sound transduction

SOUND TRANSDUCTION

Presented by: Satadru DeM.Phil 1st year, Neurophysiology Date: 04.12.2015

SOUND AND ITS ATTRIBUTES

Sound refers to pressure waves generated by vibrating air molecules, propagating in three dimension, creating spherical shells of alternating compression and rarefaction at the speed of 330m/s;

Sounds composed of single sine waves (pure tones) rarely found innature; our inner ear acts like an acoustic prism decomposing

complexsound waves into a myriad of constituent frequencies

THE AUDIBLE SPECTRUM ALONG EVOLUTION

Humans can detect periodic frequency from 20Hz – 20kHzInfants: slightly higher than 20kHzAdults: 15-17kHz

Some species of bats: 20kHz - 200kHz;

Bats and dolphins rely on very high frequency vocal sounds to resolve spatial feature of the target;Animals intent on avoiding predation have auditory systemstuned to the lower levels of vibration.

SIGNIFICANCE OF SOUND AND THE AUDITORY SYSTEM

Human experience is enriched by our ability to distinguish a wide

range of sounds;

DEAFNESS CAN BE DEVASTATING!

For the elderly: painful estrangement from family and friends; For children: deprivation of the normal avenues for

development of speech, and thus reading and writing;

Hearing and psychological well-being; Loss of social intercourse due to sudden deafness may lead to depression and even suicide

THE MAMMALIAN SOUND PERCEPTION SYSTEM: THE EAR

The auditory system is one of the engineering masterpieces of the

human body – an array of miniature acoustical detectors.

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THE MAMMALIAN SOUND PERCEPTION SYSTEM: THE EAR

EAR

External ear:• Pinna/Auricle• Concha• Auditory meatus• Tympanus

CAPTURE OF MECHANICAL ENERGY

Middle ear:• Malleus /Hammer• Incus/Anvil• Stapes/Stirrup TRANSMISSION TO RECEPTOR ORGAN

Inner ear: •The Cochlea •The Vestibular System

TRANSDUCTION TO ELECTRICAL SIGNAL

THE EXTERNAL EAR The pinna acts like a parabolic antenna as a reflector to capture sound waves into the ear canal;

The corrugated surface collects sound best when they originate at different position w.r.t head;

Length of the auditory meatus: 25mm

Diamter of tympanum: 9mm

The canal selectively boosts sound pressure 30-100 fold in the 3kHz range – which is the range of human speech;

Selective hearing loss in 2-5kHz range impairs speech recognitionPr

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THE MIDDLE EAR

Eustachian Tube

Eustachian Tube

Major function: To match the relatively low impedance airborne sounds to the higher impedance fluid of the inner ear and boost the sound pressure at tympanum to 200-folds to ensure transmission of sound energy across the air-fluid boundary to the inner ear.

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THE INNER EAR

Vestibular nerve

Auditory nerve

Cochlea

Vestibule

Round Window

Semicircular Canals

Oval window

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THE INNER EAR

Cross section of the Cochlea

Principles of Neural Science, Kandel – 5th edn.

THE INNER EAR

Tectorial membrane

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THE INNER EAR – TRANSMISSION OF SOUND FROM MIDDLE EAR TO INNER EAR

The loudest sound tolerable to humans alters the atmospheric pressure by +/- 0.01%

The ossicles – two interconnected levers (Malleus and Incus) and a piston (Stapes) Stapes produces pressure changes that propagate through the fluid of scala

vestibuli @ 330 m/s Displaced liquid causes outward bowing of round window

THE INNER EAR – BASILAR MEMBRANE The mechanical properties of the basilar membrane are key to the cochlear operation

The various parts of the membrane do not oscillate in phase with each other.

Each wave reaches its maximum amplitude at a particular position

The movement of the basilar membrane is the result of the motion of liquid masses up and down the basilar membrane; they are moved continuously by the energy supplied by Stapes’ piston-like movement at oval window

Apex – lowest audible frequency ~ 20Hz

Base – upto 20kHz

The arrangement of vibration frequency along the basilar membrane is an example of a Tonotopic map

THE INNER EAR – ORGAN OF CORTI

Reissner’s Membrane

THE INNER EAR – ORGAN OF CORTI

Organ of Corti – 16,000 hair cells each – 30,000 nerves Hair cells and nerves are tonotopically organised

IHC – 1 row; 3500 nos.

OHC – 3 rows; 12000 nos.

THE INNER EAR – HAIR CELL

Ectodermal origin – epithelial character Lacks dendrites and axonsEndolymph bathes the apical surface Tight junction separates endolymph from perilymphHair bundle – mechanoreceptor;Each bundle – 60 stereocilia; Kinocilium – true cilium( “9+2” doublet) but absent in adult cochlea. Does not take part in MET

Stereocilia – fascicle of actin filament crosslinked by Plastin/Fimbrin, Fascin, Epsin etc to provide rigidity

THE INNER EAR – HAIR CELL

Fine filamentous structure – Tip Links – connecting the tips of adjacent stereocilia

Allows the bundle to move as a unit

Tip link is a component of gating spring :Upper 2/3 – parallel homodimer of Cadherin-23 moleculesLower 1/3 – parallel homodimer of Protocadherin-15 chains

THE INNER EAR – TECTORIAL MEMBRANE

Organ of Corti and Tectorial membrane move in response to sound energy vibration;

Back-and-forth shearing motion of upper surface of Organ of Corti and lower surface of tectorial membrane is detected by hair cells

MECHANOTRANSDUCTION TO NEURAL SIGNALMechanical stimulus to a hair bundle elicits and electrical response,the receptor potential, by gating of mechanosensitive ion channels;

10% of channels involved in MET are open at resting stage; RMP is -60mV

Displacement towards tall edge opens channels – depolarisationDisplacement towards the opposite side closes channels - hyperpolarisation Displacement of +/- 100nm

= 90% response range

Ion channels are non selective cation passing pores;1.3nm diameter;100pS condustance

Each stereocilia has 2 channels

MECHANOTRANSDUCTION – GATING KINETICS

MECHANOTRANSDUCTION – GATING KINETICS

When tip links are destroyed by exposing hair cells to Ca-chelators, transduction stops

Tip links regenerate over ~ 12 hoursOHC bundles are firmly inserted into the tectorial membrane: directly deflected by TM movement;

IHC do not contact the TM: deflected by motion of endolymph

THIS MODE OF STIMULATION PROVIDES SOME DEGREE OF MECHANICAL AMPLIFICATION

IONIC BASIS OF MECHANOTRANSDUCTIONThree extracellular fluids in cochlea:

EndolymphPerilymphIntrastrial fluid

Endocochlear potential generated by Stria Vascularis – K+ equilibrium potential that is generated by the K+ channel Kir 4.1 located in the internediate cells of the stria vascularis in conjunction with very low [K+] in the cytosol of internediate cells. (Takeuchi et al. 2000; Marcus et al. 2000)

J Physiol 576.1 (2006) pp 11-21

K+ driven into hair cells by apical transduction channel (depolarisation) and out into the perilymph (hyperpolarisation) by Kcnq4, Kcnn2, Kcnma1 channels (Kros 1996);

Cl- is essential for K+ secretion and generation of endocohlear potential;

Ca2+ secretion occur via Ca-ATPases (PMCA2), and Reissner’s membrane; Ca2+ absorption through paracellular and transcellular pathways driven by endocohlear potential.

Glutamate

K+ entry electrotonically depolarises the cell;

VGCC opens – Ca2+ influx

Ca2+ modulates synaptic neurotransmitter release

Opens Kca channels for K+ efflux

Ca2+ influx ad Ca2+ induced K+ efflux – electrical resonance and tuning of hair cell

MECHANICAL AMPLIFICATION OF SOUND ENERGY

Amplification occurs in cochleaCochlear amplifier contains active processes to negate

thedamping effect of the viscous fluids; Evoked Acoustic Emmision

Spontaneous Acoustic Emmision


; OHC enhance cochlear sensitivity and frequency selectivity – energy sources for amplification; Electromotility of OHC soma at ~80kHz

VOLTAGE INDUCED MOTILITY OF AN OHC (Reproduced from Holley and Ashmore 1988)


; OHC enhance cochlear sensitivity and frequency selectivity – energy sources for amplification; Electromotility of OHC soma at ~80kHz;

Energy comes from electrical field across membrane rather than ATP hydrolysis;

Voltage induced motility of OHC augments basilar membrane motion;

Spontanoeus back-and-forth movement of hair bundles – In in-vitro hair bundles exert force against stimulus probes performing mechanical work and amplifying input

Active hair bundle motility Voltage induced electromotility

-Tuner - Power amplifier at high -Preamplifier at high frequencies low frequencies

UNIQUE FEATURES OF HAIR CELLS

Lack of axon or dendrites Form ribbon synapses with other sensory neurons Lack Synaptotagmin 1 and 2 – role performed by

Otoferlin Release of neurotransmitter is quantal and Glutamate

is principal neurotransmitter At efferent terminals of OHC, neurotransmitter is

Acetylcholine and CGRP Ach binds to α9 and α10 subunits of nAchR which are

permeable to Ca2+, k+ and Na+ Ca influx causes K+ efflux through Kca : Protracted

hyperpolarisation Efferent nerve stimulation perturbs the critical tuning,

decreases sharpness and frequency selectivity: densensitises the cochlea.

THE CENTRAL AUDITORY PATHWAYFROM COCHLEA TO CORTEX


The tonotopic organisation is maintained in all three parts of cochlear nucleus;

The auditory cortex is less well understood than visual cortex;


Auditory cortex has subdivisions – Primary Auditory cortex or A1:

- receives point to point input from ventral MGN - containes a precise tonotopic map; The secondary cortex or Belt Areas have more diffuse input

from MGN as well as A1; tonotopically less precise; A1 has a topographical map of cochlea

OTOPROTECTIVE FUNCTION OF ADENOSINE

ATP signalling in the cochlea Adenosine receptor distribution in the auditory system Adenosine metabolism Noise stress and Adenosine otoprotection Aging and Adenosine otoprotection Putative mechanisms

OTOPROTECTIVE FUNCTION OF ADENOSINE ATP SIGNALLING IN THE COCHLEA:

- Adenosine and ATP are important signalling molecules in pathological conditions;

- ATP released from Organ of Corti through connexin and pannexin hemichannels in acoustic overstimulation ;

- ATP acts on P2R (both P2X and P2Y) differentially distributed in cochlear tissues;

ADENOSINE RECEPTOR EXPRESSION AND DISTRIBUTION:

- Family of four adenosine receptors – A1, A2A, A2B, A3 (P2Y class of receptors that works through GPCR);

- A1 and A3 acts through Gi and PLC/DAG; - A2 is stimulatory, acts through Gs and IP3/PKC; - A1 and A3 presynaptically regulates Glu release in IHC - A1-R expressed in dorsal cochlear nucleus, superior olivary nucleus,

inferior colliculus; - A1 heavily distributed in regions rich in excitatory amino acids, whereas

A2a is discretely localised in inferior colliculus and layer VI of auditory cortex;

OTOPROTECTIVE FUNCTION OF ADENOSINE

OTOPROTECTIVE FUNCTION OF ADENOSINE ADENOSINE METABOLISM:

OTOPROTECTIVE FUNCTION OF ADENOSINE NOISE STRESS AND ADENOSINE OTOPROTECTION:

- Oxidative stress and ROS formation are key elements in pathogenesis of cochlear injury;

Noise exposure

Acute exposure

Repeated exposure

TTS PTS

Noise exposure inc. mitochondrial activity and free radical pdtn. Excitotoxic swelling of nerve terminals Reduces cochlear blood flow

Necrosis and apoptosis

OTOPROTECTIVE FUNCTION OF ADENOSINE NOISE STRESS AND ADENOSINE OTOPROTECTION:

Noise exposure Oxidative stress+NMDAR activation

Adenosine

Activates A1 expression via NF-kBApplication of A1-R agonist R-PIA in cochlea enhances activity of SOD and Gluthatione peroxidase, reduces levels of lipid peroxidation marker;

Reduced PTS and OHC loss;

Administering R-PIA and Glutathione Monoethylester provides protection against acute and chronic stress. (All expts. done on Chinchilla Sp. Cochlea by Hight et al, 2003)

OTOPROTECTIVE FUNCTION OF ADENOSINE PRESBYACUSIS AND ADENOSINE OTOPROTECTION:

- Presbyacusis

1. ROS production due to impaired blood flow2. Excessive noise exposure3. Increased prevalence of apoptosis in aged cochlear hair cells

One natural consequence of aging – dysfunctional adenosine homeostasis

Genetic

Environmental

Restoring the youthful balance of adenosine signalling my molecular and pharmacological means has a potential to diminish age-related hearing loss.

OTOPROTECTIVE FUNCTION OF ADENOSINE PUTATIVE MECHANISMS OF ADENOSINE OTOPROTECTION:

1. Improve cochlear blood flow and oxygen supply2. Enhances production of antioxdants3. Counters the toxic effects of ROS4. Limit inflammatory responses5. Provide vascular growth in areas of reduced oxygen.

Angiogenesis may be important in cochlear repair after injury6. Inhibition of Glu release via presynaptic A1-R to prevent

excitotoxicity

LIMITATIONS IN ADENOSINE THERAPY:

1. Prolonged activation of A1-R can cause receptor desensitisation and downregulation;

2. Profound cardiovascular effects – bradycardia, hypotension and hypothermia;

3. Poor blood-brain-barrier permeability upon systemic administration;

Also....

In addition to A1 receptor associated pathways, potential adenosine based otoprotective strategies include:

• Combined Inhibition of A2A Receptors and Adenosine Kinase

• Inhibition of Adenosine Uptake by Nucleoside Transporters

• Increasing Adenosine Production from ATP

• Manipulating Adenosine Metabolism

FUTURE PROSPECTS OF ADENOSINE IN INNER EAR PATHOLOGY:

1. Selective A1 receptor agonists that can cross the blood-brain-barrier with reduced peripheral side effects;

2. A2A receptor inhibition – they aggravate drug induced toxicity;3. A3 receptor – promote tissue survival at low concentration but

induces apoptosis at high concentration.

THANK YOU

sound transduction

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