Ageing of the somatosensory system at the periphery: age‐related changes in cutaneous mechanoreceptors

Decline of tactile sensation associated with ageing depends on modifications in skin and both central and peripheral nervous systems. At present, age‐related changes in the periphery of the somatosensory system, particularly concerning the effects on mechanoreceptors, remain unknown. Here we used immunohistochemistry to analyse the age‐dependent changes in Meissner's and Pacinian corpuscles as well as in Merkel cell‐neurite complexes. Moreover, variations in the neurotrophic TrkB‐BDNF system and the mechanoprotein Piezo2 (involved in maintenance of cutaneous mechanoreceptors and light touch, respectively) were evaluated. The number of Meissner's corpuscles and Merkel cells decreased progressively with ageing. Meissner's corpuscles were smaller, rounded in morphology and located deeper in the dermis, and signs of corpuscular denervation were found in the oldest subjects. Pacinian corpuscles generally showed no relevant age‐related alterations. Reduced expression of Piezo2 in the axon of Meissner's corpuscles and in Merkel cells was observed in old subjects, as well was a decline in the BDNF‐TrkB neurotrophic system. This study demonstrates that cutaneous Meissner's corpuscles and Merkel cell‐neurite complexes (and less evidently Pacinian corpuscles) undergo morphological and size changes during the ageing process, as well as a reduction in terms of density. Furthermore, the mechanoprotein Piezo2 and the neurotrophic TrkB‐BDNF system are reduced in aged corpuscles. Taken together, these alterations might explain part of the impairment of the somatosensory system associated with ageing.     

The enigma of sensitivity in Pacinian corpuscles: a critical review and hypothesis of mechano-electric transduction

The present report reviews the physiological and morphological specializations of Pacinian corpuscles and other mechanoreceptors that are present in the skin and connective tissues of the body as well as the cochlea. The remarkable sensitivity of Pacinian corpuscles is such that the only form of mechanical energy that could be perceived by a Pacinian corpuscle is a sound wave. In fact the human finger as demonstrated by Munger and Ide (1987) can perceive sound waves when water is the coupling agent. The structural specializations are equally remarkable with extensive membrane specializations of both the inner core and inner portion of the outer core. The halves of the inner core are each coupled with gap junctions and the inner portion of the outer core joined with numerous tight junctions. The cleft regions have specializations involving the axolemma that consist of numerous axonal spines containing bundles of filaments projecting into the cleft of the inner core. These structural specializations are thought to represent specializations for mechano-electric transduction analogous in many respects to the hair cells of the cochlea. A hypothesis for mechano-electric transduction is presented that may account in part for the extreme sensitivity of Pacinian corpuscles and other mechanoreceptors.     

Responses of vibration-sensitive receptors in the interosseous region of the duck's hind limb

1. Responses of receptors with fibres in the interosseous nerve of the duck's leg have been studied by recording unit discharges in filaments dissected from the sciatic nerve.2. Seventy-two of the ninety-four units examined served highly phasic, vibration-sensitive mechanoreceptors in the interosseous region interpreted as being Herbst corpuscles. Receptor types for most of the other units could not be determined, but some were slowly adapting mechanoreceptors.3. Rheobase threshold values for the most sensitive vibration-receptors were similar to those of mammalian Pacinian corpuscles.4. Threshold-frequency relationships for the vibration receptors showed a wider range of low frequency cut-off values, and a greater capacity to signal high frequencies, than is the case with Pacinian corpuscles.5. Fibres of the vibration-receptors had calculated diameters ranging from 5 to 10 mum and account for the bulk of the larger fibres in the interosseous nerve.6. It is suggested that Herbst corpuscles in the legs of birds might act as a warning device by detecting vibratory disturbances of the ground or other supporting surface.     

The development of receptors in the glabrous forepaw skin of pouch young opossums

To determine the state of development of mechanoreceptors during the period in which central neurol regions can be altered by peripheral lesions, the distribution of terminal neurites and specialized receptors was examined in the glabrous forepaw skin of a developmental series of pouch young opossums, using the silver stain of Sevier & Munger (1965) and electron microscopic observations. At 10 days after birth bundles of neurites approach the dermal-epidermal junction, but neither neurites nor receptors are seen in the epidermis. Some neuntes enter the epidermis by 20 days; by 25 days developing Merkel cells are seen in the epidermis; at 30 days mature Merkel cells and primordial Pacinian corpuscles are present, respectively, in the epidermis and deep dermis; at 42 postnatal days dermal papillae containing neurites were observed at the dermal-epidermal junction, which may be developing Meissner corpuscles. Numbers of neurites, and of their branchings, increase up to 60 days; as do the size, number and degree of differentiation of the Pacinian corpuscles.The critical period for the effects of peripheral lesions upon the morphology of the cuneate-gracile nuclear complex, as well as the times of initial massive synaptogenesis, cell migration and differentiation in this first and second order mechanosensory synaptic region, are completed prior to the innervation of the epidermis and the appearance of specialized mechanoreceptors. Thus input from epidermal and specialized receptors cannot be responsible for guidance of these developmental processes.     

Postnatal developmental changes in the expression of ErbB receptors in murine Pacinian cospucles

Neuregulins and their signaling ErbB receptors play a critical role during the development of the mammalian peripheral nervous system, including some kinds of mechanoreceptors such as the Pacinian corpuscles which become structurally and functionally mature postnatally. In this study, we investigated whether or not ErbBs in Pacinian corpuscles undergoes developmental changes, as well as if their expression depends on the innervation. Pacinian corpuscles from 7-day- and 3-month-old mice were assessed for the immunohistochemical detection of EGFR or ErbB1, ErbB2, ErbB3 and ErbB4. The effect of denervation on the expression of ErbBs in mature Pacinian corpuscles was also analyzed. Developing 7-day-old Pacinian corpuscles express ErbB2 and ErbB3 immunoreactivity in the inner-core (regarded as modified Schwann cells), whereas the mature 3-month-old Pacinian corpuscles exclusively displayed ErbB4 immunoreactivity in the outer core and the capsule (regarded as endoneurial and perineurial cells). Denervation was without effect on the ErbB expression. Present results demonstrate maturational related changes and cell segregation in the expression of ErbB receptors by murine Pacinian corpuscles, and that this expression is independent of the innervation.     

Comparative anatomical and neurohistological observations on the tongues of elephants (Elephas indicus and Loxodonta africana)

Frozen sections from Indian and African elephant tongues were investigated neurohistologically. On the dorsum there are 3 to 5 vallate papillae. Foliate papillae consisting of 18 to 27 clefts are observed in the posterolateral region of the tongue. Wart-like papillae are distributed along the lateral border of the tongue from the foliate papillae region to the apex. Vallate and foliate papillae contain serous glands but have no taste buds. They are supplied with abundant lamellated corpuscles of Pacinian type in their upper mucosa. The wart-like papillae are composed of two or more papillae, each of which has many secondary papillae supplied with plexiform thin and thick nerves. They bear a few taste buds and contain lamellated corpuscles of Pacinian type. From these neurohistologic characteristics wart-like papillae should be regarded as a receptive organ for secretion of the lingual glands. Lamellated corpuscles of Pacinian type are widely distributed over the whole surface of the tongue. The histologic location of these two structures is of interest in suggesting that they together play important roles as receptors of taste and tactile sensations during mastication of food. Double motor end plates are found on single muscle fibers. The mixed glands which are plentiful in the inferolateral area of the tongue are in close topographic relation with the wart-like papillae.     

Brain‐Derived Neurotrofic Factor and its Receptor TrkB are Present,but Segregated,Within Mature Cutaneous Pacinian Corpuscles of Macaca fascicularis

Some mechanoreceptors in mammals depend totally or in part on the neurotrophins brain‐derived neurotrophic factor (BDNF) and neurotrophin‐4 (NT‐4), and their receptor TrkB, for development and maintenance. These actions are presumably exerced regulating the survival of discrete sensory neurons in the dorsal root ganglia which form mechanoreceptors at the periphery. In addition, the cells forming the mechanoreceptors also express both neurotrophins and their receptors although large differences have been described among species. Pacinian corpuscles are rapidly adapting low‐threshold mechanoreceptors whose dependence from neurotrophins is not known. In the present study, we analyzed expression of TrkB and their ligands BDNF and NT‐4 in the cutaneous Pacinian corpuscles of Macaca fascicularis using immunohistochemistry and fluorescent microscopy. TrkB immunoreactivity was found in Pacinian corpuscles where it co‐localized with neuron‐specific enolase, and occasionally with S100 protein, thus suggesting that TrkB expression is primarily into axons but also in the lamellar cells and even in the outer core. On the other hand, BDNF immunoreactivity was found the inner core cells where it co‐localized with S100 protein but also in the innermost layers of the outer core; NT‐4 immunostaining was not detected. These results describe for the first time the expression and distribution of a full neurotrophin system in the axon‐inner core complex of mature Pacinian corpuscles. The data support previous findings demonstrating large differences in the expression of BDNF‐TrkB in mammalian mechanoreceptors, and also suggest the existence of a retrograde trophic signaling mechanism to maintain morphological and functional integrity of sensory neurons supplying Pacinian corpuscles. Anat Rec, 298:624–629, 2015. © 2014 Wiley Periodicals, Inc.     

Von Economo Neurons in the Elephant Brain

Von Economo neurons (VENs), previously found in humans, all of the great ape species, and four cetacean species, are also present in African and Indian elephants. The VENs in the elephant are primarily found in similar locations to those in the other species. They are most abundant in the frontoinsular cortex (area FI) and are also present at lower density in the anterior cingulate cortex. Additionally, they are found in a dorsolateral prefrontal area and less abundantly in the region of the frontal pole. The VEN morphology appears to have arisen independently in hominids, cetaceans, and elephants, and may reflect a specialization for the rapid transmission of crucial social information in very large brains. Anat Rec 2009. © 2008 Wiley‐Liss, Inc.     

Formation of new pacinian corpuscles after additional somatic innervation of the mesentery

After transplantation of a cutaneous nerve of the hind limb into the mesentery of the small intestine in cats (after preliminary removal of the Pacinian corpuscles from the mesentery), new encapsulated mechanoreceptors were observed to appear against the background of rapid regeneration of the fibers of the grafted nerve. Various stages of development of the Pacinian corpuscles were distinguished. The receptors formed under the conditions of this foreign innervation were indistinguishable in their morphological and functional properties from the ordinary type.     

Vibration-evoked responses from lamellated corpuscles in the legs of kangaroos

Summary A group of lamellated corpuscles are present in the interosseous region of the legs of macropod marsupials. Structurally, they are similar to, but simpler than the Pacinian corpuscles of eutherian mammals, in having fewer lamellae. Responses of mechanoreceptors with axons coursing in the interosseous nerve were recorded from filaments, containing single functional units, dissected from the sciatic nerve of the wallaby Thylogale billardierii. The receptors were all maximally sensitive to stimuli applied in the interosseous region, where the cluster of lamellated corpuscles is located. Most units had low mechanical thresholds and were sensitive to sinusoidal vibration over a wide range of frequencies. Functional properties generally resembled those of eutherian Pacinian corpuscles, but the marsupial receptors were less rapidly adapting. The afferent nerve fibres conducted at 45 to 60 ms^–1, while the diameter of axons in the osmium-stained interosseous nerve ranged between 7.5 and 12 m. It is suggested that one important function of the receptors might be the detection of ground-borne vibration.     

Immunohistochemical localization of acid-sensing ion channel 2 (ASIC2) in cutaneous Meissner and Pacinian corpuscles of Macaca fascicularis

Acid-sensing ion channel 2 (ASIC2) is a member of the degenerin/epithelial sodium channel superfamily, presumably involved mechanosensation. Expression of ASIC2 has been detected in mechanosensory neurons as well as in both axons and Schwann-like cells of cutaneous mechanoreceptors. In these studies we analysed expression of ASIC2 in the cutaneous sensory corpuscles of Macaca fascicularis using immunohistochemistry and laser confocal-scanner microscopy. ASIC2 immunoreactivity was detected in both Meissner and Pacinian corpuscles. It was found to co-localize with neuron-specific enolase and RT-97, but not with S100 protein, demonstrating that ASIC2 expression is restricted to axons supplying mechanoreceptors. These results demonstrate for the first time the presence of the protein ASIC2 in cutaneous rapidly adapting low-threshold mechanoreceptors of monkey, suggesting a role of this ion channel in touch sense.     

The structure of the cushions in the feet of African elephants (Loxodonta africana)

The uniquely designed limbs of the African elephant, Loxodonta africana, support the weight of the largest terrestrial animal. Besides other morphological peculiarities, the feet are equipped with large subcutaneous cushions which play an important role in distributing forces during weight bearing and in storing or absorbing mechanical forces. Although the cushions have been discussed in the literature and captive elephants, in particular, are frequently affected by foot disorders, precise morphological data are sparse. The cushions in the feet of African elephants were examined by means of standard anatomical and histological techniques, computed tomography (CT) and magnetic resonance imaging (MRI). In both the forelimb and the hindlimb a 6th ray, the prepollex or prehallux, is present. These cartilaginous rods support the metacarpal or metatarsal compartment of the cushions. None of the rays touches the ground directly. The cushions consist of sheets or strands of fibrous connective tissue forming larger metacarpal/metatarsal and digital compartments and smaller chambers which were filled with adipose tissue. The compartments are situated between tarsal, metatarsal, metacarpal bones, proximal phalanges or other structures of the locomotor apparatus covering the bones palmarly/plantarly and the thick sole skin. Within the cushions, collagen, reticulin and elastic fibres are found. In the main parts, vascular supply is good and numerous nerves course within the entire cushion. Vater-Pacinian corpuscles are embedded within the collagenous tissue of the cushions and within the dermis. Meissner corpuscles are found in the dermal papillae of the foot skin. The micromorphology of elephant feet cushions resembles that of digital cushions in cattle or of the foot pads in humans but not that of digital cushions in horses. Besides their important mechanical properties, foot cushions in elephants seem to be very sensitive structures.     

Tender papule rising on the digit: Pacinian neuroma should be considered in differential diagnosis

Pacinian corpuscles are sensory nerve-end organs located in the deep dermis and subcutaneous tissue of the palms or soles. Pacinian neuroma is an extremely rare feature, defined as hyperplasia or hypertrophy of Pacinian corpuscles. About half of Pacinian neuromas present with point tenderness. There have been a limited number of cases reported around the world. We observed a 45-year-old woman with an 8-month history of a tender whitish papule on her left thumb tip. Histopathologically, an enlarged hypertrophic Pacinian corpuscle in subcutaneous tissue, surrounded by numerous nerve fibers, was found. Herein, we report a case of Pacinian neuroma presenting as a tender papule on a fingertip that was clearly related to repetitive trauma at that site. This case shows that a meticulous history and histological examination can lead to an exact diagnosis and proper treatment.     

Immunohistochemical Detection of the Putative Mechanoproteins ASIC2 and TRPV4 in Avian Herbst Sensory Corpuscles

The avian Herbst corpuscles are the equivalent of the Pacinian corpuscles in mammals, and detect vibration and the movement of joints and feathers. Therefore, they can be regarded as rapidly adapting low‐threshold mechanoreceptors. In recent years, it has been establish that some ion channels are involved in mechanosensation and are present in both mechanosensory neurons and mechanoreceptors. Here we have used immunohistochemistry to localize some putative mechanoproteins in the Herbst corpuscles from the rictus of Columba livia. The proteins investigated were the subunits of the epithelial Na⁺ channel (ENaC), the transient‐receptor potential vanilloid 4 (TRPV4), and the acid‐sensing ion channel 2 (ASIC2). Immunoreactivity for ENaC subunits was never found in Herbst corpuscles, while the axon expressed ASIC2 and TRPV4 immunoreactivity. Moreover, TRPV4 was also detected in the cell forming the inner core. The present results demonstrate for the first time the occurrence of mechanoproteins in avian low‐threshold mechanoreceptors and provide further evidence for a possible role of the ion channels in mechanosensation. Anat Rec, 2013. © 2012 Wiley Periodicals, Inc.     

The elephant knee joint: morphological and biomechanical considerations

Elephant limbs display unique morphological features which are related mainly to supporting the enormous body weight of the animal. In elephants, the knee joint plays important roles in weight bearing and locomotion, but anatomical data are sparse and lacking in functional analyses. In addition, the knee joint is affected frequently by arthrosis. Here we examined structures of the knee joint by means of standard anatomical techniques in eight African (Loxodonta africana) and three Asian elephants (Elephas maximus). Furthermore, we performed radiography in five African and two Asian elephants and magnetic resonance imaging (MRI) in one African elephant. Macerated bones of 11 individuals (four African, seven Asian elephants) were measured with a pair of callipers to give standardized measurements of the articular parts. In one Asian and three African elephants, kinematic and functional analyses were carried out using a digitizer and according to the helical axis concept. Some peculiarities of healthy and arthrotic knee joints of elephants were compared with human knees. In contrast to those of other quadruped mammals, the knee joint of elephants displays an extended resting position. The femorotibial joint of elephants shows a high grade of congruency and the menisci are extremely narrow and thin. The four-bar mechanism of the cruciate ligaments exists also in the elephant. The main motion of the knee joint is extension-flexion with a range of motion of 142 degrees . In elephants, arthrotic alterations of the knee joint can lead to injury or loss of the cranial (anterior) cruciate ligament.     

Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity

The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch‐gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell–neurite complexes, Meissner‐like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20⁺, chromogranin A⁺ and synaptophisin⁺) Merkel cells. Most of them were in close contact with Piezo2⁻ nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2⁺, but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non‐nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low‐threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans.