Cochlear anatomy, function and pathology I

Professor Dave FurnessKeele University

d.n.furness@keele.ac.uk

Aims and objectives of these lectures

• Introduction to gross anatomy of the cochlea

• Focus (1) on the sensory epithelium:– Hair cells and the organ of Corti– The mechanism of mechanoelectrical

transduction

Aims and objectives of these lectures

• Focus (2) on the biophysics of the cochlea, the dual roles of hair cells and their innervation:– Cochlear frequency selectivity– The cochlear amplifier– Neurotransmission and innervation of the

hair cells– Spiral ganglion and the structure of the

auditory nerve

Aims and objectives of these lectures

• Focus (3) on the cochlear lateral wall and Reissner’s membrane:– The spiral ligament– The stria vascularis

– The endolymphatic potential and potassium recycling

– Reissner’s membrane

Aims and objectives of these lectures

• Focus (4) on cochlear pathology:– Presbyacusis– Ototoxicity– Noise trauma– Genetic hearing loss– Molecular mechanisms of cell loss– Regeneration and repair

Inner ear

From Bear, Connors and Paradiso, Neuroscience: exploring the brain (Lippincott Williams and Wilkins)

Cochlea• The main functions of the cochlea are to

analyse and convert the vibrations caused by sound into a pattern of electrical signals that can be conveyed along the auditory nerve fibres to the brain

• This process involves three main steps:– sensory transduction– processing of the signal– neurotransmission

The bony and membraneouslabyrinths

From Furness and Hackney, Scott-Brown’s Otorhinolaryngology: Head and Neck Surgery 7

scala vestibuli

scala media

scala tympani

Cross sections of the cochlear duct

Left: Mahendrasingam et al., 2011, JARO; Right Hackney and Furness, Noise and its Pathophysiology (eds Luxon and Prasher, 2007, Wiley)

3 week old mouse8 week old guinea pig

Fluid segregation

• The three chambers contain different fluids• Endolymph, high in potassium, in scala

media

• Perilymph, high in sodium, in scala

vestibuli and scala tympani

The cochlea is a frequency analyser

Low frequencies

High frequencies

Basilar membrane andorgan of Corti

cochlear nerve

Increasingmass

Increasingstiffness

Frequency mapping on the basilar membrane

• Discovered by Georg von Békésy who was awarded the Nobel Prize for Physiology or Medicine, 1961

• Used human cadavers and played sounds to them, whilst observing the motion of the basilar membrane

• Measured the travelling wave and noted peaks of tuning

• However, the peaks were not sharp enough to account for human frequency selectivity

• Active physiological mechanisms are also required

Frequency analysis in the cochlea• Sound sets up a travelling wave along the

basilar membrane• The peak of motion determines the frequency

selectivity (tuning) of the cochlea at that point• The peak moves further along as frequency

gets lower

Basilar membrane animation

YouTube video Copyright: Howard Hughes Institute (under license)

Cross sections of the cochlear duct

From Furness and Hackney, Scott-Brown’s Otorhinolaryngology: Head and Neck Surgery 7

Organ of Corti• Organ of Corti consists of a sensory epithelium with

hair cells and supporting cells

Nervefibres

Striavascularis

tectorial membrane

From Furness and Hackney, Scott-Brown’s Otorhinolaryngology: Head and Neck Surgery 7

The reticular lamina by scanning electron microscopy

IHCOHC

The reticular lamina by scanning electron microscopy

IHCOHC

Supporting cells: inner pillar, outer pillar, Deiter’s cell 1, Deiter’s cell 2, Deiters cell 3.

Supporting cells are rich in actin and tubulin (cytoskeletal proteins) to provide mechanical support to the organ of Corti

From Furness and Hackney, Scott-Brown’s Otorhinolaryngology: Head and Neck Surgery 7

Supporting cells are rich in actin and tubulin (cytoskeletal proteins) to provide mechanical support to the organ of Corti

From Furness and Hackney, Scott-Brown’s Otorhinolaryngology: Head and Neck Surgery 7

Immunogold shows sorting of different actin isoforms in different organ of Corti cell types

From Furness et al Hear Res. 2005 Sep;207(1-2):22-34

Hair cells• Auditory stimuli are received in the form of

mechanical energy• Hair cells are mechanosensory receptors of

the inner ear and are found in the cochlear and vestibular epithelia

• They share common characteristics which underlie their sensitivity to mechanical stimuli

Hair cells in auditory epitheliumOuter hair

cellsInner hair

cellsCochlea +

organ of Corti

Comparing the inner and outer hair cells

IHCs flask shaped; mitochondria dispersed; nucleus centralOHCs cylindrical; mitochondria mostly lateral, nucleus basal

Hair cells in the organ of Corti

• Two types, structurally and functionally distinct

• A number of similarities and differences• Bundle structure – similar rows of

stereocilia but different shapes• Both can perform mechanoelectrical

transduction• Innervation differs between the two

Overview of bundle structure

• Stereocilia form precise rows

• They are coupled by various extracellular filaments

From Hackney and Furness J Cell Sci 2013; 126(Pt 8):1721-1731

The hair bundle is the hair cell’s transducing element

• Composed of stereocilia linked together by extracellular filaments

• Contains many different proteins• The core of the stereocilium is actin• It also contains myosins and a variety of

scaffolding and calcium modulating proteins

• Extracellular filaments composed of other proteins

Other important proteins required for transduction

• Transducer elements– TMC1 (transmembrane

channel 1)– TMC2 (transmembrane

channel 2)– LHFPL5 (TMHS)

(tetraspan membrane protein of hair cell stereocilia)

– Protocadherin 15– Cadherin 23– TMIE (transmembrane

inner ear protein)

• Structural and regulatory components– Harmonin– Sans– Whirlin– Usherin– Stereocilin– EPS8, EPS8L2– PTPRQ– VLGR1– Calmodulin– PMCA2A (calcium

ATPase)

Links

• The composition of links is becoming better understood

• Their distributions tend to follow a particular pattern

Hair bundles are the site of mechanoelectrical transduction

• Hair cells are sensitive to deflections of the hair bundle along the axis of sensitivity

plus (excitation)

minus (inhibition)

0 0

Transduction occurs when the stereocilia are deflected

positive negative

+

--

+

Hair cell responses

Moving stereocilia

Cell electrical response

The tip-links

• Excitatory deflections of stereocilia open transduction channels by means of a gating spring

• The spring is represented by thetip link

A model of mechanosensitivityA single tip link

Tip links and transduction channels

TMHS

From Hackney and Furness J Cell Sci 2013; 126(Pt 8):1721-1731

Immunolocalization of TMHS/LHFPL5

Actin (green), TMHS (red)

Hair-cell transduction and neurotransmission

stimulus

response

+80 mV

-70 mV

Glutamate transporters around IHCs but not OHCs confirm glutamatergic transmission

Inner phalangeal cells around IHCs

FibrocytesOHC area

Summary

• In this lecture we have looked at the gross structural anatomy of the cochlea

• We have examined the organisation and function of the organ of Corti

• We have described and explained mechanoelectrical transduction – how the hair cells detect mechanical stimulation