Auditory System Flashcards
Congential Hearing Loss: General information
Consequences: poor language and behavioural developments, lower literacy and academic achievements
Genetic factors are thought to cause more than 50% of all incidents of congenital hearing loss in children
Currently >100 genes underpinning deafness
Other causes: intrauterine infectons, (German measles, cytomegalovirus, and HSV), prematurity, hypoxia, hyperbilirubinemia, maternal alcohol/drug use
Acquired Hearing Loss: Infection/Inflammation
- The spread of a bacterial or viral infection from the middle ear (otitis media)
- As a direct consequence of infection or tissue injury to the inner ear or hearing nerve
- Meningitis is also a source of inner ear inflammation and results from infection through the CSF
- The inner ear can rapidly mount an inflammatory response which can cause bystander tissue injury. This inflammatory response can damage delicate structures of the inner ear and cause permanent hearing loss. Macrophages and other immune cell release inflammatory cytokines
Most common causes of acquired hearing loss
- Presbyacusis
- Noise trauma
- Ototoxic drugs
Common features of hearing loss pathology
- Hair cells damaged and replaced by scar tissues
- A reduction in density of nerves
- Drugs & Age: Initial loss of basal cells and high frequencies. Noise: frequency-related damage
Effects of noise on the cochlea
Metabolic damange not mechanical unless acute impulse noise
- OHC - clashing of tectorial membrane and OHC causes damage at high noises. Cell death by apoptosis due to oxidative stress
- Spiral ligament - damange to spiral ligament type 4 fibrocytes which are important for recycling of K+. Atrophy of intermediate cells which secrete K+, reduction in endocochlear potential.
- IHC - excessive glutamate causes swelling of spiral ganglion neuron. More resistant to ROS but excessive glutamate causes damange.
- Pillar cells - acute exposure to impulse noise causes buckling and therefore results in collapsing of the organ of corti.
Glutamate excitotoxicity
Excessive release causes swelling of receptor due to water entry, can be repaired but continuous abuse causes entry of Ca2+ through NMDA channels which activates apoptotic and necrotic pathways leading to spiral ganglion neuron death. Generation of ROS and mitochondrial dysfunction
Inflammation from noise exposure
CD45+ inflammatory cells and macrophages and other cells invade through spiral ligament and cause damage.
Oxidative stress and noise-induced hearing loss
Oxidative stress in the cochlea may be a common factor for hearing loss from noise, aminoglycoside antibiotics, ototoxic anticancer drugs and aging.
Free radical are capable of breaking down lipid and protein molecules, damaging DNA and triggering cell death, all of which contribute to the loss of function after noise exposure.
How are ROS/free radicals formed as a result of noise?
During noise exposure, the electron transport chain of the mitochondira uses large amounts of oxygen, which can then create large amounts of superoxide as an unwanted byproduct.
The increased superoxide can then react with other molecules to generate higher levels of ROS in the cochlea
Examples of ROS
Oxygen based molecules that act as free radicals
* Superoxide (O2-)
* Hydroxyl radical
* Perioxynitrite radical (ONOO)
Readily capable of generating free radicals:
* Hydrogen perioxide
* Ozone
Equations of forming ROS
O2 -> to superoxide ions via an enzyme (NADPH oxidase…)
Superoxide can react with NO to form ONOO
Superoxide can form hydrogen peroxide through superoxide mutase and copper (II)
Hydrogen perioxide can undergo fenton reaction to produce hydroxyl free radical.
Hydrogen peroxide can react with catalase and Fe (II) to give water and O2
Apoptosis process - hair cell
Normal -> Cell shrinkage, membrane blebbing -> nuclear fragmentation, chromatin condensation, formation of apoptotic bodies
Necrotic process - hair cell
Normal -> cell swelling -> rupture of plasma membrane, post-lytic DNA fragmentation. Causes inflammatory reaction
Presbyacusis - General information
- A mixture of acquired auditory stresses, trauma and otological diseases superimposed upon an intrinsic, genetically controlled, ageing process
- The loss of hearing sensitivity begins at the highest frequency
- Untreated hearing impairment contributes to social isolation, depression, loss of self-esteem and cognitive decline
Characterised by:
* Reduced hearing sensitivity and speech understanding in noisy environments
* Slowed central processing of acoustic information
* Impaired localisation of sound sources in horizontal plane.
Age-related Cochlear Pathology
Loss of OHC and spiral ganglion neurons
Stria Vascularis - highest impact mainly vascular impact leading to atrophy of SV and decreased secretion of K+
Classification of Presbyacusis
Sensory (outer hair loss)
Neural (neuronal cell loss)
Metabolic (strial atrophy)
Mixed and indeterminate
Sensory presbyacusis related to accumulated environmental noise toxicity, whilst the strial pattern has a high heritability index.
Cochlear aging: animal studies
- Gerbils raised in quiet have just as much or more hearing loss with age than group of noise-related animals - strongly suggesting genetic
- Degeneration of the stria vasularis (marginal and intermediate cells) is the most prominent element
- A loss of Na+,K+ ATPase results in reduced postassium secretion and decline in endocochlear potential (EP)
- Degeneration of the stria vascularis and the resultant decline in EP has given rise to the dead battery theory of presbyacusis
Animal models of presbyacusis
C57BL/6 mouse, early onset hearing loss, ARHL locus (ahl) that contributes to hearing loss in the C57BL/6 mouse has been mapped to chromosome 10. Carries a specific mutation in the cadherin 23 gene, which encodes a component of the hair cell tip-link.
CBA/CaJ mouse, late onset hearing loss. Carries the ahl-resistance gene.
Fisher 344 albino rat - model of sensory ARHL
Mongolian gerbil - model of strial ARHL
Mechanisms of Presbyacusis
Genetic and environment factors
* Reduction of vascularisation in the stria vascularis
* Collagen damage - especially in spiral ligament fibrocytes which affects K+ cycling.
* Cumulative noise exposure - causes repeated oxidative stress causing massive apoptosis and necrosis. MtDNA damage which cant be repaired
* Oxidative stress and apoptosis
Ototoxicity
Two major classes of drugs can cause permanent hearing loss:
* Aminoglycoside antibiotics
* Platinum-based chemotherapeutic agens
Both damage the hair cells in the basal turn of the organ of Corti, spiral ganglion neurons and the lateral wall tissues resulting in functional deficits.
Aminoglycoside ototoxicity
Aminogylcoside antibiotics are used in treatment of TB and serious gram negative bacterial infections such as bacterial endocarditis, UTI and pneumonia.
AG enters and forms complex with Fe. Produces ROS. Activates JNK which leads to transcription of preapoptotic genes which put small holes in the mitochondria, leading to leakage of Cyt C and apoptosis
What type of cancer is cisplatin and carboplatin used to treat and what are complications?
- Testiciular
- Ovarian
- Bladder
- Head and Neck
- Lung
Complications: nephrotoxicity, neurotoxicity and ototoxicity
Cisplatin ototoxicity: General
- High incidence of hearing loss (up to 80%)
- Ototoxicity: tinnitus and bilateral frequency high frequency sensorineural hearing loss
- Involves the production of ROS and depletion of glutathione and antioxidant enzymes (SOD, catalase and glutathione perioxidase) in the cochlea
- Excessive ROS production activates primarily caspase-depedent apoptotic pathways
- Ototoxicity can be ameliorated by protective agents targeting oxidative stress and apoptosis.
Cisplatin Ototoxicity: Mechanism
CP form complex with monohydrated complex (MHC), activation of enzyme NOX-3. Production of ROS and activation of JNK. Transcription of proapoptotic genes. Mitochondira holes, cyt C and apoptosis.
Pharmacological interventions to reduce hearing loss
- Restoring the normal balance of free radical with antioxidants
- Reducing glutamate excitotoxicty with NMDA receptor antagonists
- Maintaining adequate cochlear blood floow during and after noise
- Supressing inflammation
- Inhibiting pathways to apoptotic cell death to preserve hair cells
Free Radical/Antioxidant balance in the cochlea
Increasing cochlear antioxidant supplies can be substantially prevent hair cell damage and hearing loss.
Antioxidant levels can be increaed in two ways:
1. Application of exogenous antioxidant molecules locally or systemically into the body
2. Endogenously by using sound conditioning
Examples of antioxidants
Antioxidants are molecules that scavenge ROS and convert them to less dangerous molecules
Mammals maintain complex system of multiple types of antioxidants such as glutathione, vitamins A, C and E, magnesium as well as enzymes such as catalase, superoxide dismutase and various peroxidases
Effects of Sound conditioning in animals
Conditioned animals with previous exposure to low noise for long periods of time resulted in mich higher antioxidant levels
Experimental therapies: Hair cell regeneration
Gene transfer technology
Replacement of hair cells by stem cells
Atoh1/GFP+ cells show morphological and molecular correlates of innervation and synaptogeneis.
Hereditary Hearing Loss (HHL)
Accounts for about 50% of congenital hearing loss
Over 100 genes underlying HHL
50% of these genes related to sensory hair cells
HHL classification according to the mode of transmission
Autosomal dominant
Autosomal recessive
X-chromosome-linked
DFNB9 Deafness
Inner hair cell synaptopathy
An auditory neuropathy defined as a hearing loss characterised by the absence of auditory brainstem responses with preserved function of the outer hair cells.
Due to a defect in synaptic protein otoferlin expressed in the inner hair cells.
Otoferlin knockout mice key to understanding DFNB9 pathogenesis
Otoferlin - Ca2+ sensor role
It is a presynaptic protein which otoferlin acts as a calcium-sensitive scaffolding protein, localizing SNARE proteins proximal to the calcium channel so as to synchronize calcium influx with membrane fusion. It forms complex with ribbons allowing docking and therefore release
Otoferlin triggers synaptic vesicle-plasma membrane fusion at the IHC ribbon synapse. Degeneration process of the IHC active zone and some afferent neurones likely to take place in DFNB patients. Early cochlear implants expected to be of major help because it bypasses synpase.
Further information about Usher subtypes
