Structure and barrier functions of the perineurium and its relationship with associated sensory corpuscles: A review.

Peripheral nerves are provided with a blood-nerve barrier which prevents the invasion of harmful substances and pathogens, and also regulates metabolic and ionic homeostasis within nerve fascicles. The barrier functions are attributed to both the concentric layer of flattened cells in the perineurium and blood vessels running in the endoneurium. The perineurial cells develop continuous tight junctions as a diffusion barrier. In order to take up a predominant nutrient, glucose, the perineurium as well as endoneurial capillaries expresses GLUT1, a glucose transporter. An axon-Schwann cell complex within peripheral nerves utilizes glucose as a major energy source via the GLUT1, as does the brain. Under conditions of a reduced utilization of glucose, only the perineurial cells can transfer other nutrients, namely monocarboxylates such as ketone bodies and lactate via MCT1. Thus, MCT1 colocalizes with GLUT1 in the perineurium but not in endoneurial capillaries. To identify the cellular origins of the nerve sheath, marker proteins such as glial specific S100 protein, GLUT1, endoneurial CD34, and EMA (epithelial membrane antigen) are useful. Immunohistochemical findings for these markers are reviewed in this paper, focusing on the perineurium and endoneurium and their derivatives, Pacinian and Meissner corpuscles. Growing evidence throws light on the critical involvement of the nerve sheaths in the development, maintenance, and diseases of peripheral nerves.

Distribution, fine structure, and three-dimensional innervation of lamellar corpuscles in rat plantar skin.

Lamellar corpuscles function as mechanoreceptors in the skin, composed of axon terminals and lamellae constructed by terminal Schwann cells. They are classified into Pacinian, Meissner, and simple corpuscles based on histological criteria. Lamellar corpuscles in rat dermal papilla cells have been reported; however, the morphological aspects have yet to be thoroughly investigated. In the present study, we analyzed the enzyme activity, distribution, fine structure, and three-dimensional innervation of lamellar corpuscles in rat plantar skin. The lamellar corpuscles exhibiting non-specific cholinesterase were densely distributed in rat footpads, evident as notable skin elevations, especially at the apex, the highest portion of the ridges in each footpad. In contrast, only a few lamellar corpuscles were found in other plantar skin areas. Lamellar corpuscle was considered composed of a flat axon terminal Schwann cell lamellae, which were roughly concentrically arranged in the dermal papilla. These histological characteristics correspond to those of the simple corpuscle. Moreover, the axon tracing method revealed that one trunk axon innervated several simple corpuscles. The territory of the trunk axons overlapped with each other. Finally, the animals' footprints were analyzed. During the pausing and walking phases, footpads are often in contact with the floor. These results demonstrate that the type of lamellar corpuscles in the dermal papillae of rat plantar skin is a simple corpuscle and implies that their distribution pattern in the plantar skin is convenient for efficient sensing and transmission of mechanical stimuli from the ground.

The Cellular and Mechanical Basis for Response Characteristics of Identified Primary Afferents in the Rat Vibrissal System.

Compared to our understanding of the response properties of receptors in the auditory and visual systems, we have only a limited understanding of the mechanoreceptor responses that underlie tactile sensation. Here, we exploit the stereotyped morphology of the rat vibrissal (whisker) array to investigate coding and transduction properties of identified primary tactile afferents. We performed in vivo intra-axonal recording and labeling experiments to quantify response characteristics of four different types of identified mechanoreceptors in the vibrissal follicle: ring-sinus Merkel; lanceolate; clublike; and rete-ridge collar Merkel. Of these types, only ring-sinus Merkel endings exhibited slowly adapting properties. A weak inverse relationship between response magnitude and onset response latency was found across all types. All afferents exhibited strong "angular tuning," i.e., their response magnitude and latency depended on the whisker's deflection angle. Although previous studies suggested that this tuning should be aligned with the angular location of the mechanoreceptor in the follicle, such alignment was observed only for Merkel afferents; angular tuning of the other afferent types showed no clear alignment with mechanoreceptor location. Biomechanical modeling suggested that this tuning difference might be explained by mechanoreceptors' differential sensitivity to the force directed along the whisker length. Electron microscopic investigations of Merkel endings and lanceolate endings at the level of the ring sinus revealed unique anatomical features that may promote these differential sensitivities. The present study systematically integrates biomechanical principles with the anatomical and morphological characterization of primary afferent endings to describe the physical and cellular processing that shapes the neural representation of touch.

What Do Sensory Organs Tell the Brain?

Understanding how perception emerges depends on the understanding of sensory acquisition by sensory organs. In this issue of Neuron, Severson et al. (2017) present a brilliant leap towards understanding active sensory coding by mechanoreceptors.

Structure-function correlations of rat trigeminal primary neurons: Emphasis on club-like endings, a vibrissal mechanoreceptor.

This study focuses on the structure and function of the primary sensory neurons that innervate vibrissal follicles in the rat. Both the peripheral and central terminations, as well as their firing properties were identified using intracellular labelling and recording in trigeminal ganglia in vivo. Fifty-one labelled neurons terminating peripherally, as club-like, Merkel, lanceolate, reticular or spiny endings were identified by their morphology. All neurons responded robustly to air puff stimulation applied to the vibrissal skin. Neurons with club-like endings responded with the highest firing rates; their peripheral processes rarely branched between the cell body and their terminal tips. The central branches of these neurons displayed abundant collaterals terminating within all trigeminal nuclei. Analyses of three-dimensional reconstructions reveal a palisade arrangement of club-like endings bound to the ringwulst by collagen fibers. Our morphological findings suggest that neurons with club-like endings sense mechanical aspects related to the movement of the ringwulst and convey this information to all trigeminal nuclei in the brainstem.

Changes in the Distribution of Periodontal Nerve Fibers during Dentition Transition in the Cat.

The periodontal ligament has a rich sensory nerve supply which originates from the trigeminal ganglion and trigeminal mesencephalic nucleus. Although various types of mechanoreceptors have been reported in the periodontal ligament, the Ruffini ending is an essential one. It is unknown whether the distribution of periodontal nerve fibers in deciduous teeth is identical to that in permanent teeth or not. Moreover, morphological changes in the distribution of periodontal nerve fibers during resorption of deciduous teeth and eruption of successional permanent teeth in diphyodont animals have not been reported in detail. Therefore, in this study, we examined changes in the distribution of periodontal nerve fibers in the cat during changes in dentition (i.e., deciduous, mixed and permanent dentition) by immunohistochemistry of protein gene product 9.5. During deciduous dentition, periodontal nerve fibers were concentrated at the apical portion, and sparsely distributed in the periodontal ligament of deciduous molars. During mixed dentition, the periodontal nerve fibers of deciduous molars showed degenerative profiles during resorption. In permanent dentition, the periodontal nerve fibers of permanent premolars, the successors of deciduous molars, increased in number. Similar to permanent premolars, the periodontal nerve fibers of permanent molars, having no predecessors, increased in number, and were densely present in the apical portion. The present results indicate that the distribution of periodontal nerve fibers in deciduous dentition is almost identical to that in permanent dentition although the number of periodontal nerve fibers in deciduous dentition was low. The sparse distribution of periodontal nerve fibers in deciduous dentition agrees with clinical evidence that children are less sensitive to tooth stimulation than adults.

Cyclooxygenase (COX)-1 and COX-2 both play an important role in the protection of the duodenal mucosa in cats.

Although nonsteroidal anti-inflammatory drugs often cause ulcers in the duodenum in humans, the role of cyclooxygenase (COX) isoforms in the pathogenesis of duodenal ulcers has not been fully elucidated. We examined in cats the 1) ulcerogenic effects of selective COX-1 (SC-560, ketorolac) and COX-2 (celecoxib, meloxicam) inhibitors on the gastrointestinal mucosa, 2) effect of feeding and cimetidine on the expression of COX isoforms and prostaglandin E(2) (PGE(2)) level in the duodenum, and 3) localization of COX isoforms in the duodenum. COX inhibitors were administered after the morning meal in cats once daily for 3 days. Gastrointestinal lesions were examined on day 4. Localization and expression of COX isoforms (by immunohistochemistry, Western blot) and PGE(2) level (by enzyme immunoassay) were examined. Results were as follows. First, selective COX-1 or COX-2 inhibitors alone produced marked ulcers in the duodenum but did not cause obvious lesions in the small intestine. Coadministration of SC-560 and celecoxib produced marked lesions in the small intestine. Second, feeding increased both the expression of COX isoforms and PGE(2) level in the duodenum, and the effects were markedly inhibited by pretreatment with cimetidine. Third, COX-1 was localized in goblet and Brunner's gland cells, Meissner's and Auerbach's plexus, smooth muscle cells, and arterioles; and COX-2 was observed in capillaries, venules, and basal granulated cells. The expression of COX isoforms in the duodenum is up-regulated by feeding, and inhibition of either COX-1 or COX-2 causes ulcers in the duodenum, suggesting that both isoforms play an important role in the protection of the duodenal mucosa.

How many hair follicles are innervated by one afferent axon? A confocal microscopic analysis of palisade endings in the auricular skin of thy1-YFP transgenic mouse.

Hairs are known as a sensory apparatus for touch. Their follicles are innervated predominantly by palisade endings composed of longitudinal and circumferential lanceolate endings. However, little is known as to how their original primary neurons make up a part of the ending. In this study, innervation of the palisade endings was investigated in the auricular skin of thy1-YFP transgenic mouse. Major observations were 1) Only a small portion of PGP9.5-immunopositive axons showed YFP-positivity, 2) All of thy1-YFP-positive sensory axons were thick and myelinated, 3) Individual thy1-YFP-positive trunk axons innervated 4-54 hair follicles, 4) Most palisade endings had a gap of lanceolate ending arrangement, 5) PGP9.5-immunopositive 10-32 longitudinal lanceolate endings were closely arranged. Only a part of them were thy1-YFP-positive axons that originated from 1-3 afferents, and 6) Single nerve bundles of the dermal nerve network included both bidirectional afferents. Palisade endings innervated by multiple sensory neurons might be highly sensitive to hair movement.

Three-dimensional analyses of touch domes in the hairy skin of the cat paw reveal morphological substrates for complex sensory processing.

The three-dimensional morphology of the innervation of touch domes in the hairy skin folds of cat forepaws was investigated by the confocal laser scanning microscopic analyses of sections stained immunocytochemically with primary antibodies for protein gene product 9.5, neurofilament 200 and cytokeratin 20 in combination with transmission electron microscopic observations. One square centimeter of interdigital skin can contain as many as 68 touch domes. Each touch dome can have up to 150 Merkel cells and all are innervated by a single large-caliber afferent myelinated nerve fiber at the level of the palisade endings around the guard hair. It gives rise to multiple long, myelinated branches. Each final myelinated branch gives rise to several short and fine unmyelinated branches, supplying approximately 15 Merkel cell-axon complexes. Each Merkel cell is typically contacted by multiple small discoid endings instead of by a large single one. Discoid endings on separate Merkel cells were usually the distal ends of the unmyelinated branches, although, some were en-passant swellings of the branches. Only a few Merkel cell-axon complexes at the marginal zone of each territory could also be supplied by adjacent final myelinated branches. Each Merkel cell is surrounded by protrusions of keratinocytes that are penetrated by several collagen bundles of the dermis. This intricate pattern of innervation may explain the unique irregular discharges of action potentials typical for this type of mechanoreceptor.

Similarities and differences in the innervation of mystacial vibrissal follicle-sinus complexes in the rat and cat: a confocal microscopic study.

Our confocal three-dimensional analyses revealed substantial differences in the innervation to vibrissal follicle-sinus complexes (FSCs) in the rat and cat. This is the first study using anti-protein gene product 9.5 (PGP9.5) immunolabeling and confocal microscopy on thick sections to examine systematically the terminal arborizations of the various FSC endings and to compare them between two species, the rat and the cat, that have similar-appearing FSCs but different exploratory behaviors, such as existence or absence of whisking. At least eight distinct endings were clearly discriminated three dimensionally in this study: 1) Merkel endings at the rete ridge collar, 2) circumferentially oriented lanceolate endings, 3) Merkel endings at the level of the ring sinus, 4) longitudinally oriented lanceolate endings, 5) club-like ringwulst endings, 6) reticular endings, 7) spiny endings, and 8) encapsulated endings. Of particular contrast, each nerve fiber that innervates Merkel cells at the level of the ring sinus in the rat usually terminates as a single, relatively small cluster of endings, whereas in the cat they terminate en passant as several large clusters of endings. Also, individual arbors of reticular endings in the rat ramify parallel to the vibrissae and distribute over wide, overlapping territories, whereas those in the cat ramify perpendicular and terminate in tightly circumscribed territories. Otherwise, the inner conical body of rat FSCs contains en passant, circumferentially oriented lanceolate endings that are lacking in the cat, whereas the cavernous sinus of the cat has en passant corpuscular endings that are lacking in the rat. Surprisingly, the one type of innervation that is the most similar in both species is a major set of simple, club-like endings, located at the attachment of the ringwulst, that had not previously been recognized as a morphologically unique type of innervation. Although the basic structure of the FSCs is similar in the rat and cat, the numerous differences in innervation suggest that these species would have different tactile capabilities and perceptions possibly related to their different vibrissa-related exploratory behaviors.