Nuclei in the section belong to lemmocytes, although some belong to fibrocytes of the endoneurium. Transverse section throung a canine vagus nerve. Only myelin sheaths plus some lipid associated wth epineurium and perineurium are stained. Notice the rage in size of myelinated fibers. Within a fascicle, the white gaps between myelinated fibers are occupied by non-myelinated fibers. Although some myelinated preganglionic fibers are present, non-myelinated postganglionic fibers predominate in this longitudinal section through a bovine sympathetic trunk.
Non-myelinated fibers are thin and they blend with lemmocyte cytoplasm. Notice the high density of lemmocyte nuclei, the wavy pattern of nerve fibers, and evidence of connective tissue sheaths.
Go Top. Spinal Cord. It thus contributes to the tensile strength of the nerve, but does not form barriers. Perineurium isolates groups of axon-Schwann cell units to form nerve fascicles and constitutes the main diffusion barrier between the endoneurium and the extrafascicular tissues.
The number of perineurial cell layers varies according to the number and size of the fascicles in the nerve; the largest fascicles in, e. The thickness of the perineurium also decreases toward the nerve periphery where smallest fascicles may only have one or two perineurial layers.
The extracellular matrix is composed of fibrillar and microfibrillar collagens and fibronectin which provide the perineurium with the ability to modulate external stretching forces thus regulating the endoneurial pressure. Thus, Schwann cell and perineurial basement membranes are somewhat distinct with respect to their laminin isoforms but the significance of this difference is not known. Endoneurium contains groups of axon-Schwann cell units embedded in extracellular matrix which has thin collagen fibrils and gel-like consistency, as evaluated under preparation microscope.
Axons are covered by Schwann cells which form either myelin or amyelin sheath. Myelinating Schwann cell membranes wrap around the axon resulting in multilamellar membrane structures. The myelin sheath is divided into compacted and non-compacted myelin compartments. Non-compact myelin is present in three locations: 1 immediately next to the nodes of Ranvier paranodal region which allow the electrical impulse to conduct quickly, 2 in Schmidt-Lanterman incisures located inside of compacted myelin sheath and 3 the inner and outer mesaxons where the volume of Schwann cell cytoplasm is increased compared with the areas of compacted myelin.
Several types of autotypic junctions, including tight junctions, participate in the adhesion of apposed membrane lamellae in the sites of non-compacted myelin Fig.
Perineurium forms a metabolically active diffusion barrier in the peripheral nerve. Perineurial barrier has three structural and functional components: 1 Basement membranes surrounding each perineurial cell layer see above , 2 tight junctions between the neighboring perineurial cells and 3 active transcytotic transport through the perineurial cells.
Strands of tight junctions have been visualized in ultrastructural studies at the interdigitating perineurial cell borders. Tracer and electrophysiological studies have shown that perineurium constitutes a tight but selective barrier.
Since this report, several new members of the claudin family and other tight junction proteins have been characterized but they have not been mapped to human perineurium so far. Transcytosis, as evidenced by the presence of numerous pinocytotic vesicles, provides an alternative route through perineurium. Ultrastructural studies have shown numerous pinocytotic vesicles in perineurial cells, but this phenomenon has not been studied at the molecular level.
Molecules can also be actively transported across the perineurium via specific membrane receptors. Of various receptors studied only Glucose transporter 1 GLUT -1 has been localized to human and rat perineurium. During the fetal life the diameter of peripheral nerves increases due to the growth of fascicles in size and in number, as well as due to the synthesis of extracellular matrix. The number and the thickness of perineurial cell layers increase and intrafascicular septae become more visible.
In human, development of the perineurial diffusion barrier takes place relatively late. During the first trimester, perineurium is composed of one or two layers of perineurial cells and thin intrafascicular septae can be distinguished. The tight junction strands with linear distribution of occludin, ZO-1 and claudin-1 and -3 are detectable at 35 fetal weeks, but the labeling of tight junctions is still not as continuous as in adults.
The basement membrane components type IV collagen and laminins appear concomitantly with the expression of tight junction proteins and basement membranes become continuous at the end of the third trimester. Blood-nerve barrier is located in the blood vessel walls of the endoneurial vasculature. Here tight junctions are found between endothelial cells and between pericytes. Endoneurial blood vessels isolate the endoneurim from the circulating blood thus preventing uncontrollable molecule and ion leak from circulatory system to peripheral nerve.
Blood-nerve barrier is thus analogous to the blood-brain barrier. The blood vessels entering the endoneurium through perineurium are first covered by a sleeve of perineurial cells. The pericytes are also covered by continuous basement membrane. Endoneurial capillaries differ ultrastructurally from epi- and perineurial vessels since the endoneurial capillaries are lined by non-fenestrated endothelial cells containing few plasmalemmal vesicles.
Also this fact suggests that endoneurial vessels have tighter permeability characteristics than epineurial vessels. The barrier properties of the endoneurial blood vessels have been studied mainly in animal models. The endothelial cell cultures from rat sciatic nerves have been shown to develop higher transendothelial electrical resistance TEER than HUVEC cultures, which is an indication of well-developed tight junctions.
Downregulation of claudin-5 and ZO-1 in endothelium has been shown in chronic inflammatory demyelinating neuropathy. The endoneurial pericytes have been shown to be essential for the function of the blood-nerve-barrier.
In analogy to perineurial cells, pericytes actively transfer molecules through cells. In analogy to cells of simple epithelia whose polarity is defined by localization of junctional proteins, a myelinating cell is divided to compacted and non-compacted areas by autotypic junctions between the membranes of the same Schwann cell Fig.
The exact function of Schwann cell autotypic junctions is not known but it has been suggested that they separate the outer membrane and the extracellular space from the compact myelin and also provide the membrane associations for mechanical strength. The composition of the Schwann cell autotypic junctions has mainly been studied in rodents which express claudin-1,-2,-5,, ZO-1 and ZO-2 in Schwann cells Table 1. Claudin is highly expressed in mouse peripheral nerve and localized to Schmidt-Lanterman incisures, paranodal region and inner and outer mesaxons.
Expression of mRNA for claudin-1,-2,-3, -5,-9 and has been detected in adult human peripheral nerve. Schmidt-Lanterman incisures were positive for claudin-1,-2, -3 and -5, occludin, ZO-1 and E-cadherin. Claudin-1,-2,and -3, ZO-1, occludin and E-cadherin, but not claudin-5, were localized to mesaxons Table 1. Tight junction components have also been examined in developing endoneurium of human sciatic nerves. During the first trimester, tight junction components were not reliably detectable.
On fetal week 22, antibodies for claudin-1, claudin-3, occludin and ZO-1 showed punctate and linear labeling suggesting mesaxonal localization.
At the end of third trimester week 37 labeling pattern of all four tight junction components was linear and occasionally claudin-1 and claudin-3 labeling could be mapped to Schmidt-Lanterman incisures as a sign of myelination. Several claudin mouse models have been reported but only two of them focus on claudin in peripheral nerve. Claudin knockout resulted in abnormal gait because of peripheral nervous system defect and specifically Schwann cell barrier defect, but did not show defects in kidney.
Tight junctions of epithelial cells have been reported to participate in membrane trafficking and vesicle transport, and tight junction proteins are in close contact with other proteins guiding traffic to apical or basolateral membranes. To conclude, myelinating cells have distinct structures, including autotypic junctions, dense membrane lamellae, paranodal regions and Schmidt-Lanterman incisures.
Various events which disturb function or integrity of myelinating cell structure can lead to neuronal defects. While the perineurial barrier serves as protection, it simultaneously inhibits delivery of analgesic drugs to peripheral nerve. Rodent studies have shown that hypertonic saline transiently opens the barrier allowing also hydrophilic drugs to reach their target, such as opioid receptors. When studied further, the ability to regulate perineurial diffusion by downregulating claudin-1 may potentially be an important clinical application of claudin research.
Perineurium has an important role in the nerve repair process after trauma. Tight and gap junctions have been elucidated in several experimental studies during recovery of perineurium. The traditional and most widely used peripheral nerve injury model is crush injury which leads to opening of the perineurial barrier and distortion of the neural homeostasis.
A more sophisticated injury model is the perineurial window model, in which excision of perineum induces focal demyelination of the remaining nerve fibers in the center of nerve fascicles. Detectable signs of recovery process, such as thin perineurial cell layer and first evidence of tight junctions appear within one week, and by three weeks perineurium has tight junction strands and gap junctions.
Perineurial window model emphasizes the role of tight junctions in perineurial repair process. Gap junctions appeared rather late, within five days and the nerve recovery was accomplished during seven days.
Endoneurial blood vessels recovered quickly and full function of blood-nerve barrier was achieved during five days. Expression of claudin-1 belongs to constant characteristics of perineurial cells, and claudin-1 can be used as a marker for neoplastic perineurial cells, along with Glut-1 and EMA.
Claudin-1 is expressed by benign and malignant perineurial tumor cells. Studies on tight junction proteins of nervous system are mainly focused on the blood-brain barrier in conditions such as Alzheimer disease, brain stroke, epilepsy and Parkinson disease. Failures in structure or function of blood-brain barrier may result in the development of neurological disease.
The importance of pericytes is emphasized in diabetic neuropathy in which pericyte degeneration and loss with thickening of basement membranes are the main features. Decreased claudin-5 expression in endothelial cells weakens blood-nerve barrier and may lead to demyelinating polyradiculoneuropathy. Human mutations in claudin-1, , and genes have been discovered but none of these have led to symptomps of peripheral nerve. Studies on neural barriers have mainly concentrated on blood-brain and blood-nerve barriers while knowledge of functions and molecular basis of perineurial barrier are still sparse.
Thus, there are many unanswered questions concerning, e. Only a few claudin types have been mapped to perineurium and there may still be tight junction components which have not been studied for this respect. In the central nervous system, the analogous structures are known as tracts. Neurons are sometimes referred to as nerve cells, although this term is misleading since many neurons do not occupy nerves, and nerves also include non-neuronal support cells glial cells that contribute to the health of enclosed neurons.
Each nerve contains many axons that are sometimes referred to as fibers. Within a nerve, each axon is surrounded by a layer of connective tissue called the endoneurium. The axons are bundled together into groups called fascicles. Each fascicle is wrapped in a layer of connective tissue called the perineurium. Finally, the entire nerve is wrapped in a layer of connective tissue called the epineurium.
See the following illustrations of these structures. The endoneurium consists of an inner sleeve of material called the glycocalyx and a mesh of collagen. Nerves are bundled along with blood vessels, which provide essential nutrients and energy to the enclosed, and metabolically demanding, neurons. Within the endoneurium, individual nerve fibers are surrounded by a liquid called the endoneurial fluid.
The endoneurium has properties analogous to the blood—brain barrier. It prevents certain molecules from crossing from the blood into the endoneurial fluid. In this respect, endoneurial fluid is similar to cerebrospinal fluid in the central nervous system. During nerve irritation or injury, the amount of endoneurial fluid may increase at the site of damage. This increase in fluid can be visualized using magnetic resonance neurography to diagnose nerve damage. An illustration of a cross-section of a nerve highlighting the epineurium and perineurium.
Individual axons can also be seen as tiny circles within each perineurium. A nerve conveys information in the form of electrochemical impulses known as nerve impulses or action potentials carried by the individual neurons that make up the nerve.
The impulses travel from one neuron to another by crossing a synapse, and the message is converted from electrical to chemical and then back to electrical. Neurologists usually diagnose disorders of the nerves by a physical examination, including the testing of reflexes, walking and other directed movements, muscle weakness, proprioception, and the sense of touch.
This initial exam can be followed with tests such as nerve conduction study, electromyography, or computed tomography. Nerves are primarily classified based on their direction of travel to or from the CNS, but they are also subclassified by other nerve characteristics. Nerves are categorized into three, primary groups based on the direction of signal transmission within the nervous system.
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