Axon

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Axon
Blausen 0657 MultipolarNeuron.png
An axon of a multipolar neuron
Identifiers
MeSH D001369
Anatomical terminology

An axon (from Greek ἄξων áxōn, axis), or nerve fiber, is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons (pseudounipolar neurons), such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body, and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction has caused many inherited and acquired neurological disorders which can affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

Neuron electrically excitable cell

A neuron, also known as a neurone and nerve cell, is an electrically excitable cell that communicates with other cells via specialized connections called synapses. All multicellular organisms except sponges and Trichoplax have neurons. A neuron is the main component of nervous tissue.

Action potential A process in which membrane potential cycles through a depolarizing spike, triggered in response to depolarization above some threshold, followed by repolarization. This cycle is driven by the flow of ions through various voltage gated channels with

In physiology, an action potential occurs when the membrane potential of a specific axon location rapidly rises and falls: this depolarisation then causes adjacent locations to similarly depolarise. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, endocrine cells, and in some plant cells.

Soma (biology) The portion of the cell soma (neuronal cell body) that excludes the nucleus.

The soma, perikaryon, neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. The word 'soma' comes from the Greek 'σῶμα', meaning 'body'. Although it is often used to refer to neurons, it can also refer to other cell types as well, including astrocytes, oligodendrocytes, and microglia. There are many different specialized types of neurons, and their sizes vary from as small as about 5 micrometres to over 10 millimetre for some of the smallest and largest neurons of invertebrates, respectively.

Contents

An axon is one of two types of cytoplasmic protrusions from the cell body of a neuron; the other type is a dendrite. Axons are distinguished from dendrites by several features, including shape (dendrites often taper while axons usually maintain a constant radius), length (dendrites are restricted to a small region around the cell body while axons can be much longer), and function (dendrites receive signals whereas axons transmit them). Some types of neurons have no axon and transmit signals from their dendrites. In some species, axons can emanate from dendrites and these are known as axon-carrying dendrites. [1] No neuron ever has more than one axon; however in invertebrates such as insects or leeches the axon sometimes consists of several regions that function more or less independently of each other. [2]

Cytoplasm all of the contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures

In cell biology, the cytoplasm is all of the material within a cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The main components of the cytoplasm are cytosol – a gel-like substance, the organelles – the cell's internal sub-structures, and various cytoplasmic inclusions. The cytoplasm is about 80% water and usually colorless.

Dendrite neuron projection that has a short, tapering, often branched, morphology, receives and integrates signals from other neurons or from sensory stimuli, and conducts a nerve impulse towards the axon or the cell body

Dendrites, also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project. Electrical stimulation is transmitted onto dendrites by upstream neurons via synapses which are located at various points throughout the dendritic tree. Dendrites play a critical role in integrating these synaptic inputs and in determining the extent to which action potentials are produced by the neuron. Dendritic arborization, also known as dendritic branching, is a multi-step biological process by which neurons form new dendritic trees and branches to create new synapses. The morphology of dendrites such as branch density and grouping patterns are highly correlated to the function of the neuron. Malformation of dendrites is also tightly correlated to impaired nervous system function. Some disorders that are associated with the malformation of dendrites are autism, depression, schizophrenia, Down syndrome and anxiety.

Axons are covered by a membrane known as an axolemma; the cytoplasm of an axon is called axoplasm. Most axons branch, in some cases very profusely. The end branches of an axon are called telodendria. The swollen end of a telodendron is known as the axon terminal which joins the dendron or cell body of another neuron forming a synaptic connection. Axons make contact with other cells—usually other neurons but sometimes muscle or gland cells—at junctions called synapses. In some circumstances, the axon of one neuron may form a synapse with the dendrites of the same neuron, resulting in an autapse. At a synapse, the membrane of the axon closely adjoins the membrane of the target cell, and special molecular structures serve to transmit electrical or electrochemical signals across the gap. Some synaptic junctions appear along the length of an axon as it extends—these are called en passant ("in passing") synapses and can be in the hundreds or even the thousands along one axon. [3] Other synapses appear as terminals at the ends of axonal branches.

The axolemma is the cell membrane surrounding an axon. It is responsible for maintaining the membrane potential of the neuron, and it contains ion channels through which ions can flow rapidly. When this occurs, the voltage inside the axon changes, and depolarization or hyperpolarization of the membrane can occur. Adequate depolarization can lead to an action potential, which travels down the axon in a self-propagating manner as more ion channels open due to stimulation by the influx of positive ions. An unmyelinated axolemma has a high capacitance which imposes a restraint on the conduction speed.. The constricted axon segment is one of the few locations in which there is ten times more schwann cell membrane than axolemma, while other portions they have equal distributions.

Axoplasm is the cytoplasm within the axon of a neuron. Neurites contain about 99.6% of the cell’s cytoplasm, and 99.7% of that is in the axons.

Axon terminal Terminal inflated portion of the axon, containing the specialized apparatus necessary to release neurotransmitters. The axon terminus is considered to be the whole region of thickening and the terminal bouton is a specialized region of it.

Axon terminals are distal terminations of the telodendria (branches) of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses called action potentials away from the neuron's cell body, or soma, in order to transmit those impulses to other neurons, muscle cells or glands.

A single axon, with all its branches taken together, can innervate multiple parts of the brain and generate thousands of synaptic terminals. A bundle of axons make a nerve tract in the central nervous system, [4] and a fascicle in the peripheral nervous system. In placental mammals the largest white matter tract in the brain is the corpus callosum, formed of some 20 million axons in the human brain. [4]

Nerve tract bundle of nerve fibers (axons) connecting nuclei of the central nervous system

A nerve tract is a bundle of nerve fibers (axons) connecting nuclei of the central nervous system. In the peripheral nervous system this is known as a nerve. The main nerve tracts in the central nervous system are of three types: association fibers, commissural fibers, and projection fibers. A tract may also be referred to as a commissure, fasciculus or decussation. A commissure connects the two cerebral hemispheres at the same levels. Examples are the posterior commissure and the corpus callosum. A decussation is a connection made by fibres that cross at different levels (obliquely), such as the sensory decussation. Examples of a fascicle are the subthalamic fasciculus and the lenticular fasciculus.

Central nervous system part of the nervous system consisting of the brain and spinal cord

The central nervous system (CNS) is the part of the nervous system consisting of the brain and spinal cord. The central nervous system is so named because it integrates the received information and coordinates and influences the activity of all parts of the bodies of bilaterally symmetric animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish—and it contains the majority of the nervous system. Many consider the retina and the optic nerve, as well as the olfactory nerves and olfactory epithelium as parts of the CNS, synapsing directly on brain tissue without intermediate ganglia. As such, the olfactory epithelium is the only central nervous tissue in direct contact with the environment, which opens up for therapeutic treatments. The CNS is contained within the dorsal body cavity, with the brain housed in the cranial cavity and the spinal cord in the spinal canal. In vertebrates, the brain is protected by the skull, while the spinal cord is protected by the vertebrae. The brain and spinal cord are both enclosed in the meninges. In central nervous systems, the interneuronal space is filled with a large amount of supporting non-nervous cells called neuroglial cells.

Nerve fascicle

A nerve fascicle, or fasciculus is a bundle of funiculi. A funiculus is a bundle of axons.

Anatomy

A typical myelinated axon Neuron.svg
A typical myelinated axon
A dissected human brain, showing grey matter and white matter Human brain right dissected lateral view description.JPG
A dissected human brain, showing grey matter and white matter

Axons are the primary transmission lines of the nervous system, and as bundles they form nerves. Some axons can extend up to one meter or more while others extend as little as one millimeter. The longest axons in the human body are those of the sciatic nerve, which run from the base of the spinal cord to the big toe of each foot. The diameter of axons is also variable. Most individual axons are microscopic in diameter (typically about one micrometer (µm) across). The largest mammalian axons can reach a diameter of up to 20 µm. The squid giant axon, which is specialized to conduct signals very rapidly, is close to 1 millimetre in diameter, the size of a small pencil lead. The numbers of axonal telodendria (the branching structures at the end of the axon) can also differ from one nerve fiber to the next. Axons in the central nervous system (CNS) typically show multiple telodendria, with many synaptic end points. In comparison, the cerebellar granule cell axon is characterized by a single T-shaped branch node from which two parallel fibers extend. Elaborate branching allows for the simultaneous transmission of messages to a large number of target neurons within a single region of the brain.

Nervous system Control the whole body function

The nervous system is the part of an animal that coordinates its actions by transmitting signals to and from different parts of its body. The nervous system detects environmental changes that impact the body, then works in tandem with the endocrine system to respond to such events. Nervous tissue first arose in wormlike organisms about 550 to 600 million years ago. In vertebrates it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers or axons, that connect the CNS to every other part of the body. Nerves that transmit signals from the brain are called motor or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory or afferent. Spinal nerves serve both functions and are called mixed nerves. The PNS is divided into three separate subsystems, the somatic, autonomic, and enteric nervous systems. Somatic nerves mediate voluntary movement. The autonomic nervous system is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state. The enteric nervous system functions to control the gastrointestinal system. Both autonomic and enteric nervous systems function involuntarily. Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves.

Sciatic nerve large nerve in humans and other animals

The sciatic nerve is a large nerve in humans and other animals. It begins in the lower back and runs through the buttock and down the lower limb. It is the longest and widest single nerve in the human body, going from the top of the leg to the foot on the posterior aspect. The sciatic nerve provides the connection to the nervous system for nearly the whole of the skin of the leg, the muscles of the back of the thigh, and those of the leg and foot. It is derived from spinal nerves L4 to S3. It contains fibers from both the anterior and posterior divisions of the lumbosacral plexus.

Spinal cord long, thin, tubular bundle of nervous tissue and support cells that extends from the brain

The spinal cord is a long, thin, tubular structure made up of nervous tissue, that extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column. It encloses the central canal of the spinal cord that contains cerebrospinal fluid. The brain and spinal cord together make up the central nervous system (CNS). In humans, the spinal cord begins at the occipital bone where it passes through the foramen magnum, and meets and enters the spinal canal at the beginning of the cervical vertebrae. The spinal cord extends down to between the first and second lumbar vertebrae where it ends. The enclosing bony vertebral column protects the relatively shorter spinal cord. It is around 45 cm (18 in) in men and around 43 cm (17 in) long in women. Also, the spinal cord has a varying width, ranging from 13 mm thick in the cervical and lumbar regions to 6.4 mm thick in the thoracic area.

There are two types of axons in the nervous system: myelinated and unmyelinated axons. [5] Myelin is a layer of a fatty insulating substance, which is formed by two types of glial cells Schwann cells and oligodendrocytes. In the peripheral nervous system Schwann cells form the myelin sheath of a myelinated axon. In the central nervous system oligodendrocytes form the insulating myelin. Along myelinated nerve fibers, gaps in the myelin sheath known as nodes of Ranvier occur at evenly spaced intervals. The myelination enables an especially rapid mode of electrical impulse propagation called saltatory conduction.

Myelin fatty white substance, multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction; it is an outgrowth of a type of glial cell

Myelin is a lipid-rich (fatty) substance formed in the central nervous system (CNS) by glial cells called oligodendrocytes, and in the peripheral nervous system (PNS) by Schwann cells. Myelin insulates nerve cell axons to increase the speed at which information travels from one nerve cell body to another or, for example, from a nerve cell body to a muscle. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, each myelin sheath insulates the axon over a single section and, in general, each axon comprises multiple long myelinated sections separated from each other by short gaps called Nodes of Ranvier. Each myelin sheath is formed by the concentric wrapping of an oligodendrocyte or Schwann cell process around the axon.

Schwann cell

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

Oligodendrocyte

Oligodendrocytes, or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of some vertebrates, equivalent to the function performed by Schwann cells in the peripheral nervous system. Oligodendrocytes do this by creating the myelin sheath, which is 80% lipid and 20% protein. A single oligodendrocyte can extend its processes to 50 axons, wrapping approximately 1 μm of myelin sheath around each axon; Schwann cells, on the other hand, can wrap around only one axon. Each oligodendrocyte forms one segment of myelin for several adjacent axons.

The myelinated axons from the cortical neurons form the bulk of the neural tissue called white matter in the brain. The myelin gives the white appearance to the tissue in contrast to the grey matter of the cerebral cortex which contains the neuronal cell bodies. A similar arrangement is seen in the cerebellum. Bundles of myelinated axons make up the nerve tracts in the CNS. Where these tracts cross the midline of the brain to connect opposite regions they are called commissures. The largest of these is the corpus callosum that connects the two cerebral hemispheres, and this has around 20 million axons. [4]

The structure of a neuron is seen to consist of two separate functional regions, or compartments – the cell body together with the dendrites as one region, and the axonal region as the other.

Axonal region

The axonal region or compartment, includes the axon hillock, the initial segment, the rest of the axon, and the axon telodendria, and axon terminals. It also includes the myelin sheath. The Nissl bodies that produce the neuronal proteins are absent in the axonal region. [3] Proteins needed for the growth of the axon, and the removal of waste materials, need a framework for transport. This axonal transport is provided for in the axoplasm.

Axon hillock

Detail showing microtubules at axon hillock and initial segment. Neuron Cell Body.png
Detail showing microtubules at axon hillock and initial segment.

The axon hillock is the area formed from the cell body of the neuron as it extends to become the axon. It precedes the initial segment. The received action potentials that are summed in the neuron are transmitted to the axon hillock for the generation of an action potential from the initial segment.

Initial segment

The axonal initial segment (AIS) is a structurally and functionally separate microdomain of the axon. [6] [7] One function of the initial segment is to separate the main part of an axon from the rest of the neuron; another function is to help initiate action potentials. [8] Both of these functions support neuron cell polarity, in which dendrites (and, in some cases, soma) of a neuron receive input signals and the neuron's axon provides output signals. [9]

The axon initial segment is unmyelinated and contains a specialized complex of proteins. It is between approximately 20 and 60 µm in length and functions as the site of action potential initiation. [10] [11] Both the position on the axon and the length of the AIS can change showing a degree of plasticity that can fine-tune the neuronal output. [10] [12] A longer AIS is associated with a greater excitability. [12] Plasticity is also seen in the ability of the AIS to change its distribution and to maintain the activity of neural circuitry at a constant level. [13]

The AIS is highly specialized for the fast conduction of nerve impulses. This is achieved by a high concentration of voltage-gated sodium channels in the initial segment where the action potential is initiated. [13] The ion channels are accompanied by a high number of cell adhesion molecules and scaffolding proteins that anchor them to the cytoskeleton. [10] Interactions with ankyrin G are important as it is the major organizer in the AIS. [10]

Axonal transport

The axoplasm is the equivalent of cytoplasm in the cell. Microtubules form in the axoplasm at the axon hillock. They are arranged along the length of the axon, in overlapping sections, and all point in the same direction – towards the axon terminals. [14] This is noted by the positive endings of the microtubules. This overlapping arrangement provides the routes for the transport of different materials from the cell body. [14] Studies on the axoplasm has shown the movement of numerous vesicles of all sizes to be seen along cytoskeletal filaments – the microtubules, and neurofilaments, in both directions between the axon and its terminals and the cell body.

Outgoing anterograde transport from the cell body along the axon, carries mitochondria and membrane proteins needed for growth to the axon terminal. Ingoing retrograde transport carries cell waste materials from the axon terminal to the cell body. [15] Outgoing and ingoing tracks use different sets of motor proteins. [14] Outgoing transport is provided by kinesin, and ingoing return traffic is provided by dynein. Dynein is minus-end directed. [15] There are many forms of kinesis and dynein motor proteins, and each is thought to carry a different cargo. [14] The studies on transport in the axon led to the naming of kinesin. [14]

Myelination

Transmission electron micrograph of a myelinated axon in cross-section. Generated by the electron microscopy unit at Trinity College, Hartford CT Myelinated neuron.jpg
Transmission electron micrograph of a myelinated axon in cross-section. Generated by the electron microscopy unit at Trinity College, Hartford CT
Cross section of an axon.
1. Axon
2. Nucleus of Schwann cell
3. Schwann cell
4. Myelin sheath
5. Neurilemma Myelin sheath (1).svg
Cross section of an axon.
1. Axon
2. Nucleus of Schwann cell
3. Schwann cell
4. Myelin sheath
5. Neurilemma

In the nervous system, axons may be myelinated, or unmyelinated. This is the provision of an insulating layer, called a myelin sheath. In the peripheral nervous system axons are myelinated by glial cells known as Schwann cells. In the central nervous system the myelin sheath is provided by another type of glial cell, the oligodendrocyte. Schwann cells myelinate a single axon. An oligodendrocyte can myelinate up to 50 axons. [16]

Nodes of Ranvier

Nodes of Ranvier (also known as myelin sheath gaps) are short unmyelinated segments of a myelinated axon, which are found periodically interspersed between segments of the myelin sheath. Therefore, at the point of the node of Ranvier, the axon is reduced in diameter. [17] These nodes are areas where action potentials can be generated. In saltatory conduction, electrical currents produced at each node of Ranvier are conducted with little attenuation to the next node in line, where they remain strong enough to generate another action potential. Thus in a myelinated axon, action potentials effectively "jump" from node to node, bypassing the myelinated stretches in between, resulting in a propagation speed much faster than even the fastest unmyelinated axon can sustain.

Axon terminals

An axon can divide into many branches called telodendria (Greek–end of tree). At the end of each telodendron is an axon terminal (also called a synaptic bouton, or terminal bouton). Axon terminals contain synaptic vesicles that store the neurotransmitter for release at the synapse. This makes multiple synaptic connections with other neurons possible. Sometimes the axon of a neuron may synapse onto dendrites of the same neuron, when it is known as an autapse.

Action potentials

Structure of a typical chemical synapse

Most axons carry signals in the form of action potentials, which are discrete electrochemical impulses that travel rapidly along an axon, starting at the cell body and terminating at points where the axon makes synaptic contact with target cells. The defining characteristic of an action potential is that it is "all-or-nothing" — every action potential that an axon generates has essentially the same size and shape. This all-or-nothing characteristic allows action potentials to be transmitted from one end of a long axon to the other without any reduction in size. There are, however, some types of neurons with short axons that carry graded electrochemical signals, of variable amplitude.

When an action potential reaches a presynaptic terminal, it activates the synaptic transmission process. The first step is rapid opening of calcium ion channels in the membrane of the axon, allowing calcium ions to flow inward across the membrane. The resulting increase in intracellular calcium concentration causes synaptic vesicles (tiny containers enclosed by a lipid membrane) filled with a neurotransmitter chemical to fuse with the axon's membrane and empty their contents into the extracellular space. The neurotransmitter is released from the presynaptic nerve through exocytosis. The neurotransmitter chemical then diffuses across to receptors located on the membrane of the target cell. The neurotransmitter binds to these receptors and activates them. Depending on the type of receptors that are activated, the effect on the target cell can be to excite the target cell, inhibit it, or alter its metabolism in some way. This entire sequence of events often takes place in less than a thousandth of a second. Afterward, inside the presynaptic terminal, a new set of vesicles is moved into position next to the membrane, ready to be released when the next action potential arrives. The action potential is the final electrical step in the integration of synaptic messages at the scale of the neuron. [5]

(A) pyramidal cell, interneuron, and short durationwaveform (Axon), overlay of the three average waveforms;
(B) Average and standard error of peak-trough time for pyramidal cells interneurons, and putative axons;
(C) Scatter plot of signal to noise ratios for individual units againstpeak-trough time for axons, pyramidal cells (PYR) and interneurons (INT). Example of Waveforms from Extracellular Tetrode Recordings in the Hippocampus from Different Cell Types and Axons.tif
(A) pyramidal cell, interneuron, and short durationwaveform (Axon), overlay of the three average waveforms;
(B) Average and standard error of peak-trough time for pyramidal cells interneurons, and putative axons;
(C) Scatter plot of signal to noise ratios for individual units againstpeak-trough time for axons, pyramidal cells (PYR) and interneurons (INT).

Extracellular recordings of action potential propagation in axons has been demonstrated in freely moving animals. While extracellular somatic action potentials have been used to study cellular activity in freely moving animals such as place cells, axonal activity in both white and gray matter can also be recorded. Extracellular recordings of axon action potential propagation is distinct from somatic action potentials in three ways: 1. The signal has a shorter peak-trough duration (~150μs) than of pyramidal cells (~500μs) or interneurons (~250μs). 2. The voltage change is triphasic. 3. Activity recorded on a tetrode is seen on only one of the four recording wires. In recordings from freely moving rats, axonal signals have been isolated in white matter tracts including the alveus and the corpus callosum as well hippocampal gray matter. [18]

In fact, the generation of action potentials in vivo is sequential in nature, and these sequential spikes constitute the digital codes in the neurons. Although previous studies indicate an axonal origin of a single spike evoked by short-term pulses, physiological signals in vivo trigger the initiation of sequential spikes at the cell bodies of the neurons. [19] [20]

In addition to propagating action potentials to axonal terminals, the axon is able to amplify the action potentials, which makes sure a secure propagation of sequential action potentials toward the axonal terminal. In terms of molecular mechanisms, voltage-gated sodium channels in the axons possess lower threshold and shorter refractory period in response to short-term pulses. [21]

Development and growth

Development

The development of the axon to its target, is one of the six major stages in the overall development of the nervous system. [22] Studies done on cultured hippocampal neurons suggest that neurons initially produce multiple neurites that are equivalent, yet only one of these neurites is destined to become the axon. [23] It is unclear whether axon specification precedes axon elongation or vice versa, [24] although recent evidence points to the latter. If an axon that is not fully developed is cut, the polarity can change and other neurites can potentially become the axon. This alteration of polarity only occurs when the axon is cut at least 10 μm shorter than the other neurites. After the incision is made, the longest neurite will become the future axon and all the other neurites, including the original axon, will turn into dendrites. [25] Imposing an external force on a neurite, causing it to elongate, will make it become an axon. [26] Nonetheless, axonal development is achieved through a complex interplay between extracellular signaling, intracellular signaling and cytoskeletal dynamics. Ultimately, these processes lead to subcellular specialization at the molecular level, endowing developing axons with their specialized transcriptomes and proteomes. [27]

Extracellular signaling

The extracellular signals that propagate through the extracellular matrix surrounding neurons play a prominent role in axonal development. [28] These signaling molecules include proteins, neurotrophic factors, and extracellular matrix and adhesion molecules. Netrin (also known as UNC-6) a secreted protein, functions in axon formation. When the UNC-5 netrin receptor is mutated, several neurites are irregularly projected out of neurons and finally a single axon is extended anteriorly. [29] [30] [31] [32] The neurotrophic factors – nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NTF3) are also involved in axon development and bind to Trk receptors. [33]

The ganglioside-converting enzyme plasma membrane ganglioside sialidase (PMGS), which is involved in the activation of TrkA at the tip of neutrites, is required for the elongation of axons. PMGS asymmetrically distributes to the tip of the neurite that is destined to become the future axon. [34]

Intracellular signaling

During axonal development, the activity of PI3K is increased at the tip of destined axon. Disrupting the activity of PI3K inhibits axonal development. Activation of PI3K results in the production of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns) which can cause significant elongation of a neurite, converting it into an axon. As such, the overexpression of phosphatases that dephosphorylate PtdIns leads into the failure of polarization. [28]

Cytoskeletal dynamics

The neurite with the lowest actin filament content will become the axon. PGMS concentration and f-actin content are inversely correlated; when PGMS becomes enriched at the tip of a neurite, its f-actin content is substantially decreased. [34] In addition, exposure to actin-depolimerizing drugs and toxin B (which inactivates Rho-signaling) causes the formation of multiple axons. Consequently, the interruption of the actin network in a growth cone will promote its neurite to become the axon. [35]

Growth

Axon of nine-day-old mouse with growth cone visible Axon two photon.jpg
Axon of nine-day-old mouse with growth cone visible

Growing axons move through their environment via the growth cone, which is at the tip of the axon. The growth cone has a broad sheet-like extension called a lamellipodium which contain protrusions called filopodia. The filopodia are the mechanism by which the entire process adheres to surfaces and explores the surrounding environment. Actin plays a major role in the mobility of this system. Environments with high levels of cell adhesion molecules (CAMs) create an ideal environment for axonal growth. This seems to provide a "sticky" surface for axons to grow along. Examples of CAM's specific to neural systems include N-CAM, TAG-1—an axonal glycoprotein [36] —and MAG, all of which are part of the immunoglobulin superfamily. Another set of molecules called extracellular matrix-adhesion molecules also provide a sticky substrate for axons to grow along. Examples of these molecules include laminin, fibronectin, tenascin, and perlecan. Some of these are surface bound to cells and thus act as short range attractants or repellents. Others are difusible ligands and thus can have long range effects.

Cells called guidepost cells assist in the guidance of neuronal axon growth. These cells are typically other, sometimes immature, neurons.

It has also been discovered through research that if the axons of a neuron were damaged, as long as the soma (the cell body of a neuron) is not damaged, the axons would regenerate and remake the synaptic connections with neurons with the help of guidepost cells. This is also referred to as neuroregeneration. [37]

Nogo-A is a type of neurite outgrowth inhibitory component that is present in the central nervous system myelin membranes (found in an axon). It has a crucial role in restricting axonal regeneration in adult mammalian central nervous system. In recent studies, if Nogo-A is blocked and neutralized, it is possible to induce long-distance axonal regeneration which leads to enhancement of functional recovery in rats and mouse spinal cord. This has yet to be done on humans. [38] A recent study has also found that macrophages activated through a specific inflammatory pathway activated by the Dectin-1 receptor are capable of promoting axon recovery, also however causing neurotoxicity in the neuron. [39]

Classification

The axons of neurons in the human peripheral nervous system can be classified based on their physical features and signal conduction properties. Axons were known to have different thicknesses (from 0.1 to 20 µm) [3] and these differences were thought to relate to the speed that an action potential could travel along the axon – its conductance velocity. Erlanger and Gasser proved this hypothesis, and identified several types of nerve fiber, establishing a relationship between the diameter of an axon and its nerve conduction velocity. They published their findings in 1941 giving the first classification of axons.

Axons are classified in two systems. The first one introduced by Erlanger and Gasser, grouped the fibers into three main groups using the letters A, B, and C. These groups, group A, group B, and group C include both the sensory fibers (afferents) and the motor fibres (efferents). The first group A, was subdivided into alpha, beta, gamma, and delta fibers — Aα, Aβ, Aγ, and Aδ. The motor neurons of the different motor fibers, were the lower motor neuronsalpha motor neuron, beta motor neuron, and gamma motor neuron having the Aα, Aβ, and Aγ nerve fibers respectively.

Later findings by other researchers identified two groups of Aa fibers that were motor fibers. These were then introduced into a system that only included sensory fibers (though some of these were mixed nerves and were also motor fibers). This system refers to the sensory groups as Types and uses Roman numerals: Type Ia, Type Ib, Type II, Type III, and Type IV.

Motor

Lower motor neurons have two kind of fibers:

Motor fiber types
TypeErlanger-Gasser
Classification
Diameter
(µm)
MyelinConduction
velocity (m/s)
Associated muscle fibers
α 13-20Yes80–120 Extrafusal muscle fibers
β
γ 5-8Yes4–24 [40] [41] Intrafusal muscle fibers

Sensory

Different sensory receptors innervate different types of nerve fibers. Proprioceptors are innervated by type Ia, Ib and II sensory fibers, mechanoreceptors by type II and III sensory fibers and nociceptors and thermoreceptors by type III and IV sensory fibers.

Sensory fiber types
TypeErlanger-Gasser
Classification
Diameter
(µm)
MyelinConduction
velocity (m/s)
Associated sensory receptors ProprioceptorsMechanoceptorsNociceptors and
thermoreceptors
Ia 13-20Yes80–120Primary receptors of muscle spindle (annulospiral ending)
Ib13-20Yes80–120 Golgi tendon organ
II 6-12Yes33–75Secondary receptors of muscle spindle (flower-spray ending).
All cutaneous mechanoreceptors
III 1-5Thin3–30 Free nerve endings of touch and pressure
Nociceptors of lateral spinothalamic tract
Cold thermoreceptors
IV C 0.2-1.5No0.5-2.0 Nociceptors of anterior spinothalamic tract
Warmth receptors

Autonomic

The autonomic nervous system has two kinds of peripheral fibers:

Fiber types
TypeErlanger-Gasser
Classification
Diameter
(µm)
Myelin [42] Conduction
velocity (m/s)
preganglionic fibers B1–5Yes3–15
postganglionic fibers C0.2–1.5No0.5–2.0

Clinical significance

In order of degree of severity, injury to a nerve can be described as neurapraxia, axonotmesis, or neurotmesis. Concussion is considered a mild form of diffuse axonal injury. [43] Axonal injury can also cause central chromatolysis. The dysfunction of axons in the nervous system is one of the major causes of many inherited neurological disorders that affect both peripheral and central neurons. [5]

Demyelination of axons causes the multitude of neurological symptoms found in the disease multiple sclerosis.

Dysmyelination is the abnormal formation of the myelin sheath. This is implicated in several leukodystrophies, and also in schizophrenia. [44] [45] [46]

A traumatic brain injury can result in widespread lesions to nerve tracts damaging the axons in a condition known as diffuse axonal injury. This can lead to a persistent vegetative state. [47]

History

German anatomist Otto Friedrich Karl Deiters is generally credited with the discovery of the axon by distinguishing it from the dendrites. [5] Swiss Rüdolf Albert von Kölliker and German Robert Remak were the first to identify and characterize the axon initial segment. Kölliker named the axon in 1896. [48] Alan Hodgkin and Andrew Huxley also employed the squid giant axon (1939) and by 1952 they had obtained a full quantitative description of the ionic basis of the action potential, leading to the formulation of the Hodgkin–Huxley model. Hodgkin and Huxley were awarded jointly the Nobel Prize for this work in 1963. The formulae detailing axonal conductance were extended to vertebrates in the Frankenhaeuser–Huxley equations. Louis-Antoine Ranvier was the first to describe the gaps or nodes found on axons and for this contribution these axonal features are now commonly referred to as the nodes of Ranvier. Santiago Ramón y Cajal, a Spanish anatomist, proposed that axons were the output components of neurons, describing their functionality. [5] Joseph Erlanger and Herbert Gasser earlier developed the classification system for peripheral nerve fibers, [49] [ not in citation given ] based on axonal conduction velocity, myelination, fiber size etc. The understanding of the biochemical basis for action potential propagation has advanced further, and includes many details about individual ion channels.

Other animals

The axons in invertebrates have been extensively studied. The longfin inshore squid, often used as a model organism has the longest known axon. [50] The giant squid has the largest axon known. Its size ranges from a half (typically) to one millimetre in diameter and is used in the control of its jet propulsion system. The fastest recorded conduction speed of 210 m/s, is found in the ensheathed axons of some pelagic Penaeid shrimps [51] and the usual range is between 90 and 200 m/s [52] (cf 100–120 m/s for the fastest myelinated vertebrate axon.)

In other cases as seen in rat studies an axon originates from a dendrite; such axons are said to have "dendritic origin". Some axons with dendritic origin similarly have a "proximal" initial segment that starts directly at the axon origin, while others have a "distal" initial segment, discernibly separated from the axon origin. [53] In many species some of the neurons have axons that emanate from the dendite and not from the cell body, and these are known as axon-carrying dendrites. [1] In many cases, an axon originates at an axon hillock on the soma; such axons are said to have "somatic origin". Some axons with somatic origin have a "proximal" initial segment adjacent the axon hillock, while others have a "distal" initial segment, separated from the soma by an extended axon hillock. [53]

See also

Related Research Articles

White matter part of the brain

White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distribution of action potentials, acting as a relay and coordinating communication between different brain regions.

Saltatory conduction propagation of action potentials along a nerve cell

Saltatory conduction is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials. The uninsulated nodes of Ranvier are the only places along the axon where ions are exchanged across the axon membrane, regenerating the action potential between regions of the axon that are insulated by myelin, unlike electrical conduction in a simple circuit.

Nervous tissue main component of the nervous system

Nervous tissue, also called neural tissue or nerve tissue, is the main tissue component of the nervous system. The nervous system regulates and controls bodily functions and activity and consists of two parts: the central nervous system (CNS) comprising the brain and spinal cord, and the peripheral nervous system (PNS) comprising the branching peripheral nerves. It is composed of neurons, or nerve cells, which receive and transmit impulses, and neuroglia, also known as glial cells or glia, which assist the propagation of the nerve impulse as well as provide nutrients to the neurons.

Axon hillock Portion of the neuronal cell soma from which the axon originates.

The axon hillock is a specialized part of the cell body of a neuron that connects to the axon. It can be identified using light microscopy from its appearance and location in a neuron and from its sparse distribution of Nissl substance.

Node of Ranvier An axon part that is a gap in the myelin where voltage-gated sodium channels cluster and saltatory conduction is executed.

Nodes of Ranvier, also known as myelin-sheath gaps, occur along a myelinated axon where the axolemma is exposed to the extracellular space. Nodes of Ranvier are uninsulated and highly enriched in ion channels, allowing them to participate in the exchange of ions required to regenerate the action potential. Nerve conduction in myelinated axons is referred to as saltatory conduction due to the manner in which the action potential seems to "jump" from one node to the next along the axon. This results in faster conduction of the action potential.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

Lamellar corpuscle You can eta the me

Lamellar corpuscles are one of the four major types of mechanoreceptor cell in glabrous (hairless) mammalian skin. They are nerve endings in the skin responsible for sensitivity to vibration and pressure. They respond only to sudden disturbances and are especially sensitive to vibration. The vibrational role may be used to detect surface texture, e.g., rough vs. smooth. Lamellar corpuscles are also found in the pancreas, where they detect vibration and possibly very low frequency sounds. Lamellar corpuscles act as very rapidly adapting mechanoreceptors. Groups of corpuscles respond to pressure changes, e.g. on grasping or releasing an object.

Myelin-associated glycoprotein protein-coding gene in the species Homo sapiens

Myelin-associated glycoprotein is a type 1 transmembrane protein glycoprotein localized in periaxonal Schwann cell and oligodendrocyte membranes, where it plays a role in glial-axonal interactions. MAG is a member of the SIGLEC family of proteins and is a functional ligand of the NOGO-66 receptor, NgR. MAG is believed to be involved in myelination during nerve regeneration in the PNS and is vital for the long-term survival of the myelinated axons following myelinogenesis. In the CNS MAG is one of three main myelin-associated inhibitors of axonal regeneration after injury, making it an important protein for future research on neurogenesis in the CNS.

Nerve injury damage to a nerve

Nerve injury is injury to nervous tissue. There is no single classification system that can describe all the many variations of nerve injury. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, (peripheral) nerve injury is classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved. Unlike in the central nervous system, neuroregeneration in the peripheral nervous system is possible. The processes that occur in peripheral regeneration can be divided into the following major events: Wallerian degeneration, axon regeneration/growth, and nerve reinnervation. The events that occur in peripheral regeneration occur with respect to the axis of the nerve injury. The proximal stump refers to the end of the injured neuron that is still attached to the neuron cell body; it is the part that regenerates. The distal stump refers to the end of the injured neuron that is still attached to the end of the axon; it is the part of the neuron that will degenerate but that remains in the area toward which the regenerating axon grows. The study of peripheral nerve injury began during the American Civil War and has greatly expanded to the point of using growth-promoting molecules.

Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms and especially the extent and speed. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

Neural backpropagation is the phenomenon in which after the action potential of a neuron creates a voltage spike down the axon another impulse is generated from the soma and propagates toward to the apical portions of the dendritic arbor or dendrites, from which much of the original input current originated. In addition to active backpropagation of the action potential, there is also passive electrotonic spread. While there is ample evidence to prove the existence of backpropagating action potentials, the function of such action potentials and the extent to which they invade the most distal dendrites remains highly controversial.

Dendritic spike

In neurophysiology, a dendritic spike refers to an action potential generated in the dendrite of a neuron. Dendrites are branched extensions of a neuron. They receive electrical signals emitted from projecting neurons and transfer these signals to the cell body, or soma. Dendritic signaling has traditionally been viewed as a passive mode of electrical signaling. Unlike its axon counterpart which can generate signals through action potentials, dendrites were believed to only have the ability to propagate electrical signals by physical means: changes in conductance, length, cross sectional area, etc. However, a large body of evidence now makes it clear that dendrites are active neuronal structures. Dendrites contain voltage-gated ion channels giving them the ability to generate action potentials. Dendritic spikes have been recorded in numerous types of neurons in the brain and are thought to have great implications in neuronal communication, memory, and learning. They are one of the major factors in long-term potentiation.

Cellular neuroscience is a branch of neuroscience that concerned with the study of neurons at a cellular level. This includes morphology and physiological properties of single neurons. Several techniques such as intracellular recording, patch-clamp, and voltage-clamp technique, pharmacology, confocal imaging, molecular biology, two photon laser scanning microscopy and Ca2+ imaging have been used to study activity at the cellular level. Cellular neuroscience examines the various types of neurons, the functions of different neurons, the influence of neurons upon each other, and how neurons work together.

Nonsynaptic plasticity

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs). Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

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