hair and SAI afferents contribute to different components of sympathetically evoked activity in WDR neurons and that both types of afferents are likely to be involved in sympathetically maintained pain in humans.