What is the effect on the hair cell if the stereocilia are bent away from the kinocilium?

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1 CASE 44 A 53-year-old man presents to his primary care physician with complaints of feeling like the room is spinning, dizziness, decreased hearing, ringing in the ears, and fullness in both ears. He states that the symptoms have been occurring episodically but increasing in frequency. The ringing in his ears was not present initially but has become more prominent. He denies any recent ear infections or trauma. He is not taking any medications. On examination he is noted to have low-frequency hearing loss. The remainder of the examination is normal. After a complete workup is done, the patient is diagnosed with Ménière disease. What part of the vestibular system detects angular acceleration and rotation? What is the effect on the hair cell if the stereocilia are bent away from the kinocilium? Where in the auditory pathway is tonotopic organization first established?

2 358 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 44: AUDITORY AND VESTIBULAR SYSTEM Summary: A 53-year-old man has vertigo, tinnitus, and decreased hearing consistent with Ménière disease. Angular acceleration and rotation: Semicircular canals. Effect of bending stereocilia away from the kinocilium: Hyperpolarization. Tonotopic organization initially established in: Organ of Corti. CLINICAL CORRELATION Vertigo is a common complaint in the primary care setting. Vertigo can have numerous etiologies, including benign paroxysmal positional vertigo (most common), Ménière disease, toxic damage to labyrinth (medications), tumors (acoustic neuroma), migraine headaches, viral labyrinthitis, vertebrobasilar vascular disease (especially with cerebrovascular disease), head trauma, and multiple sclerosis. Treatment depends on the underlying etiology. Ménière disease is a syndrome of recurrent attacks of vertigo and tinnitus associated with hearing loss. The underlying pathophysiology is a disorder of fluid balance within the endolymphatic system, leading to degeneration of vestibular and cochlear hair cells. APPROACH TO AUDITORY AND VESTIBULAR SYSTEM PHYSIOLOGY Objectives 1. Know the physiology of the vestibular system. 2. Describe the physiology of the auditory system. Definitions Otolith organs: Vestibular organs (utricle and saccule) which provide tonic information about the position of the head in space as well as linear acceleration, aided by forces exerted by otoliths dense calcium carbonate particles embedded in the gelatinous cap on the sensory epithelium. Tonotopic mapping: Encoding of auditory information by the structural features of the cochlear basilar membrane, with higher pitches encoded at the base of the membrane and lower pitches encoded near its apex.

3 CLINICAL CASES 359 DISCUSSION Sensory transduction in the vestibular system occurs in hair cells. Each hair cell has a hair bundle on the apical end that consists of a large kinocilium and 50 to 100 shorter stereocilia. Vestibular hair cells are located in the otolithic organs, the saccule and utricle, which detect gravitational forces during steady head positions. These hair cells project their hair bundles into a gelatinous cap that is encrusted with dense calcium carbonate otoliths. Gravity pulls the otoliths against the gelatinous cap, deflecting the stereocilia. Hair cells in the saccule and utricle are organized so that their polarities cover all directions, allowing these organs to detect changes in linear acceleration in any direction. Hair cells also are located in the three semicircular canals (anterior, posterior, and lateral), which transduce angular acceleration of the head in three dimensions. These organs lack otoliths; bending of stereocilia is produced by inertial forces of the endolymph when the head is rotated. In all vestibular organs, bending of the stereocilia toward the kinocilium depolarizes the hair cell, leading to release of the transmitter glutamate from the basal end, whereas deflection away from the kinocilium hyperpolarizes the cell, reducing background release of glutamate. The changes in potential produced by bending involve an unusual mechanism. The tips are bathed in endolymph, which has a remarkably high K + concentration (150 mm) that exceeds the intracellular K + concentration (140 mm). Bending toward the kinocilium increases tension on the extracellular filaments ( tip links ) that connect the tips of the stereocilia. This opens cation channels in the tips, and the resulting influx of K + (driven by both the modest concentration gradient and the negative membrane potential) causes depolarization. At rest, a few of the cation channels remain open. When the stereocilia bend away from the kinocilium, these channels are closed, reducing tonic K + influx and hyperpolarizing the cell. Release of glutamate from basal ends of hair cells excites peripheral terminals of primary sensory neurons that have their cell bodies in the ipsilateral vestibular ganglion, and the resulting action potentials travel along axons in the vestibular nerve to the vestibular nuclei in the medulla. Postsynaptic neurons in the vestibular nuclei then project to the spinal cord (helping to control posture), to motor nuclei that control eye movement (mediating vestibulo-ocular reflexes), and to the reticular formation (which can produce vertigo and the gag reflex). Hearing also begins with sensory transduction in hair cells, which in this case are located within the scala media of the cochlea, in the organ of Corti. The inner hair cells, which are less numerous but more richly innervated than the outer hair cells, are primarily responsible for sensing auditory information. The primary function of the outer hair cells is to lengthen when depolarized, which increases the distance between the basilar and tectorial membranes, allowing the basilar membrane to bend more and thus produce cochlear amplification of subsequent sound waves. Amplification of the effects of sound waves is also a consequence of the tips of the stereocilia of inner and outer hair cells being embedded in the tectorial membrane. This

4 360 CASE FILES: PHYSIOLOGY results in shearing forces being transmitted to the stereocilia during displacements of the basilar membrane by sound waves. Auditory hair cells in adults lack kinocilia, but other properties are the same as in vestibular hair cells. The endolymph has the same high concentration of K +, and bending of the stereocilia toward the longest stereocilium opens cation channels, permitting an influx of K + to depolarize the cell, whereas bending in the opposite direction closes the channels, hyperpolarizing the cell. Pitch perception is determined primarily, although not exclusively, by the location in the organ of Corti that is maximally stimulated. Each tone produces a traveling wave in the cochlea; high pitches produce waves that peak near the base of the cochlea, and low pitches produce waves that peak near the apex. This results in a tonotopic organization of the hair cells, and this positional relationship is maintained throughout the auditory pathway. The inner hair cells release glutamate at synapses between their basal ends and the terminals of primary afferent neurons that have their cell bodies in the spiral ganglion in the cochlea. The central axons travel in the auditory nerve to make synapses on neurons in the cochlear nuclei, which project successively to the inferior olivary nuclei, the inferior colliculus, the medial geniculate nucleus, and then the primary auditory cortex. At each level, pitch is encoded by tonotopic organization and perhaps some coding by action potential frequency ( phase-lock code), whereas loudness depends on the total number of active neurons and their firing rates. Sound localization depends on processing in the auditory cortex that analyzes differences in both the phase and the loudness of sound waves on the two sides of the head. In addition, directional differences in sound quality resulting from the shape and orientation of the pinna are detected. COMPREHENSION QUESTIONS [44.1] Otoliths have which of the following properties? A. They contain kinocilia and cation channels that are opened when pulled by extracellular filaments. B. They are located only in the saccule and utricle. C. They are located only in the semicircular canals. D. They bend stereocilia toward but not away from the kinocilium. E. They stimulate hair cells, transducing angular acceleration. [44.2] Depolarization of hair cells during the bending of stereocilia occurs because bending causes which of the following responses? A. Closing channels that carry an outward K + current B. Closing channels that carry an inward Na + current C. Closing channels that carry an inward Ca 2+ current D. Opening channels that carry an inward Na + current E. Opening channels that carry an inward K + current

5 CLINICAL CASES 361 [44.3] A high-pitched tone is associated with which of the following features? Answers A. Bending of stereocilia toward the kinocilium B. Encoding primarily by the frequency of firing of primary afferent axons in the cochlear nerve C. Being detected by maximal activation of hair cells near the apex of the cochlea D. Encoding by the type of neurotransmitter released by primary afferent neurons in the auditory pathway E. Being recognized by comparing phase differences between waves detected on the left and right sides of the head [44.1] B. Otoliths are located in the otolithic organs, the saccule and utricle, not in the three semicircular canals. They are pulled by gravity against the gelatinous cap containing stereocilia, which can bend either toward or away from the kinocilium. This bending preferentially transduces linear acceleration rather than angular acceleration (which is transduced by hair cells in the semicircular canals). [44.2] E. Opening of K + channels in the stereocilia depolarizes the hair cells because the [K + ] o in the endolymph surrounding the hair cell exceeds the [K + ] i in the stereocilia. [44.3] C. A high-pitched sound maximally excites hair cells near the apex of the cochlea, and those cells provide tonotopically organized input to central components of the auditory system. Hair cells in the organ of Corti in adults lack kinocilia, and they all use glutamate as their primary neurotransmitter. Although lower pitches may be encoded partially by action potential frequency, higher pitches have frequencies that are too high to allow this type of phase-lock code and thus rely solely on tonotopic coding.

6 362 CASE FILES: PHYSIOLOGY PHYSIOLOGY PEARLS In both the vestibular and auditory systems, sensation depends on transduction of mechanical energy by stereocilia in hair cells. Modest depolarization of a hair cell under basal conditions is maintained by a continuous influx of K + through a fraction of the cation channels in stereocilia. Bending toward the kinocilium (in vestibular organs) or the tallest stereocilium (in the organ of Corti) opens additional channels, producing further depolarization, whereas bending in the opposite direction closes the channels, hyperpolarizing the hair cell. Depolarization of hair cells increases vesicular release of glutamate, which depolarizes peripheral terminals of primary afferent neurons, initiating action potentials that travel along the vestibular or cochlear nerve into the brainstem. Hair cells in the saccule and utricle detect the effects of gravity on otoliths, providing information about steady head positions and linear acceleration of the head. Hair cells in the anterior, posterior, and lateral semicircular canals detect inertial forces exerted by the endolymph when the head is rotated, providing information about angular acceleration in three dimensions. Hair cells in different regions of the organ of Corti are activated maximally by different pitches because each pitch produces a traveling wave that peaks at a different position along the cochlea, thus providing an initial tonotopic coding of pitch that is propagated throughout the auditory system. REFERENCES Connors BW. Sensory transduction. In Boron WF, Boulpaep EL, eds. Medical Physiology. Philadelphia, PA: Saunders; 2003: Johnson DA. The vestibular system, The auditory system. In: Johnson LR, ed. Essential Medical Physiology. San Diego, CA: Elsevier Academic Press; 2003: