Distribution of Pacini-Like Lamellar Corpuscles in the Vascular Sheath of the Femoral Artery.

Pacinian corpuscles are vibration-sensing mechanoreceptors that are densely distributed in the dermis of the human hand. Although they are also known to occur in various other regions/structures throughout the human body, including the adventitia of large vessels, their precise distribution and function in arteries remain unclear. In the present study, we identified Pacini-like lamellar corpuscles (LCs) adjacent to the femoral artery, and investigated their distribution with respect to that structure via a histological analysis. We identified nine LCs that were localized in the connective tissue surrounding the femoral artery and vein. We showed that although their distribution was heterogeneous, they were predominantly concentrated on the dorsal side of the femoral artery. Immunohistochemical analyses revealed that the identified femoral artery LCs exhibited features characteristic of typical LCs located in the dermis of the index finger. Thus, the results of the present study contribute to an improved understanding of the function of femoral artery LCs. Anat Rec, 301:1809-1814, 2018. © 2018 Wiley Periodicals, Inc.

Hand fasciae innervation: The palmar aponeurosis.

There are few data in the scientific literature about the innervation of fasciae of the hand. The present study first elucidates the density and location of nervous structures in the palmar aponeurosis and, for comparison, in the flexor retinaculum (both can be considered specializations of the deep fascia of the upper limbs). Second, it compares nonpathological with pathological palmar aponeurosis. Samples of nonpathological fascia were taken from the flexor retinaculum and palmar aponeurosis of 16 upper limbs of unembalmed cadavers. Samples of pathological palmar aponeurosis were taken from seven patients with Dupuytren's disease. All samples were stained immunohistochemically with anti-S100 and anti-tubulin antibodies, and analyzed quantitatively and qualitatively by microscopy. The palmar aponeurosis showed higher median density than the retinacula of free nerve endings (22 and 20 elements/cm2 , respectively), Pacinian corpuscles (2 and 0 elements/cm2 ) and Golgi-Mazzoni corpuscles (1.0 and 0.5 element/cm2 ). Some corpuscles were located at the intersections of the fibers in the three directions. Free nerve endings were denser in pathological palmar aponeurosis (38 elements/cm2 ). The results indicate that the palmar aponeurosis is central to proprioception of the hand and that surgery should therefore avoid injuring it. The higher density of free nerve endings in pathological samples indicates that the nervous structures are implicated in the amplified fibrosis of Dupuytren's disease. Clin. Anat. 31:677-683, 2018. © 2018 Wiley Periodicals, Inc.

Endoneurial-CD34 positive cells define an intermediate layer in human digital Pacinian corpuscles.

The endoneurial and/or perineurial origin of the outer core; i.e. the concentric and continuous lamellae located outside the complex formed by the axon and the Schwann-related cells, in human Pacinian corpuscles is still debated. Here we used immunohistochemistry coupled with a battery of antibodies to investigate the expression of perineurial (Glucose transporter 1 and epithelial membrane antigen) or endoneurial (CD34 antigen) markers in human digital Pacinian corpuscles. CD34 immunoreactivity was restricted to one layer immediately outside the inner core, whereas the proper outer core displayed antigens typical of the perineurial cells. These results demonstrate an intermediate endoneurial layer that divides the Pacinian corpuscles into two distinct compartments: the avascular inner neural compartment (formed by the axon and the Schwann-related cells that form the inner core), and the outer non-neural compartment (formed by the outer core). The functional relevance of these findings, if any, remains to be clarified.

Terminal innervation of the male genitalia, cutaneous sensory receptors of the male foreskin.

PURPOSE: Understanding the types of sensory nerve termini within the glabrous skin of the human male foreskin could throw light on surgical outcomes and therapeutic possibilities for the future. Various receptor types sense changes in temperature, position, pressure, pain, light touch, itch, burning and pleasurable sexual sensations. Similarities and differences in innervation characteristics and density might become apparent when the glans penis is compared with homologous structures in the female genitalia. The aim of this study is to document the presence and characteristics of cutaneous sensory receptors in the human penile foreskin using a histopathological study of the nerve termini to achieve a more complete understanding of sensory experiences. METHODS: Foreskin samples were obtained from ten boys (aged 1-9 years) who had undergone circumcision. Informed consent was obtained from the parent/legal guardian. The samples were examined after modified Bielschowsky silver impregnation of neural tissue, and immunocytochemistry against gene protein product (PGP) 9.5 and neuron-specific enolase (NSE). RESULTS: PGP 9.5 appeared to be the most sensitive neural marker. Free nerve endings were identified in the papillary dermis visualized as thin fibers, mostly varicose, with either branched or single processes, either straight or bent. Two types of sensory corpuscle were identified: capsulated and non-capsulated. Meissner-like corpuscles were located in the papillary dermis. Capsulated corpuscles resembled typical Pacinian corpuscles, comprising a single central axon surrounded by non-neural periaxonic cells and lamellae. The capsulated corpuscles were strongly positive for PGP 9.5 and NSE. CONCLUSIONS: Free nerve endings, Meissner's corpuscles and Pacinian corpuscles are present in the human male foreskin and exhibit characteristic staining patterns.

Terminal innervation of female genitalia, cutaneous sensory receptors of the epithelium of the labia minora.

INTRODUCTION: Little information is available regarding the sensory nerve endings within the glabrous skin of the external female genitalia. The diversity of possible sensations suggests a variety of receptor types. Comprehensive knowledge of the sensory stimuli, including stimulus position, changes in temperature, pressure and pain, is critical for addressing pain and sexual function disorders clinically. The aim of this neuro-histological study is document the presence and characteristics of cutaneous sensory receptors in female genital tissue. MATERIALS AND METHODS: Labial skin samples were obtained from ten normal girls (aged 1-9 years). The specimens were waste tissue obtained during surgical intervention. They were all obtained by the senior investigator, a pediatric urologist, after the parent or legal guardian had given informed consent. The specimens were stained by Cajal-type silver impregnation and by immunocytochemistry against protein gene product (PGP) 9.5 and neuron-specific enolase (NSE). RESULTS: PGP 9.5 was the most sensitive neural marker for identifying cutaneous sensory receptors. Free nerve endings (FNEs) in the papillary dermis appeared as thin fibers, varicose, branched or single processed, straight or bent. In the labia minora, FNEs were identified in the strata basale, spinosum and granulosum of the epidermis. Non-capsulated (Meissner-like) corpuscles in the dermal papillae interdigitated with epidermal ridges of the skin. Capsulated corpuscles protruded from the deep dermis into the epidermis. Encapsulated corpuscles and cells located in the inner and outer cores were strongly positive for PGP 9.5. CONCLUSIONS: FNEs, Meissner's corpuscles and Pacinian corpuscles are present in the female labia minora and exhibit characteristic staining patterns.

Evidence of nestin-positive cells in the human cutaneus Meissner and Pacinian corpuscles.

Nestin is an intermediate filament protein expressed in neuroepithelial stem cells during development and it is later replaced by cell specific neuronal or glial filaments. Nevertheless, nestin⁺ cells remain within adult tissues and they can be regarded as potential neural stem cell (NSC). Nestin⁺ cells have been detected in Schwann cells related with sensory corpuscles of rodent and they have been demonstrated to be NSC. We have investigated the existence of nestin⁺ in human cutaneous cells Meissner and Pacinian corpuscles through the use of immunohistochemistry techniques and in situ hybridization. S100 protein (also regarded as a marker for NSC) and vimentin (the intermediate filament of mature Schwann cells in sensory corpuscles) were also investigated. The results show that the adult human cutaneous sensory Meissner and Pacinian corpuscles contains a small population of Schwann-related cells (vimentin⁺) which on the basis of their basic immunohistochemical characteristics (S100 protein⁺, nestin⁺) can be potential NSCs. Cells sharing identical immunohistochemical profile were also found in the close vicinity of Meissner corpuscles. Because their localization they are easily accessible and may represent a peripheral niche of NSC to be used for therapeutic goals.

The transcription factor c-Maf controls touch receptor development and function.

The sense of touch relies on detection of mechanical stimuli by specialized mechanosensory neurons. The scarcity of molecular data has made it difficult to analyze development of mechanoreceptors and to define the basis of their diversity and function. We show that the transcription factor c-Maf/c-MAF is crucial for mechanosensory function in mice and humans. The development and function of several rapidly adapting mechanoreceptor types are disrupted in c-Maf mutant mice. In particular, Pacinian corpuscles, a type of mechanoreceptor specialized to detect high-frequency vibrations, are severely atrophied. In line with this, sensitivity to high-frequency vibration is reduced in humans carrying a dominant mutation in the c-MAF gene. Thus, our work identifies a key transcription factor specifying development and function of mechanoreceptors and their end organs.

Dependence on the transcription factor Shox2 for specification of sensory neurons conveying discriminative touch.

Touch sensation is mediated by specific subtypes of sensory neurons which develop in a hierarchical process from common early progenitor neurons, but the molecular mechanism that underlies diversification of touch-sensitive mechanoreceptive neurons is not fully known. Here, we use genetically manipulated mice to examine whether the transcription factor short stature homeobox 2 (Shox2) participates in the acquisition of neuronal subtypes conveying touch sensation. We show that Shox2 encodes the development of category I low-threshold mechanoreceptive neurons in glabrous skin, i.e. discriminative touch-sensitive neurons which form innervations of epidermal Merkel cell and Meissner corpuscles. In contrast, other sensory fiber endings, including those innervating Pacinian corpuscles, are not dependent on Shox2. Shox2 is expressed in neurons of most or all classes of sensory neurons at early embryonic stages and is later confined to touch-sensitive neurons expressing Ret and/or TrkB. Conditional deletion of Shox2 and analysis of Runx3(-/-);Bax(-/-) mutant mice reveals that Runx3 is suppressing Shox2 while Shox2 is necessary for TrkB expression, and that these interactions are necessary for diversification of TrkB(+) and TrkC(+) mechanoreceptive neurons. In particular, development of TrkB(+)/Ret(+) and TrkB(+)/Ret(-) touch-sensitive neurons is critically dependent on Shox2. Consistently, Shox2 conditional mutant mice demonstrate a dramatic impairment of light touch responses. These results show that Shox2 is required for specification of a subclass of TrkB(+) sensory neurons which convey the sensation of discriminative touch arising from stimuli of the skin.

Differential localization of Acid-sensing ion channels 1 and 2 in human cutaneus pacinian corpuscles.

Acid-sensing ion channels (ASICs) are the members of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily which mediate different sensory modalities including mechanosensation. ASICs have been detected in mechanosensory neurons as well as in peripheral mechanoreceptors. We now investigated the distribution of ASIC1, ASIC2, and ASIC3 proteins in human cutaneous Pacinian corpuscles using immunohistochemistry and laser confocal-scanner microscopy. We detected different patterns of expression of these proteins within Pacinian corpuscles. ASIC1 was detected in the central axon co-expressed with RT-97 protein, ASIC2 was expressed by the lamellar cells of the inner core co-localized with S100 protein, and ASIC3 was absent. These results demonstrate for the first time the differential distribution of ASIC1 and ASIC2 in human rapidly adapting low-threshold mechanoreceptors, and suggest specific roles of both proteins in mechanotransduction.

RETouching upon mechanoreceptors.

The rapidly adapting (RA) low-threshold mechanoreceptors respond to movement of the skin and vibration and are critical for the perception of texture and shape. In this issue of Neuron, two papers (Bourane et al. and Luo et al.) demonstrate that early-born Ret+ sensory neurons are RA mechanoreceptors, whose peripheral nerve terminals are associated with Meissner corpuscles, longitudinal lanceolate endings, and Pacinian corpuscles. The studies further show that Ret signaling is essential for the development of these mechanoreceptors.

Molecular identification of rapidly adapting mechanoreceptors and their developmental dependence on ret signaling.

In mammals, the first step in the perception of form and texture is the activation of trigeminal or dorsal root ganglion (DRG) mechanosensory neurons, which are classified as either rapidly (RA) or slowly adapting (SA) according to their rates of adaptation to sustained stimuli. The molecular identities and mechanisms of development of RA and SA mechanoreceptors are largely unknown. We found that the "early Ret(+)" DRG neurons are RA mechanoreceptors, which form Meissner corpuscles, Pacinian corpuscles, and longitudinal lanceolate endings. The central projections of these RA mechanoreceptors innervate layers III through V of the spinal cord and terminate within discrete subdomains of the dorsal column nuclei. Moreover, mice lacking Ret signaling components are devoid of Pacinian corpuscles and exhibit a dramatic disruption of RA mechanoreceptor projections to both the spinal cord and medulla. Thus, the early Ret(+) neurons are RA mechanoreceptors and Ret signaling is required for the assembly of neural circuits underlying touch perception.

Mesenteric and tactile Pacinian corpuscles are anatomically and physiologically comparable.

Pacinian corpuscles (PCs) in cat mesentery have been studied extensively to help determine the structural and functional bases of tactile mechanotransduction. Although we, like many other investigators, have found that the mesenteric receptors are anatomically very similar to those found in mammalian skin, few physiological characteristics of the mesenteric PCs and those of the skin have been compared. Action-potential rate-amplitude and frequency characteristics (10 Hz-1 KHz), as well as interval (IH) and peri-stimulus-time (PSTH) histograms in response to sinusoidal displacements were obtained from nerve fibers innervating mesenteric PCs and from PC fibers innervating cat glabrous skin. The intensity characteristics obtained on both preparations showed similar response profiles, including equal slopes for low stimulus intensities (approximately 10, with impulse ratios/20 dB displacement) and one and two impulse/cycle entrainment. The frequency characteristics of both groups were U-shaped with similar low-frequency slopes (-12.5 dB/octave) and bandwidths (Q(3dB) = 1.4). The best frequency for both the tactile PCs' and mesenteric PCs was 250 Hz, which is in the expected range. The IHs showed entrainment and the PSTHs showed neither transient responses nor adaptation to steady-state sinusoidal stimuli. The functional similarity between mesenteric PCs' nerve responses and those of tactile PC afferents, as well as the receptors' anatomical similarity, lead us to suggest that the mesenteric PC can act as a model for those in the skin. Furthermore, since the frequency characteristics of the two PC types are similar, it is concluded that the skin, while attenuating stimulus intensity, does not impart temporal filtering of vibratory stimuli.

Effect of contact location on vibrotactile thresholds at the fingertip.

Vibrotactile thresholds depend on the characteristics of the vibration, the location of contact with the skin, and the geometry of the contact with the skin. This experimental study investigated vibrotactile thresholds (from 8 to 250 Hz) at five locations on the distal phalanx of the finger with two contactors: (i) a 1-mm diameter circular probe (0.78-mm(2) area) with a 1-mm gap to a fixed circular surround (i.e., 7.1-mm(2) excitation area), and (ii) a 6-mm diameter circular probe (28-mm(2) area) with a 2-mm gap to a fixed circular surround (i.e., 79-mm(2) excitation area). With both contactors, especially the smaller contactor at low frequencies (i.e., 8, 16, and 31.5 Hz), thresholds decreased towards the tip of the finger, although there was little variation around the whorl. With low frequencies of vibration, and at all five locations on the finger, similar thresholds were obtained with both contactors, consistent with the NPI channel not changing in sensitivity with a change in the area of stimulation. At high frequencies (i.e., 63, 125, and 250 Hz), thresholds were lower with the larger area of stimulation at all locations, except at the extreme tip of the finger, consistent with spatial summation in the Pacinian channel. It is concluded that with a 6-mm diameter contactor, moderate variations in location around the whorl have little influence on the measured thresholds. With the 1-mm diameter contactor there were greater variations in thresholds and extreme locations, near the nail and the distal interphalangeal joint, may be unsuitable for investigating sensorineural disorders.

Sensitive innervation of the copulatory organ in Struthio camelus: comparison to the corresponding district in female proctodeum.

The AA. have studied the nerve component of male copulatory organ and ventral part of female proctodeum in the ostrich. This paper represents the concluding part of the plan of research that aimed to verify some data and hypothesis referred in previous observations. The innervation of the considered districts was always constituted by autonomic and sensitive somatic nerve components. The autonomic innervation was represented by isolated and grouped ganglion cells located along the course of nerve bundles or in the point where different nerve bundles converged. This nerve component was frequently in close connection with the blood vessels. The sensitive somatic innervation was constituted by free and capsulated nerve endings. The latter, always supplied by a typical structure and morphologically classified as Pacini, Pacini-like and genital's corpuscles, could be found either isolated or grouped within the different layers of both the examined anatomical territories. The grouped corpuscles, in particular Pacini's corpuscles, could organize simple and complex flower sprays, opposito-polar corpuscles and poikilomorphous fibres. For the first time the capsule's lamellar organization in Pacini's corpuscles in Birds was documented by means of light microscope. The occurrence of genital corpuscles seemed to be exclusive in the ventral part of female ostrich proctodeum, corresponding to the male site in which lies the copulatory organ.

Autonomic and sensitive somatic innervation of the ostrich elbow and knee joints articular capsule.

The present research was carried out on the fibrous layer of the ostrich's elbow and knee joints articular capsule, employing opportunely modified gold chloride Ruffini's method, to study the autonomic and sensitive somatic nerve components. The distribution of both nerve components followed frequently the vascular networks. The autonomic innervation was represented by isolated or grouped ganglion cells, frequently placed along the course of nerve trunks, close to the epineurium or located within the perineural connective tissue. The sensitive somatic innervation was constituted by free and encapsulated corpuscles. The last one, morphologically classified as Pacini, Pacini-like and Golgi-Mazzoni's corpuscles, were found isolated or grouped to constitute simple and complex flower sprays, "opposito-polar corpuscles" and "poichilomorphous fibres". The very few Golgi-Mazzoni's corpuscles were found only in the knee joint articular capsule. The two nerve components, found in the considered districts, did not shown significant quanti-qualitative and topographic differences. This datum, at least in appearance, seems to conflict with the ostrich functional aptitudes. In fact, the ostrich is a bird unable to fly but very able to run.

The sensitive innervation of the ostrich nasal mucosa.

The sensitive innervation of the ostrich's nasal mucosa, through impregnative gold chloride methods, was investigated. The autonomy innervation, constituted by ganglion cells placed along the course of nerve trunks was particularly represented in the respiratory tract of the nasal cavity. The somatic nerve component, composed by free and capsulated endings, was especially distributed in the vestibular district. The nerve corpuscles were morphologically classified as Pacini, Pacini-like, Golgi-Mazzoni and Herbst. Further investigations must be expected to attribute an effective functional role particularly to this last nerve component.

On the sensitive innervation of the ostrich's foot pads.

The sensitive and autonomic innervation of foot pads in the ostrich was studied employing an usual histological technique as hematoxylin-eosin or different gold chloride impregnations. The autonomic innervation is represented by isolated or grouped ganglion cells located along the course of nerve bundles. The sensitive somatic innervation is composed by free and capsulated nerve endings usually distributed in the thickness of the connective arrangement of the foot pads, in the most superficial part the first one, while the latter was generally located close to the blood vessels. The capsulated nerve endings, morphologically classified as Pacini, Pacini-like and Herbst corpuscles, show the typical structure. They are not uniformly distributed throughout the considered districts and their number are always higher in the plantar pad compared with digital pads. These corpuscles could be found isolated or assembled to organize simple flower-sprays and to constitute opposito-polar corpuscles. The Authors have put forward a hypothesis on the possible functional role of the above-mentioned nerve components.

Further observations on the sensitive innervation of some bird's proctodeum.

The AA. studied the autonomic and sensitive somatic innervation of some female bird's proctodeum, through the properly modified Ruffini's gold chloride method. The vegetative component was constituted by ganglion cells of different size, isolated or grouped to form ganglia, found along the course of nerve trunks or in the concurrent point of different nerve bundles. The sensitive somatic innervation was represented by free and encapsulated endings differently distributed in the thickness of the wall. The former were composed of thin networks, while the latter, located more frequently in the muscular tunica and in the subadventitial connective, were composed of encapsulated receptors classified as Pacini, Pacini-like and Herbst corpuscles. The morphology of these receptors was described and hypotheses were brought up about their probable functional role. The AA, also found, even if very rarely, helicoidal collagen fibres around nerve fascicles.

Distribution and terminal arborizations of cutaneous mechanoreceptors in the glabrous finger pads of the monkey.

Recent electrophysiological studies demonstrated that neurons in the somatosensory cortex of monkeys respond to tangential forces applied to glabrous skin. To unravel the peripheral basis for this cortical response, we determined the distribution of presumptive low-threshold mechanoreceptors innervating the distal finger pads of monkeys. Endings were reconstructed in immunolabeled serial sections imaged by epifluorescence and confocal microscopy. Although classically implicated as cutaneous stretch receptors, no Ruffini corpuscles were found in the glabrous skin. Ruffini-like endings were only detected at the base of the finger nails. Pacinian corpuscles were sparsely distributed in the deep dermis. Meissner corpuscles (MCs) in dermal papillary ridges had a comparably high density in the thumb, index, and fifth fingers. Each MC was innervated by several large-caliber axons. Within the limits of our reconstructions, some of these axons terminated in only one MC, whereas others innervated several MCs. Merkel endings covered about 80% of the base of the intermediate epidermal ridges that form the pattern of fingerprints. In some cases, the distal tip of a Merkel-related axon gave rise to a several terminal branches that supplied endings to tightly circumscribed (30-70 microm) clusters of Merkel cells. In other cases, the nodes of axons gave rise to en passant branches that formed extended chains of endings among Merkel cells spread over territories up to 300 microm long. Based on their relatively diffuse distributions, the axons that innervate multiple MCs or the axons with en passant Merkel terminations seem most suited to transduce tangential forces.

Localization of beta and gamma subunits of ENaC in sensory nerve endings in the rat foot pad.

The molecular mechanisms underlying mechanoelectrical transduction and the receptors that detect light touch remain uncertain. Studies in Caenorhabditis elegans suggest that members of the DEG/ENaC cation channel family may be mechanoreceptors. Therefore, we tested the hypothesis that subunits of the mammalian epithelial Na(+) channel (ENaC) family are expressed in touch receptors in rat hairless skin. We detected betaENaC and gammaENaC, but not alphaENaC transcripts in cervical and lumbar dorsal root ganglia (DRG). Using immunofluorescence, we found betaENaC and gammaENaC expressed in medium to large lumbar DRG neurons. Moreover, we detected these two subunits in Merkel cell-neurite complexes, Meissner-like corpuscles, and small lamellated corpuscles, specialized mechanosensory structures of the skin. Within these structures, betaENaC and gammaENaC were localized in the nerve fibers believed to contain the sensors responsive to mechanical stress. Thus beta and gammaENaC subunits are good candidates as components of the molecular sensor that detects touch.