3.4.3. 4.3. Axon
the level of the 12 thoracic vertebra; so the axon in an average-sized person is about 120 cm. The sensory fiber innervating the skin of the sole has similar length; its pseudounipolar cell body is in the spinal ganglion of the corresponding segment, and its central process terminates on interneurons of L4-L5. The pseudounipolar cell bodies of the proprioceptive sensory fibers starting from the muscle spindles of the abductor hallucis muscle are in the same level ganglion; however, their central process travels up about 50 cm to the medulla oblongata and synapses with the next neurons in the gracile nucleus. So this neuron, depending on body size, may be 150-180 cm long!
Figure 1.22. Figure 10.: Pyramidal cell, Golgi impregnation. The red arrows show the
axon. The branchindg apical dendrite and basal dendrites are also visible
50
Created by XMLmind XSL-FO Converter.
and vesicles are found in it but no ribosomes; hence, there is no protein synthesis. In the axon, the (-)-ends of microtubules are always directed toward the cell body. They are connected to each other with tau-proteins. This has neuropathological importance, because the altered chemical structure of tau-proteins in some neurodegenerative diseases causes the neurotubular system to fall apart and build “neurofibrillary tangles”. With this degradation, the microtubules are not able to fulfill their proper function (e. g. Alzheimer’s disease). The link below shows this process, and it gives an insight into the functioning of neurons and axonal transport:
http://www.youtube.com/watch?v=NjgBnx1jVIU
All elements of the sarcoplasm and sarcolemma are synthesized in the soma and are transported via axonal transport to the site of use. Mitochondria, vesicles containing transmitter, membrane proteins, enzymes and the membrane-coated substances move with fast anterograde transport to their destination (40 cm/day). The transported substances are bound to a protein called kinesin and walk along the microtubule. The function of kinesin is demonstrated in these animations:
http://www.youtube.com/watch?v=YAva4g3Pk6k http://www.youtube.com/watch?v=B_zD3NxSsD8
The soluble components of cytoskeleton are replaced by slow anterograde transport (1-6 mm/day).
The used membrane particles and cell organelles are wrapped in vacuoles at the axon terminals and are dragged back to the perikaryon by a protein named dynein along the microtubules (retrograde transport, 20 cm/day).
http://www.youtube.com/watch?v=-7AQVbrmzFw&playnext=1&list=PLGBItKa3GzCr0ArDTlF8ekj7iUXnDCy0B&feature=results_video
The pathological importance of the retrograde transport is that through this route toxins may be taken up by the nerve cells, and this is how some viruses cause disease, e.g. herpes simplex, poliovirus (cause of poliomyelitis), and the rabies virus.
3.4.4. 4.4. Sheaths of nerve fibers
3.4.4.1. 4.4.1. Sheaths of nerve fibers within the central nervous system
Within the central nervous system, the myelin sheath is formed by the flattened processes of oligodendrocytes that wrap around axons in their close vicinity in multiple layers (Fig. 11). A single oligodendrocyte ensheaths nearby segments of 10-50 axons. Along one axon between the myelin sheath segments made by different oligodendrocytes, Ranvier nodes are found (4.2.2.***) that are covered by astrocyte processes. In the CNS there is no lamina basalis on the surface of the nerve fibers.
Figure 1.23. Figure 11.: Myelinated nerve fibers in the central nervous system (electron
micrograph ). (Courtesy of Dr. Hajnalka Ábrahám, PTE ÁOK Electron Microscopy
Laboratory)
The bare axons, or axons covered only by astrocytes processes, are called neuropil; they only occur in the gray matter.
A demyelinating disease of the CNS is multiple sclerosis.
3.4.4.2. 4.4.2. Sheaths of nerve fibers in the peripheral nervous system
Figure 1.24. Figure 12.: Radicular filament (FR) exiting the spinal cord, HE staining.
The yellow arrow shows the Redlich-Obersteiner line. Above this line the myelin sheath is the product of Schwann cells. Below the line the axons are ensheathed by Schwann cells
Schwann cells may form two types of sheaths:
3.4.4.2.1. 4.4.2.1. Non-myelinated fibers
4.4.2.1. In case of non-myelinated fibers, several thin axons are embedded into the cytoplasm of one Schwann cell. The Schwann cell may be up to 500 micrometers in length. The cell membrane of the Schwann cell embraces the axon, connecting only with a double layer to the surface, but the axolemma is not hermetically sealed from the extracellular space. The entire fiber is surrounded by a lamina basalis, a product of the Schwann cell.
3.4.4.2.2. 4.4.2.2. Myelinated fibers
4.4.2.2. In case of myelinated fibers, a single axon is embedded into a Schwann cell, then the Schwann cell makes multiple rotations around the axon. Its mesaxon wraps around the axon. The external surface of these multiple layers of membranes is covered by a thin layer of the cytoplasm of the Schwann cell that contains the nucleus, too. The gap between myelin segments established by two neighboring Schwann cells is called Ranvier’s node. The segment itself is the internodium. The length of an internodium varies between 200-2000 micrometers. Thicker axons have thicker myelin sheath and longer internodiums, and their conduction velocity is faster. With growth, the internodium gets longer.
In the territory of the nodes of Ranvier, the axolemma is rich is Na+ channels, this allows the saltatory propagation of action potential. In these territories, microvillus-like projections of Schwann cells cover the axolemma.
the Schmidt-Lanterman incisures.
3.4.5. 4.5. Types of nerve fibers
Nerve fibers are classified according to their thickness and function. In the literature two types of classifications are present, the Erlanger/Gasser and the Lloyd/Hunt classification (Table 1).
The conduction velocity is dependent and proportional to the diameter of the axon. A rough calculation may be made based on the diameter of the nerve fiber; with each micrometer of the fiber, it increases by 5-6 m/sec. The thicker fibers are needed for fast reactions. (Consider, upon cutting bread with a sharp knife, if the knife cuts our hand we must act immediately, even 1-second delay would lead to a severe injury. After a mosquito bite or in case of appendicitis, it does not make a difference if we feel itching or pain a few seconds later.)
Table 1.5. Table 1.
Erlanger/
Gasser
Lloyd/ Hunt Diameter micrometer
Velocity m/sec
Myelinated fibers
A-alfa I.a, I.b 10-22 60-120 muscle spindle(Ia) and Golgi
tendon organ (Ib) afferents, skeletomotor efferents
A-beta II 7-15 40-90 muscle spindle afferents, afferents
from mechanoreceptors of the skin
A-gamma 4-9 30-45 muscle spindle efferents
A-delta III 3-5 5-25 skin afferents ( heat, pain)
B 1-3 3-15 preganglionic autonomic fibers
Non-myelinated fibers (only Schwann-sheath)
C IV 0,1-1 0,5-2 dull pain afferents, viscerosensory
and postganglionic autonomic fiber
3.5. 5. Peripheral nerve
In the peripheral nerve there are no perikarya. The number one element in the peripheral nerve is the nerve fiber, which is the axon of the nerve cell with its sheath. The sheath may be myelin sheath (4.4.2.2.***), or Schwann sheath (in this latter only the cytoplasm of the Schwann cell surrounds the axon). The axon exits from the sheath just before its termination.
(The terms nerve fiber and axon are not always used consistently in the books.) A peripheral nerve may contain:
• Afferent (sensory) nerve fibers, which are the peripheral processes of the pseudounipolar cells residing in the sensory ganglia.
• Efferent (motor) nerve fibers: these may belong to the somatic nervous system (in this case they are the myelinated axons of ventral horn motoneurons) and innervate skeletal muscle. In other cases, they belong to the autonomic nervous system, and they are either preganglionic thin myelinated fibers or postganglionic non-myelinated fibers.
If in anatomical terms we call a nerve “sensory”, it does not mean that it contains exclusively afferent fibers;
e.g., besides the afferent fibers, they may carry efferent fibers for vessels, glands, or arrector pili muscle.
Similarly, the “motor nerve” – besides the efferent fibers innervating skeletal muscle – contains also afferent fibers from muscle spindle receptor, Golgi tendon organ, and other receptors in the fascia (7.1.3, 7.1.4.***).
bundles; distally the number of bundles increases, but their size decreases.
Figure 1.25. Figure 13.: Peripheral nerve (e.g. median nerve), HE staining A: low magnification, Ep= epineurium, P=perineurium (The perineurium surrounds the nerve fiber bundles) B: Detail of a nerve fiber bundle P=perineurium, En=endoneurium between the nerve fibers C: nerve fibers, high magnification En=endoneurium, A=
axon, surrounded by myelin sheath, above it the semilunar shaped nucleus of the Schwann cell. The green ring marks a territory with thin myelinated and non-myelinated fibers.)
Each fascicle is surrounded by the ring of perineurium. Inside the fascicle, the individual nerve fibers are separated by delicate connective tissue. The fascicles are embedded into a loose connective tissue with fat cells and occasional thick collagen bundles; this is the epineurium. The proportion of connective tissue elements varies depending on the possible mechanical trauma affecting the nerve. One may find examples for this during dissection; the intracranial parts of cranial nerves or the radicular filaments of the spinal cord contain minimal connective tissue elements; hence, they are very vulnerable. The “true” peripheral nerves are protected by the connective tissue coverings from mechanical and chemical trauma. Nerves are a little “elastic” because of the slightly spiraling course of nerve fibers. As a consequence, the course of the fibers in histological slides may appear whirlpool-like, especially if in a thicker slide the fine adjustment is turned a little.
3.5.1.1. 5.1.1. Endoneurium
The endoneurium consists of thin bundles of collagen type I fibers, which run parallel with the nerve fibers.
Around the endoneurial vessels we see some condensation. The nuclei within a fascicle belong mostly to Schwann cells. About 4 % of the cells are fibrocytes; and endothelial cells, macrophages and mast cells are also present. The muscle layer of the endoneurial vessels is very thin, their innervation is poor. The pressure of the endoneurial interstitial fluid is slightly higher than outside the perineurium.
3.5.1.2. 5.1.2. Perineurium
The inner layer of the perineurium consists of flattened cells, which may build up 15-20 layers. The cells are connected by tight-junctions, have a thick lamina basalis (0.5 micrometer), and between them few collagen fibers are interpositioned. Within the perineurial cells, microfilament bundles and pinocytotic vesicles may be observed. These cells make a diffusion barrier and the blood-nerve barrier between nerve fibers and surrounding tissues, and they maintain the higher pressure and the proper osmotic milieu within the perineurial compartment.
The flat cells of the perineurium are possibly derived from fibrocytes, but it is also raised that they are special glial cells of ectodermal origin.
The external layer of the perineurium is called pars fibrosa. This is a meshwork of collagen fibers. As the nerve gets thinner, it may completely disappear,
(In case of a peripheral nerve injury, to ensure proper regeneration (6.***) the nerve is surgically separated to perineurium-covered fascicles and the perineurium is reunited.)
3.5.1.3. 5.1.3. Epineurium
Epineurium is continuous with dura mater, but it is of mesodermal origin. It is loose connective tissue with longitudinal bundles of collagen fibers and numerous fat cells. It contains the blood and lymph vessels supplying the nerve. The epineurium gives 30-70% of the total volume of the nerve.
In the largest nerves, an outermost connective tissue layer - the paraneurium – allows the nerve to slide freely within the surrounding tissues.
3.6. 6. Degeneration and regeneration of nerve fibers
If the injury is close to the perikaryon, the nerve cell dies in most cases. If the injury is further away, distally from the transsection, the axon and myelin sheath disintegrates with Wallerian degeneration. The proximal axon stump degenerates up to the first Ranvier node, the soma swells, and signs of chromatolysis may be observed in the cytoplasm. The rough endoplasmic reticulum releases the ribosomes, the nucleus is excentric, and the number of dendrites and synapses is reduced. In the restitution phase, the perikaryon tries to regenerate the axon.
In the CNS, the chances for successful regeneration are minimal, and the re-growing axon is lost, since there is nothing that would help it to find the right way. Distally from the transsection, the oligodendrocyte myelin sheath disintegrates with Wallerian degeneration.
In peripheral nerves distal from the injury, the axon disintegrates through Wallerian degeneration (the axon swells and disintegrates with its myelin sheath), but the Schwann cell itself stays alive and keeps its lamina basalis. They are arranged in rows and form bundles of Büngner. This tube-shaped structure – in case the cut ends are close enough – allows the growing axon to find its innervation territory. The proximal axon stump sprouts, and the central growth cone grows in the direction where it finds appropriate extracellular milieu. This milieu is provided by the Schwann cells of the Büngner bundles and endoneurial fibroblasts, which produce nerve growth factor (NGF), fibrocyte growth factor (FGF), insulin-like growth factor (IGF) and other transcription factors.
Uniting the cut ends of nerves requires precise surgical technique. The damaged parts of the nerves have to be removed, and the perineurium has to be sewn together with no gap and without tension. The axon grows 2-5 mm per day. For successful regeneration, younger individuals have greater chances.
3.7. 7. Nerve terminals
A part of the peripheral terminals respond to stimuli coming from the internal or external environment. These are called receptors in the skin, sensory organs, and viscera. From the terminals, these stimuli are conveyed to the CNS. Complicated neuronal networks elaborate the response, and the “command” is executed by the terminals of motoneurons; these terminals are called effectors. Effectors may connect to skeletal muscle, smooth muscle, or glands.
resemblance to epithelia; hence, traditionally they are called sensory epithelia. Receptors may be categorized according to their location: exteroceptors transmit stimuli from the external environment; proprioceptors give information about joint angle and muscle length; while the visceroceptors are located in the wall of inner organs.
According to modality, they may be mechano-, thermo-, chemo, and baroreceptors, or nociceptors, which react to pain.
Receptors typically consist of three components: the peripheral processes of pseudounipolar cells in the sensory ganglia, glial cells, and connective tissue elements.
3.7.1.1. 7.1.1. Primary sensory epithelium
In the mucous membrane of the nasal cavity, in the olfactory region, placode-derived primary sensory epithelial cells are embedded, surrounded by supporting cells. These cells resemble bipolar neurons. Their peripheral processes, the olfactory cilia, perceive odors. The axons starting from the basal part of the cells are the fila olfactoria, which pass through the cribriform plate and synapse with the mitral cells of the olfactory bulb.
3.7.1.2. 7.1.2. Secondary sensory epithelium
Secondary sensory epithelial cells are found in taste buds and in the vestibulocochlear system (Fig.14). They are surrounded by supporting cells. From a certain aspect, the Merkel cells could also belong to this group; they will be described with the mechanoreceptors of the skin (7.1.3.1.***). These sensory epithelial cells release transmitter. The sensory epithelial cells connect to the axons through synapse-like structures and elicit action potential. The axon is the peripheral ending of an afferent fiber; its perikaryon may be pseudounipolar or bipolar and may be located in a spinal ganglion or a sensory ganglion of a cranial nerve, from where the central process of the nerve cell leads to the CNS.
Figure 1.26. Figure 14.: Corti organ, HE staining. The arrows point at the nuclei of secondary sensory epithelial cells
3.7.1.3. 7.1.3. Exteroceptors
Exteroceptors are located typically in the skin, in the subcutaneous connective tissue, or in mucous membranes close to body openings. They receive information from outside the body (mechano-, thermo-, chemoreceptors, and nociceptors). The fibers terminating in these receptors are in most cases myelinated fibers.
The fibers are surrounded by small organelles built from Schwann cells, perineurial cells, and connective tissue.
Their function is to amplify and convey information from the environment.
epidermis and are connected to the neighboring cells by desmosomes. Because there are neuropeptides (e.g.
metencephalin, bombesin) and serotonin in their cytoplasm, they may be classified also as neuroendocrine cells.
The axon connects to the basal surface of Merkel cells with synapse-type structures.
3.7.1.3.2. 7.1.3.2. Meissner body
Meissner bodies are rapidly adapting touch and pressure receptors. They are ovoid organelles, sitting in the connective tissue papillae, close to the epidermis. They are especially numerous in fingertips and in the lip.
They consist of flattened Schwann cells arranged as irregular disks, fixed to each other with fine collagen fibrils.
The fibrils are also connected to the basal lamina, and they react well to its movement. The Meissner body has a fine capsule in its basal part that is derived from perineurial cells. The axons approaching the Meissner body step out from their myelin sheath and enter the capsule. One to seven axons enter the Meissner body from below and follow a spiraling course between the Schwann cell lamellae.
3.7.1.3.3. 7.1.3.3. Receptors in the vicinity of hair follicles
Receptors in the vicinity of hair follicles are rapidly adapting receptors arranged like a collar in the connective tissue around the hair follicle. The flattened axon terminals are covered by Schwann cells. They react to the movement of the hair follicle. In addition, the hair follicle contains Merkel cells, and in its vicinity free nerve ending and lamellar body-like receptors are also found.
3.7.1.3.4. 7.1.3.4. Pacinian corpuscle (lamellar body)
Pacinian corpuscles are oval, 1-4 mm large, very rapidly adapting lamellar receptors located subcutaneously (Fig. 15). They receive information from a large area; they react to pressure acceleration and especially to vibration. They have great importance in carrying out fine manipulation. They are present also in the mesentery, pancreas, bladder, intermuscular septa, fascia of muscles, and vagina.
In the longitudinal axis of the Pacinian corpuscle, there are one or two axon terminals with many mitochondria.
The axon may branch sometimes or have a spiral course, and it is surrounded by Schwann cells; this is the inner cylinder. The external lamellar layers (up to 50) consist of perineurial cells. Each layer is covered by basal lamina. Between the layers there are collagen fibrils, proteoglycans, interstitial fluid, and small vessels. The external surface of the Pacinian corpuscle is covered by a connective tissue capsule.
Figure 1.27. Figure 15.: Pacinian corpuscle, silver-nitrate impregnation
3.7.1.3.5. 7.1.3.5. Ruffini’s end organ
collagenous fibers are fixed in multiple directions.
3.7.1.3.6. 7.1.3.6. Free nerve endings
Free nerve endings may be nociceptors (pain perception), or thermo- and mechanoreceptor. They occur in the skin, inner organs, and motor system. Sharp pain is conveyed by A-delta fibers, dull pain by non-myelinated C-fibers.
3.7.1.4. 7.1.4. Proprioceptors
Proprioceptors (=sense of self) report to CNS about tone and tension of muscles, tendons, ligaments, and articular capsules.
3.7.1.4.1. 7.1.4.1. Golgi tendon organ
Golgi tendon organs provide information about muscle tension. Their typical location is the connection between muscle and tendon. They are spindle-shaped structures, 1-1.5 mm long and 100-120 micrometer wide. The outer layer is made up from flattened perineurial cells. The collagen fibrils in the inside connect the muscle fibers to the capsule of the organ. The external surface is covered by collagenous fibers of the tendon. The capsule is pierced by several nerve fibers (type Ib). These nerve fibers lose their myelin sheath and branch richly. The branching axons are covered by Schwann cells, the lamina basalis of which connect to the meshwork of collagen fibrils in the inside of the tendon organ.
This receptor is designed to monitor the tension of the muscle. In case the muscle contracts too strongly and there is a danger of muscle rupture, then the impulses of the tendon organ inhibit the activity of motoneurons.
3.7.1.4.2. 7.1.4.2. Muscle spindle
3.7.1.4.2. 7.1.4.2. Muscle spindle