Cochlear anatomy, function and pathology I Professor Dave Furness Keele University [email protected] 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 membraneous labyrinths 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 3 week old mouse 8 week old guinea pig Left: Mahendrasingam et al., 2011, JARO; Right Hackney and Furness, Noise and its Pathophysiology (eds Luxon and Prasher, 2007, Wiley) 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 Increasing mass Low frequencies Basilar membrane and organ of Corti High frequencies Increasing stiffness cochlear nerve 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 Stria vascularis tectorial membrane Nerve fibres From Furness and Hackney, Scott-Brown’s Otorhinolaryngology: Head and Neck Surgery 7 The reticular lamina by scanning electron microscopy OHC IHC The reticular lamina by scanning electron microscopy OHC IHC 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 epithelium Cochlea + Inner hair Outer hair organ of Corti cells cells Comparing the inner and outer hair cells IHCs flask shaped; mitochondria dispersed; nucleus central OHCs 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 • Structural and regulatory – TMC1 (transmembrane components channel 1) – Harmonin – TMC2 (transmembrane – Sans channel 2) – Whirlin – LHFPL5 (TMHS) – Usherin (tetraspan membrane – Stereocilin protein of hair cell stereocilia) – EPS8, EPS8L2 – Protocadherin 15 – PTPRQ – Cadherin 23 – VLGR1 – TMIE (transmembrane – Calmodulin inner ear protein) – 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 plus (excitation) along the axis of sensitivity 0 0 minus (inhibition) 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 the tip link A model of mechanosensitivity A 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 +80 mV stimulus -70 mV response Glutamate transporters around IHCs but not OHCs confirm glutamatergic transmission OHC area Inner phalangeal Fibrocytes cells around IHCs 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.