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Hair cells are the
sensory receptor Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The cel ...
s of both the
auditory system The auditory system is the sensory system for the sense of hearing. It includes both the sensory organs (the ears) and the auditory parts of the sensory system. System overview The outer ear funnels sound vibrations to the eardrum, increasi ...
and the
vestibular system The vestibular system, in vertebrates, is a sensory system that creates the sense of balance and spatial orientation for the purpose of coordinating movement with balance. Together with the cochlea, a part of the auditory system, it constitut ...
in the
ear An ear is the organ that enables hearing and, in mammals, body balance using the vestibular system. In mammals, the ear is usually described as having three parts—the outer ear, the middle ear and the inner ear. The outer ear consists ...
s of all
vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
, and in the lateral line organ of fishes. Through
mechanotransduction In cellular biology, mechanotransduction ('' mechano'' + '' transduction'') is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity. This form of sensory transduction is responsible for a number of s ...
, hair cells detect movement in their environment. In
mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fu ...
s, the auditory hair cells are located within the spiral
organ of Corti The organ of Corti, or spiral organ, is the receptor organ for hearing and is located in the mammalian cochlea. This highly varied strip of epithelial cells allows for transduction of auditory signals into nerve impulses' action potential. Transd ...
on the thin
basilar membrane The basilar membrane is a stiff structural element within the cochlea of the inner ear which separates two liquid-filled tubes that run along the coil of the cochlea, the scala media and the scala tympani. The basilar membrane moves up and down i ...
in the
cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus. A core component of the cochlea is the Organ of Corti, the sensory org ...
of the
inner ear The inner ear (internal ear, auris interna) is the innermost part of the vertebrate ear. In vertebrates, the inner ear is mainly responsible for sound detection and balance. In mammals, it consists of the bony labyrinth, a hollow cavity in the ...
. They derive their name from the tufts of
stereocilia Stereocilia (or stereovilli or villi) are non-motile apical cell modifications. They are distinct from cilia and microvilli, but are closely related to microvilli. They form single "finger-like" projections that may be branched, with normal cell ...
called ''hair bundles'' that protrude from the apical surface of the cell into the fluid-filled
cochlear duct The cochlear duct (bounded by the scala media) is an endolymph filled cavity inside the cochlea, located between the tympanic duct and the vestibular duct, separated by the basilar membrane and the vestibular membrane (Reissner's membrane) re ...
. The stereocilia number from 50-100 in each cell while being tightly packed together and decrease in size the further away they are located from the
kinocilium A kinocilium is a special type of cilium on the apex of hair cells located in the sensory epithelium of the vertebrate inner ear. Anatomy in humans Kinocilia are found on the apical surface of hair cells and are involved in both the morphogenesis ...
. The hair bundles are arranged as stiff columns that move at their base in response to stimuli applied to the tips.
Mammalian Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
cochlear hair cells are of two anatomically and functionally distinct types, known as outer, and inner hair cells. Damage to these hair cells results in decreased hearing sensitivity, and because the inner ear hair cells cannot regenerate, this damage is permanent. Damage to hair cells can cause damage to the vestibular system and therefore causing difficulties in balancing. However, other organisms, such as the frequently studied
zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
, and
bird Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweig ...
s have hair cells that can regenerate. The human cochlea contains on the order of 3,500 inner hair cells and 12,000 outer hair cells at birth. The outer hair cells mechanically amplify low-level sound that enters the
cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus. A core component of the cochlea is the Organ of Corti, the sensory org ...
. The amplification may be powered by the movement of their hair bundles, or by an electrically driven motility of their cell bodies. This so-called somatic electromotility amplifies sound in all land vertebrates. It is affected by the closing mechanism of the mechanical sensory ion channels at the tips of the hair bundles. The inner hair cells transform the sound vibrations in the fluids of the cochlea into electrical signals that are then relayed via the
auditory nerve The cochlear nerve (also auditory nerve or acoustic nerve) is one of two parts of the vestibulocochlear nerve, a cranial nerve present in amniotes, the other part being the vestibular nerve. The cochlear nerve carries auditory sensory information ...
to the auditory
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
and to the
auditory cortex The auditory cortex is the part of the temporal lobe that processes auditory information in humans and many other vertebrates. It is a part of the auditory system, performing basic and higher functions in hearing, such as possible relations to ...
.


Inner hair cells – from sound to nerve signal

The deflection of the hair-cell
stereocilia Stereocilia (or stereovilli or villi) are non-motile apical cell modifications. They are distinct from cilia and microvilli, but are closely related to microvilli. They form single "finger-like" projections that may be branched, with normal cell ...
opens mechanically gated
ion channels Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
that allow any small, positively charged ions (primarily
potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...
and
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
) to enter the cell. Unlike many other electrically active cells, the hair cell itself does not fire an
action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
. Instead, the influx of positive ions from the endolymph in the scala media depolarizes the cell, resulting in a receptor potential. This receptor potential opens voltage gated calcium channels; calcium ions then enter the cell and trigger the release of
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
s at the basal end of the cell. The neurotransmitters diffuse across the narrow space between the hair cell and a nerve terminal, where they then bind to
receptors Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
and thus trigger action potentials in the nerve. In this way, the mechanical sound signal is converted into an electrical nerve signal. Repolarization of hair cells is done in a special manner. The
perilymph Perilymph is an extracellular fluid located within the inner ear. It is found within the scala tympani and scala vestibuli of the cochlea. The ionic composition of perilymph is comparable to that of plasma and cerebrospinal fluid. The major cati ...
in the
scala tympani The tympanic duct or scala tympani is one of the perilymph-filled cavities in the inner ear of humans. It is separated from the cochlear duct by the basilar membrane, and it extends from the round window to the helicotrema, where it continues as ...
has a very low concentration of positive ions. The
electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in solute concentration across a membrane, and ...
makes the positive ions flow through channels to the perilymph. Hair cells chronically leak Ca2+. This leakage causes a tonic release of neurotransmitter to the synapses. It is thought that this tonic release is what allows the hair cells to respond so quickly in response to mechanical stimuli. The quickness of the hair cell response may also be due to the fact that it can increase the amount of neurotransmitter release in response to a change of as little as 100 μV in membrane potential. Hair cells are also able to distinguish tones through one of two methods. The first method uses electrical resonance in the
basolateral membrane Epithelial polarity is one example of the cell polarity that is a fundamental feature of many types of cells. Epithelial cells feature distinct 'apical', 'lateral' and 'basal' plasma membrane domains. Epithelial cells connect to one another via th ...
of the hair cell. The electrical resonance for this method appears as a damped oscillation of membrane potential responding to an applied current pulse. The second method uses tonotopic differences of the basilar membrane. This difference comes from the different locations of the hair cells. Hair cells that have high-frequency resonance are located at the basal end while hair cells that have significantly lower frequency resonance are found at the apical end of the
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercel ...
.


Outer hair cells – acoustical pre-amplifiers

In mammalian outer hair cells, the varying receptor potential is converted to active vibrations of the cell body. This mechanical response to electrical signals is termed somatic electromotility; it drives variations in the cell's length, synchronized to the incoming sound signal, and provides mechanical amplification by feedback to the traveling wave. Outer hair cells are found only in mammals. While hearing sensitivity of mammals is similar to that of other classes of vertebrates, without functioning outer hair cells, the sensitivity decreases by approximately 50 dB. Outer hair cells extend the hearing range to about 200 kHz in some marine mammals. They have also improved frequency selectivity (frequency discrimination), which is of particular benefit for humans, because it enabled sophisticated speech and music. Outer hair cells are functional even after cellular stores of ATP are depleted. The effect of this system is to nonlinearly amplify quiet sounds more than large ones so that a wide range of sound pressures can be reduced to a much smaller range of hair displacements. This property of amplification is called the cochlear amplifier. The molecular biology of hair cells has seen considerable progress in recent years, with the identification of the
motor protein Motor proteins are a class of molecular motors that can move along the cytoplasm of cells. They convert chemical energy into mechanical work by the hydrolysis of ATP. Flagellar rotation, however, is powered by a proton pump. Cellular functio ...
(
prestin Prestin is a protein that is critical to sensitive hearing in mammals. It is encoded by the ''SLC26A5'' (solute carrier anion transporter family 26, member 5) gene. Prestin is the motor protein of the outer hair cells of the inner ear of the mam ...
) that underlies somatic electromotility in the outer hair cells. Prestin's function has been shown to be dependent on
chloride channel Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Several ...
signaling and that it is compromised by the common marine pesticide
tributyltin Tributyltin (TBT) is an umbrella term for a class of organotin compounds which contain the (C4H9)3 Sn group, with a prominent example being tributyltin oxide. For 40 years TBT was used as a biocide in anti-fouling paint, commonly known as b ...
. Because this class of pollutant bioconcentrates up the food chain, the effect is pronounced in top marine predators such as
orcas The orca or killer whale (''Orcinus orca'') is a toothed whale belonging to the oceanic dolphin family, of which it is the largest member. It is the only extant species in the genus '' Orcinus'' and is recognizable by its black-and-white ...
and
toothed whales The toothed whales (also called odontocetes, systematic name Odontoceti) are a parvorder of cetaceans that includes dolphins, porpoises, and all other whales possessing teeth, such as the beaked whales and sperm whales. Seventy-three species of ...
.


Hair cell signal adaption

Calcium ion influx plays an important role for the hair cells to adapt to the amplification of the signal. This allows humans to ignore constant sounds that are no longer new and allow us to be acute to other changes in our surrounding. The key adaptation mechanism comes from a motor protein myosin-1c that allows slow adaptation, provides tension to sensitize transduction channels, and also participate in signal transduction apparatus. More recent research now shows that the calcium-sensitive binding of
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bi ...
to myosin-1c could actually modulate the interaction of the adaptation motor with other components of the transduction apparatus as well. Fast Adaptation: During fast adaptation, Ca2+ ions that enter a stereocilium through an open MET channel bind rapidly to a site on or near the channel and induce channel closure. When channels close, tension increases in the
tip link Tip links are extracellular filaments that connect stereocilia to each other or to the kinocilium in the hair cells of the inner ear.Pickles JO, Comis SD, Osborne MP. 1984.Cross-links between stereocilia in the guinea pig organ of Corti, and their ...
, pulling the bundle in the opposite direction. Fast adaptation is more prominent in sound and auditory detecting hair cells, rather in vestibular cells. Slow Adaption: The dominating model suggests that slow adaptation occurs when myosin-1c slides down the stereocilium in response to elevated tension during bundle displacement. The resultant decreased tension in the tip link permits the bundle to move farther in the opposite direction. As tension decreases, channels close, producing the decline in transduction current. Slow adaptation is most prominent in vestibular hair cells that sense spatial movement and less in cochlear hair cells that detect auditory signals.


Neural connection

Neurons of the auditory or
vestibulocochlear nerve The vestibulocochlear nerve or auditory vestibular nerve, also known as the eighth cranial nerve, cranial nerve VIII, or simply CN VIII, is a cranial nerve that transmits sound and equilibrium (balance) information from the inner ear to the bra ...
(the eighth
cranial nerve Cranial nerves are the nerves that emerge directly from the brain (including the brainstem), of which there are conventionally considered twelve pairs. Cranial nerves relay information between the brain and parts of the body, primarily to and f ...
) innervate cochlear and vestibular hair cells. The neurotransmitter released by hair cells that stimulates the terminal neurites of peripheral axons of the afferent (towards the brain) neurons is thought to be
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
. At the presynaptic juncture, there is a distinct ''presynaptic dense body'' or
ribbon A ribbon or riband is a thin band of material, typically cloth but also plastic or sometimes metal, used primarily as decorative binding and tying. Cloth ribbons are made of natural materials such as silk, cotton, and jute and of synthetic mat ...
. This dense body is surrounded by synaptic vesicles and is thought to aid in the fast release of neurotransmitter. Nerve fiber innervation is much denser for inner hair cells than for outer hair cells. A single inner hair cell is innervated by numerous nerve fibers, whereas a single nerve fiber innervates many outer hair cells. Inner hair cell nerve fibers are also very heavily myelinated, which is in contrast to the unmyelinated outer hair cell nerve fibers. The region of the basilar membrane supplying the inputs to a particular afferent nerve fibre can be considered to be its
receptive field The receptive field, or sensory space, is a delimited medium where some physiological stimuli can evoke a sensory neuronal response in specific organisms. Complexity of the receptive field ranges from the unidimensional chemical structure of od ...
. Efferent projections from the brain to the cochlea also play a role in the perception of sound. Efferent synapses occur on outer hair cells and on afferent axons under inner hair cells. The presynaptic terminal bouton is filled with vesicles containing
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Pa ...
and a
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
called
calcitonin gene-related peptide Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 ( intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produc ...
. The effects of these compounds vary; in some hair cells the acetylcholine hyperpolarizes the cell, which reduces the sensitivity of the cochlea locally.


Regrowth

Research on the regrowth of cochlear cells may lead to medical treatments that restore hearing. Unlike birds and fish, humans and other mammals are generally incapable of regrowing the cells of the inner ear that convert sound into neural signals when those cells are damaged by age or disease. Researchers are making progress in
gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
and
stem-cell therapy Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition. , the only established therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone-marrow transplantation, but ...
that may allow the damaged cells to be regenerated. Because hair cells of auditory and
vestibular system The vestibular system, in vertebrates, is a sensory system that creates the sense of balance and spatial orientation for the purpose of coordinating movement with balance. Together with the cochlea, a part of the auditory system, it constitut ...
s in birds and fish have been found to regenerate, their ability has been studied at length. In addition,
lateral line The lateral line, also called the lateral line organ (LLO), is a system of sensory organs found in fish, used to detect movement, vibration, and pressure gradients in the surrounding water. The sensory ability is achieved via modified epithelial ...
hair cells, which have a
mechanotransduction In cellular biology, mechanotransduction ('' mechano'' + '' transduction'') is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity. This form of sensory transduction is responsible for a number of s ...
function, have been shown to regrow in organisms, such as the
zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
. Researchers have identified a mammalian gene that normally acts as a
molecular switch A molecular switch is a molecule that can be reversibly shifted between two or more stable states. The molecules may be shifted between the states in response to environmental stimuli, such as changes in pH, light, temperature, an electric curre ...
to block the regrowth of cochlear hair cells in adults. The Rb1 gene encodes the
retinoblastoma protein The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
, which is a
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
. Rb stops cells from dividing by encouraging their exit from the cell cycle. Not only do hair cells in a culture dish regenerate when the Rb1 gene is deleted, but mice bred to be missing the gene grow more hair cells than control mice that have the gene. Additionally, the
sonic hedgehog Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis an ...
protein has been shown to block activity of the
retinoblastoma protein The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
, thereby inducing cell cycle re-entry and the regrowth of new cells. Several
Notch signaling pathway The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembr ...
inhibitors, including the
gamma secretase Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. Th ...
inhibitor LY3056480, are being studied for their potential ability to regenerate hair cells in the cochlea.
TBX2 T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the ''Tbx2'' gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T ...
(T-box transcription factor 2) has been shown to be a
master regulator In genetics, a master regulator is a gene at the top of a gene regulation hierarchy, particularly in regulatory pathways related to cell fate and differentiation. Examples Most genes considered master regulators code for transcription factor pr ...
in the differentiation of inner and outer hair cells. This discovery has allowed researchers to direct hair cells to develop into either inner or outer hair cells, which could help in replacing hair cells that have died and prevent or reverse hearing loss. The cell cycle inhibitor p27kip1 (
CDKN1B Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the ''Cip/Kip'' family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded pro ...
) has also been found to encourage regrowth of cochlear hair cells in mice following genetic deletion or knock down with siRNA targeting p27. (primary source) Research on hair cell regeneration may bring us closer to clinical treatment for human
hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken ...
caused by hair cell damage or death.


Additional images

File:Gray932.png, The lamina reticularis and subjacent structures. File:Stereocilia of frog inner ear.01.jpg, Stereocilia of frog inner ear


References


Bibliography

* * * * * * ** * **


External links


Molecular Basis of Hearing

Outer hair cell dancing "rock around the clock"

''Dancing OHC''
video Yale Ear Lab
NIF Search – Hair Cell
via the
Neuroscience Information Framework The Neuroscience Information Framework is a repository of global neuroscience web resources, including experimental, clinical, and translational neuroscience databases, knowledge bases, atlases, and genetic/ genomic resources and provides many au ...

Hair-Tuning-Sound-Sensor
A concise report on the recent development of sound sensors based on hair tuning by students of SMMEE
IIT Ropar
{{Nervous tissue Auditory system Receptor cells Human cells