1. SOUND TRANSDUCTION
Presented by: Satadru De
M.Phil 1st year, Neurophysiology
Date: 04.12.2015

2. 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 in
nature; our inner ear acts like an acoustic prism decomposing complex
sound waves into a myriad of constituent frequencies

3. THE AUDIBLE SPECTRUM ALONG EVOLUTION
Humans can detect periodic frequency from 20Hz – 20kHz
Infants: slightly higher than 20kHz
Adults: 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 systems
tuned to the lower levels of vibration.

4. 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

5. 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.

6. Neuroscience–DalePurves,5thedn.

7. 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

8. 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 recognition
PrinciplesofNeuroscience–Kandel,5thedn.

9. 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.
Neuroscience,DalePurves–5thedn.

10. THE INNER EAR
Vestibular nerve
Auditory nerve
Cochlea
Vestibule
Round Window
Semicircular Canals
Oval window
Neuroscience,DalePurves–5thedn.

11. THE INNER EAR
Cross section of the Cochlea
PrinciplesofNeuralScience,Kandel–5thedn.

12. THE INNER EAR
Tectorial membrane
PrinciplesofNeuralScience,Kandel–5thedn.

13. 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

14. 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

15. 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

16. Apex – lowest audible frequency ~ 20Hz
Base – upto 20kHz
The arrangement of vibration frequency along the basilar membrane is
an example of a Tonotopic map

17. THE INNER EAR – ORGAN OF CORTI
Reissner’s Membrane

18. 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.

19. THE INNER EAR – HAIR CELL
 Ectodermal origin – epithelial
character
 Lacks dendrites and axons
Endolymph bathes the apical surface
 Tight junction separates endolymph
from perilymph
Hair 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

20. 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 molecules
Lower 1/3 – parallel homodimer of
Protocadherin-15 chains

21. 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

22. MECHANOTRANSDUCTION TO NEURAL SIGNAL
Mechanical 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 – depolarisation
Displacement 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

23. MECHANOTRANSDUCTION – GATING KINETICS

24. MECHANOTRANSDUCTION – GATING KINETICS
 When tip links are destroyed by exposing hair cells to Ca-chelators,
transduction stops
 Tip links regenerate over ~ 12 hours
OHC 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

25. IONIC BASIS OF MECHANOTRANSDUCTION
Three extracellular fluids in cochlea:
Endolymph
Perilymph
Intrastrial fluid

26. 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.

27. 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

28. MECHANICAL AMPLIFICATION OF SOUND ENERGY
Amplification occurs in cochlea
Cochlear amplifier contains active processes to negate the
damping effect of the viscous fluids;
Evoked Acoustic Emmision Spontaneous Acoustic Emmision

29. MECHANICAL AMPLIFICATION OF SOUND ENERGY
;
 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)

30. MECHANICAL AMPLIFICATION OF SOUND ENERGY
;
 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

31. 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.

32. THE CENTRAL AUDITORY PATHWAY
FROM COCHLEA TO CORTEX

34. THE CENTRAL AUDITORY PATHWAY
FROM 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;

35. THE CENTRAL AUDITORY PATHWAY
FROM COCHLEA TO 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

36. 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

37. 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;

38. OTOPROTECTIVE FUNCTION OF ADENOSINE

39. OTOPROTECTIVE FUNCTION OF ADENOSINE
 ADENOSINE METABOLISM:

40. 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

41. OTOPROTECTIVE FUNCTION OF ADENOSINE
 NOISE STRESS AND ADENOSINE OTOPROTECTION:
Noise exposure Oxidative stress+NMDAR activation
Adenosine
Activates A1 expression via NF-kB
Application 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)

42. OTOPROTECTIVE FUNCTION OF ADENOSINE
 PRESBYACUSIS AND ADENOSINE OTOPROTECTION:
- Presbyacusis
1. ROS production due to impaired blood flow
2. Excessive noise exposure
3. 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.

43. OTOPROTECTIVE FUNCTION OF ADENOSINE
 PUTATIVE MECHANISMS OF ADENOSINE OTOPROTECTION:
1. Improve cochlear blood flow and oxygen supply
2. Enhances production of antioxdants
3. Counters the toxic effects of ROS
4. Limit inflammatory responses
5. Provide vascular growth in areas of reduced oxygen. Angiogenesis
may be important in cochlear repair after injury
6. 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;

44. 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.

45. THANK YOU