Proceedings of the Australian Physiological Society (2008) 39: 137-147 http://www.aups.org.au/Proceedings/39/137-147 ©D. Robertson 2008

Centrifugal control in mammalian

Donald Robertson

The Auditory Laboratory,Discipline of Physiology, School of Biomedical Biomolecular and Chemical Sciences, The University of Western Australia, WA6009, Australia

Summary and visual systems.2 Some centrifugal pathways influence sensory processing by acting evenbefore the most 1. Centrifual contol of manysensory systems is well peripheral sensory transduction events in the sense organ. γ established, notably in the motorneuron of skeletal muscle Generally these pathways work by modulating the stimulus stretch receptors. energy reaching the sensing elements of the sense organ 2. Efferent (olivocochlear) innervation of the itself. Familiar examples in the visual system are the control mammalian was first established through of the pupil and the lens of the eye. In the anatomical studies. Histological studies confirmed synaptic the external ear or pinna in some animals is highly mobile terminals in contact with hair cells and afferent dendrites. and this plays a special role in sound localization.3 The tiny 3. Electrophysiology has elucidated the cellular tensor tympani and stapedius muscles attached to the mechanisms of efferent modulation in the cochlea. middle ear bones are also under centrifugal motor control, 4. The system has potential roles in noise protection, altering the stiffness of the ossicular chain to reduce sound homeostatic feedback control of cochlear function and transmission to the ,particularly at low signal processing. There is some evidence in support of frequencies.4 each, but also contraindications. This reviewfocuses on auditory centrifugal pathways 5. It is concluded that the role of the olivocochlear that innervate the sensory structures of the cochlea and that innervation is still contentious, but on balance the evidence alter details of the primary afferent responses to sound. An appears to favour a role in enhancing signal detection in early example of this kind of centrifugal control in which noise. the peripheral sense organitself is modulated, comes from the work of Kuffler & Eyzaguirre5 who made an intensive Introduction study of the crustacean stretch receptor and the efferent The general concept of centrifugal or efferent control neurons that regulate the response of the sensory afferent of sensory processing is familiar to physiologists and neuron to mechanical stimulation. The most familiar and neuroscientists. Afferent neural pathways carry information arguably the best studied vertebrate example comes from to the higher centres about particular forms of stimulus the sensorimotor system. The length-sensitive muscle energy,transduced in the sense organs and encoded as spindle organwith its afferent sensory neurons is also action potential firing in populations of neurons. There are innervated by γ efferent motor neurons whose action is to also parallel descending, centrifugal, or efferent pathways at contract the distal ends of the muscle spindle, enhancing the most stages by which higher centres influence and shape the spindle afferent firing. Numerous studies beginning in the activity at lower levels. These pathways are of interest 1950’sshowed that this efferent system is activated during because theyprovide a mechanism for the brain to modify voluntary muscle contraction and serves to maintain the sensory experience and an understanding of their action and afferent spindle discharge during active muscle shortening. role is clearly important for a full understanding of the link This shift in the dynamic range of the sense organduring between physical events in the nervous system and active muscle shortening ensures that there is a continuing perceptual performance. In addition, from the pathological stream of precise length-related afferent sensory perspective,there is as yet untapped potential for therapies information going to the movement control centres during that exploit the inherent properties of these pathways and a voluntary movements.6,7 little researched, but potentially important area, is how History of auditory efferents malfunction of these descending pathways may contribute to sensory deficits and disturbances. Efferent innervation of the vertebrate hearing organ, Some descending pathways operate wholly within the the cochlea, was first demonstrated by Rasmussen in the central nervous system. For example, descending inputs 1940s.8 Rasmussen lesioned the auditory pathways at from sensory cortexare known to modify information different levels and used histological techniques to look for processing in thalamic and other nuclei in a number of degenerating nervefibres. He concluded that neurons sensory systems. Afamiliar example is provided by the located in the regions called the superior olivary descending neural pathways that can modulate transmission complex, sent their axons out through the vestibular branch 1 of ascending pain information. Well studied examples exist of the VIIIth cranial nerve, joined the cochlear branch in the in other systems including the mammalian auditory system anastomosis that had been described by Oort in 1918,9 and

Proceedings of the Australian Physiological Society (2008) 39 137 Centrifugal control in mammalian hearing entered the cochlea. Rasmussen described both crossed and endocochlear potential that is produced by electrogenic uncrossed projections and called the system of efferent pumps in the transporting epithelium known as the stria axons the olivocochlear bundle (Figure 1A). Not long after vascularis.14 Finally,the micromechanical behaviour of the this, Galambos electrically stimulated the olivocochlear cochlea is such that there is a systematic map of sound axons and reported that the firing of auditory nerveafferents frequencyalong the organ, with hair cells and nervefibres wassuppressed.10 at the base responding to high frequencysounds and those A further along towards the cochlear apexresponding to progressively lower frequencies. The details of the olivocochlear innervation of this 1a . 1b . organwere not unravelled until some 20 years after 1c . Rasmussen’soriginal description of the olivocochlear fibre 2. bundles. The advent of the electron microscope revealed the presence of an extensive efferent innervation with vesicle-filled efferent terminations on both receptors cells 3. and on afferent nervedendrites (Figure 1B). Beneath the inner hair cells vesicle-filled varicosities are found in close contact with afferent dendrites (the type I afferent neurons of the auditory nerve). In contrast, in the outer B region, enormous vesicle-filled nerveendings are found actually on the receptor cells themselves. The outer hair Fourth Ventricle Ventral cochlear cells themselves do possess an afferent innervation (the nucleus Type II afferent neurons) which comprises only 5-10% of Auditory nerve the afferent cochlear neural output. However, the inner hair outer hair cells cells relationship, both anatomical and functional, between this sparse outer hair cell afferent innervation and the massive

Lateral neurons afferent olivocochlear innervation of the outer hair cells is unclear 15 Medial Neurons Vestibulo-cochlear (see for example Thiers, Nadol & Liberman, 2008 )and anastomosis MOCS for simplicity this has been omitted from Figure 1B and LOCS (ACh) (ACh from the remainder of this review. Dopamine The next major step in our understanding of the GABA CGRP anatomical organization of the efferent innervation of the Enkephalins) cochlea beganwith the autoradiographic studies of Guinan, Warr and colleagues.16,17 Theyshowed that injections of Figure 1. A: Summary of the course of afferent (solid lines) radio-labelled amino acids into medial zones of the superior and efferent (dotted lines) fibres of the auditory brainstem. olivary complexresulted in bilateral labelling overthe outer Efferent olivocochlear axons exit the brainstem in the hair cells, whereas injections into the lateral superior olive vestibular banchofthe VIIIth neve and cross to the cochlear resulted in mainly labelling overthe inner hair cell region. branchatthe anastamosis of Oort. (Adapted from Ras- These studies were combined with the then newmethods of mussen, 19538). B: Organization of medial (MOCS) and retrograde labelling of the cell bodies of origin of the lateral (LOCS) olivocochlear systems, their cochlear termi- cochlear efferent innervation and as a result, Rasmussen’s nations and putative neurotranmsitters. (Adapted from original division of crossed and uncrossed components was Spoendlin, 197211 and Warren & Liberman, 198935). substantially modified. As shown in Figure 1B we now describe the olivocochlear efferent pathway as comprising a medial olivocochlear system (with both crossed and At this point the non-specialized reader needs to be uncrossed components) with large cell bodies located in oriented with a fewkey facts about the structure and medial and ventral olivary regions and innervating the outer function of the mammalian hearing organ. There are two hair cells of the cochlea, and a lateral olivocochlear system sets of mechano-sensitive hair cells, the inner and outer hair of small cell bodies in and around the lateral superior olive cells, with very different roles in auditory transduction and innervating mainly afferent dendrites beneath the inner which will be considered again later.Inall mammals looked hair cells of the ipsilateral cochlea. With minor variations at so far,90-95% of the primary afferent neurons are this basic organization has been confirmed in several hooked up to the inner hair cells at chemical .11-13 mammalian species. Various studies have shown that the The vibration of the basilar membrane caused by sound large outer hair cell endings are primarily cholinergic provides the mechanical drive tothe hair cells that opens whereas the axo-dendritic synapses beneath the inner hair their stretch-activated transduction channels. The driving cells contain a range of transmitters; , force for the movement of ions through the transduction dopamine, enkephalins and other peptides.18,19 channels is a combination of the intracellular potential of the hair cells and the large (+90mV) extracellular voltage found in the scala media above the hair cells – the so-called

138 Proceedings of the Australian Physiological Society (2008) 39 D. Robertson

Functional effects of efferent activation afluctuation in voltage between a cochlear electrode and a remote reference, it is in fact a reflection of the oscillating 10 The early studies by Galambos showed that rise and fall in current through the hair cells, modulated by stimulating the olivocochlear system resulted in suppression the opening and closing of their apical mechano-sensitive of auditory nerveafferent responses to sound. This transduction channels.) stimulation can be achievedbyplacing stimulating These latter twoeffects are explained by a drop in the th electrodes at the floor of the IV ventricle, at the levelof basolateral resistance of the outer hair cells as a result of the the facial genua where the medial efferent axons coalesce to action of the medial olivocochlear system efferent form the olivocochlear bundle. Various measures of transmitter acetylcholine. We knowthat the α9/10 variant cochlear function can be performed relatively easily in the of the acetylcholine receptor of the outer hair cells is intact animal. Wecan, for example record with calcium permeable and its activation by the medial efferents microelectrodes the d.c. voltage in scala media (the leads to opening of Ca2+-activated K+ channels in the outer endocochlear potential), and with gross electrodes in hair cell membrane.21 The drop in outer hair cell resistance electrical continuity with the cochlear tissues we can obtain drains charge from the scala media causing the drop in its informative measures of the afferent nerveand hair cell d.c. voltage, and by simultaneously increasing the standing responses to sound stimulation. current through the outer hair cells, also results in an increase in the modulation of external current flowbya B sound stimulus as it alternately opens and closes the stretch- A Click activated transduction channels at the top of the cells (Figure 3A). Endocochlear 0.1 mV potential (EP) A Scala media voltage +90mV 1 mV 0.5 mV

10 ms C outer hair cell compound AP receptor current transduction 50 µV current

MOC stim.

1 mV K + 2+ 50 ms Ca

ACh MOC terminal Figure 2. Effects of electrical stimulation of medial effer- ent axons on cochlea physiology.A: Schematic illustration of sites of measurement of various cochlear potentials. B: + MOC shocks suppression of compound action potential response to a clickstimulus (top two traces) and simultaneously recorded 40µV scala media d.c. voltage (lower trace). C: simultaneous 1ms recording of cochlear microphonic potential (upper two B Reduced basolateral traces -note increase caused by MOC stimulation) and fall wall resistance in scala media voltage (lower trace). (Parts B and C 20 transduction adapted from Desmedt & Robertson, 1975 ) current

motor proteins Reduced voltage drive Figure 2 shows results obtained in the cat with John to motor proteins K+ 20 + Desmedt in 1972. After a train of shocks to the efferent Ca 2 axons, the compound cochlear action potential response to a afferent firing ACh brief acoustic stimulus is reduced in amplitude as described MOC Reduced terminal by Galambos. However, there are other changes that show afferent sensitivity to sound that this effect is mediated by the efferent terminations on Figure 3. A: Schematic illustration of the MOC action the outer hair cells (i.e. the medial olivocochlear system). on outer hair cell nicotinic ion channels. Opening of K+ Along with the suppression of the afferent nerveresponse channels causes drop in scala media voltage and increase in there is a drop in the voltage above the hair cells. The externally recorded receptor current (measured as cochlear endocochlear potential, normally about 90mV positive with micophonic potential-see text for explanation). B: Action on respect to the rest of the animal, falls by up to 3mV as a outer hair cells affects cochlear amplifier function and result of efferent stimulation. In addition, there is a parallel reduces sensitivity of inner hair cell primary afferent neu- increase in the externally recorded receptor current ev oked rons. by a tonal stimulus, the so-called cochlear microphonic. (Note that although the cochlear microphonic is recorded as So all the action in the cochlea caused by medial

Proceedings of the Australian Physiological Society (2008) 39 139 Centrifugal control in mammalian hearing

wasworked out with major contributions from the Perth laboratory from about 1982 onwards (for reviews see A 22 23 100 Patuzzi & Robertson, 1988 and Yates et al. 1992 ). Transduction currents through the outer hair cells drive a fast electromechanical motor response of the hair cells that 10 is responsible for amplifying vibration of the sense organ. This outer hair cell action, referred to as the “cochlear amplifier”,24 is an essential element in a positive feedback 1 loop that determines the sensitivity to sound of the afferent neurons connected to the inner hair cells. The drive tothe 0.1 outer hair cell electromechanical motor is provided by the Velocity (mm/s) voltage drop across the basolateral wall of the outer hair cells and this is reduced when medial efferent action lowers 0.01 the basolateral wall resistance of the outer hair cells. The outer hair cell damage overall mechanical gain of the cochlea is reduced as a 0.001 consequence and the sensitivity to sound of the inner hair 10 30 50 70 90 110 cells and their associated primary afferents is reduced Sound pressure level (dB re. 20Pa) (Figure 3B). There is an important basic property of this B mechanism of efferent-mediated suppression. The outer hair cell active feedback loop has a limited dynamic range as shown here in measurements made of the organvibration in the Perth lab (Figure 4A). At the most sensitive 20 2kHz frequencythe vibration amplitude near threshold grows 18 6kHz roughly linearly with sound intensity but then flattens off 10kHz 16 markedly as the active amplification reaches saturation. At 14kHz 14 16kHz much higher sound levels vibration is dominated by the passive linear mechanical properties. This is shown 12 dramatically by the data in which loud sound was used to 10 damage the outer hair cells.25 This results in a loss of the 8 sensitive outer hair cell-assisted vibration whereas the 6 higher levellinear vibration is untouched. The consequence 4 of this is that in the normal cochlea, the medial efferent action on the cochlear amplifier (and hence on afferent 2 neuron sensitivity to sound) is most effective atlow to 0 medium sound levels as shown in Figure 4B. Electrical 0 10 20 30 40 50 60 70

Afferent nerve threshold change (dB) stimulation of the medial efferent axons causes a maximum Tone level re. nerve threshold (dB) suppression of the afferent nerveresponse equivalent to a sound pressure reduction of about 20dB, but this suppression declines to almost nothing for sound levels Figure 4. A: Examples of nonlinear vibration of basilar only 40-50dB above threshold.26 This issue of the limited membrane in normal cochlea (solid circles) and in the same dynamic range of medial efferent effects is pertinent when cochlea after loud sound exposurethat depresses function considering the possible roles of the system in hearing. of outer hair cell cochlear amplifier (open circles). Note Medial efferent neuron activation can also affect the that high intensity vibration is not affected, but sensitive spontaneous firing rate of primary afferents. This can also portion of input-output curve is lost. (Adapted from 25 be explained by the effect on the basolateral resistance of Patuzzi, Johnstone & Sellick, 1984 ). B: effect of MOC the outer hair cells. The drop in the standing voltage above stimulation on afferent nerve thresholds to sound stimula- the hair cells results in a hyperpolarization of the inner hair tion of various intensities. Note lackofeffect on responses cell membrane potential and hence reduced spontaneous at medium and high stimulus levels, consistent with MOC transmitter release. It has been shown by independently action on outer hair cell cochlear amplifier contribution to 26 altering the scala media voltage that a change of only a few low level sensitivity.(from Seluakumaran, 2007 ). millivolts in this d.c. voltage is sufficient to cause measurable changes in spontaneous afferent firing.27 efferent stimulation is occurring at the outer hair cells, and What is the mode of action of the lateral yet 90-95% of the afferent neural output of the cochlea olivocochlear system that terminates on the primary afferent comes from the inner hair cells. To understand howthe dendrites? Wewould expect this system to modulate afferent responses to sound from the inner hair cells are primary afferent excitability independently of the cochlear suppressed by action on the outer hair cells, we have toturn electromechanical gain. In fact it has provedextremely to the modern viewofcochlear physiology,much of which difficult to demonstrate reliable effects of electrical

140 Proceedings of the Australian Physiological Society (2008) 39 D. Robertson stimulation of this component of the efferent system brainstem nucleus of origin of the lateral system. Injections probably because of its very small diameter unmyelinated into basal cochlear regions (the high frequencyparts of the axons and the diverse range of that it place-frequencymap) labelled efferent cell bodies in a employs. Lesions of the nucleus of origin, the lateral region of the lateral superior olivary nucleus that is known superior olive,hav e been reported to have a variety of to receive afferent input from high frequencycochlear effects on compound afferent nerveactivity.28-30 Although regions. Injections into other turns of the cochlea labelled suggestive,some of these effects may not reflect an efferent neurons located in systematically lower frequency immediate loss of tonic drive but rather a longer term effect coding zones of the brainstem nucleus. These data strongly of loss of neuromodulatory input. Data from our own lab suggest that, likethe medial efferents, the lateral efferents (Garrett unpublished results) showthat selective antagonists can also act in a precise feedback manner to alter cochlear to receptors for one of the lateral system transmitters neural output from the same frequencyregion from which dopamine, when perfused into the cochlea, cause reductions theyreceive their input. in the afferent nerveresponses to sound. This suggests that Do the efferent neurons receive synaptic input from there is a tonic excitatory action of some lateral system higher centres? Medial and lateral olivocochlear neurons efferents on the primary afferent dendrites beneath the inner are contacted by noradrenergic terminals that arise from the hair cells, but data from other labs suggest that both locus coeruleus39,40 and these inputs may activate both inhibitory and excitatory actions are possible.28-33 medial and lateral efferent systems.41 Substance P–positive synaptic terminals are found on medial olivocochlear Functional organization of inputs neurons and these possibly arise directly from substance P- positive neurons in the primary .42,43 What is known about the normal synaptic inputs to Electrical stimulation of the results in the efferent neurons in the brainstem? First, there are reduction of primary afferent nerveresponses to sound and inputs at the brainstem levelthat are drivenbysound. increases in outer hair cell receptor current consistent with Recordings of the activity of single efferent axons activation of medial efferents by descending projections combined with intracellular tracing methods, have shown from the , although the nature of the that individual efferent neurons respond sensitively to involved is still unknown.44 Xueyong sound and showresponses that are highly frequency Wang carried out a series of extensive studies on selective,with each neuron tuned to a specific sound olivocochlear neurons in brainstem slices. The neurons frequencyinamanner very similar to the sharp tuning of were identified as efferent by pre-labelling them using primary afferents. Single efferents responded to sound in intracochlear injections of retrograde label. Wang recorded one or other ear and sometimes both. These responses to the responses of these identified neurons to a range of sound arise because of connections to the efferent neurons transmitters and agonists. In both sharp electrode and whole in the brainstem from either the ipsilateral or contralateral cell patch recordings, medial efferents were found to be which have been demonstrated using strongly excited by noradrenaline and substance P.45-48 double labelling methods.34 In summary,although there are manydetails still to Numerous studies have shown that acoustic activation be unravelled, the olivocochlear pathways comprise an of these brainstem inputs to medial efferent neurons, can organized set of projections to the cochlea, drivenby result in measurable effects on cochlear responses, in a auditory brainstem inputs and probably by a variety of manner consistent with a reduction in the gain of the outer higher centres as well. The medial and lateral systems offer hair cell amplifier.35 twodifferent ways of regulating cochlear neural output, Most important of all, in the microelectrode studies either by altering outer hair cell gain and the scala media of single efferents, it was possible to map the region of the d.c. voltage, or by directly manipulating the excitability of cochlea innervated by single medial efferents that had been the afferent dendrites. Furthermore the system does not characterized physiologically.The data from such constitute a diffuse non-specific projection. On the contrary, experiments showed that the position along the cochlea the innervation of the cochlea and the wiring in the where individual medial efferent neurons terminated on brainstem is such that efferent neurons innervate the outer hair cells closely corresponded to that expected from discrete cochlear regions close to the region from which the sound frequencytowhich theywere most sensitive, theyreceive their most effective acoustic input. based on the well-known place-frequencymap of the cochlea. These findings established that medial efferent Role in hearing neurons are able, in principle, to influence outer hair cell function in a more or less precise, tonotopically organized One possible role is in early development of the feedback manner.37 peripheral sense organ. Efferent innervation of the cochlea No-one has succeeded in recording from single is present in neonates well before the onset of hearing49 and lateral system neurons so we do not knowhow theyrespond it has been shown that early de-efferentation results in a to sound, but indirect evidence suggests that a similar failure of the normal outer hair cell amplification process to precise organization exists here too. Robertson et al.,38 fully develop.50 This effect could be because of a loss of injected the fluorescent retrograde label DYinto the cochlea trophic factors supplied by the efferent endings. and looked at the location of labelled cell bodies in the It is important howevertostress that the centrifugal

Proceedings of the Australian Physiological Society (2008) 39 141 Centrifugal control in mammalian hearing innervation is not required in anyway for the normal These are thought to result in slowcellular length changes baseline operation of the normal adult organ. The basic mediated by conventional contractile proteins. Such length functional properties of the cochlear afferent output are changes might affect parameters such as the set point of the achievedwithout neural networks, by the micromechanical hair bundle angle which could have animportant influence behaviour of the organand its receptors cells. Interrupting on the effect of loud sound on the transduction channels, the centrifugal pathways acutely in adult animals does not resulting in a protection of the transduction currents. interfere with this basic operation. So if the efferents have In addition to this unresolved issue of the mechanism arole it must be in altering cochlear function under of protection, the functional significance of the protective particular circumstances. The roles which have been effect is unclear.Ithas been argued that it is unlikely that attributed to the efferent system in the mature cochlea are: the efferent innervation of the cochlea could have evolved 1) protection from acoustic overstimulation; 2) homeostatic for this purpose in a pre-industrial world.55 It is therefore regulation; 3) enhanced signal processing. These are possible that the protective effect is an accidental result of considered in turn below. efferent-mediated processes that have other functions.

Protection from overstimulation Homeostatic regulation?

Excessive exposure to loud sound can cause both The cochlea presents a classic example of the need temporary and permanent loss of neural sensitivity in the for physiological regulation. Two fundamental aspects of cochlea. This is believedtobeessentially a modern cochlear neural output need to be tightly regulated. One is problem created by the industrialization of society – noise- the sensitivity to sound of the primary afferents emanating induced deafness was first described as “boilermakers’ from the inner hair cells and the other is their spontaneous deafness”. For most types of loud noise exposure, we know firing rate. from a host of experiments, that the deafness is the result of Sensitivity to sound is highly dependent on the outer either temporary or permanent damage to the outer hair hair cell electromechanical gain. This gain needs to be cells and the loss of their unique amplification function. In controlled carefully because it forms part of a positive our laboratory,Alan Cody51 first showed in an animal feedback loop that is inherently in danger of running out of model that binaural exposures to loud sound resulted in less control and causing spontaneous mechanical oscillation. We cochlear damage than monaural exposures. Cody showed knowthat such runawayoscillations can occur because of that this binaural effect was eliminated if animals were the presence of otoacoustic emissions in which sound administered strychnine prior to the loud noise exposure, energy can be spontaneously emitted from the ear, implicating the olivocochlear pathways. Ramesh Rajan sometimes accompanied by the perception of phantom followed up these observations in his PhD work in Perth sounds.56 and showed conclusively that stimulation of the Spontaneous afferent firing rate also needs to be olivocochlear efferents protects the cochlea from loud carefully regulated. Anychanges in spontaneous firing rate sound induced damage.52,53 could result in confusion in the central nervous system as to Patuzzi & Thompson54 followed up these studies by what constitutes sound and what constitutes silence and looking at the relationship between the loss of neural potentially could give rise to phantom auditory sensations sensitivity and the outer hair cell receptor current after loud or tinnitus. On the presynaptic side, we knowthat a change noise exposure. Their results indicated twothings; first that in inner hair cell membrane potential of less than 1mV is protection is mediated somehowbyprotecting the outer hair sufficient to alter spontaneous firing rates in primary cell receptor current from the damaging effect of loud afferents. Because of its influence on inner hair cell sound and second, that individual variations in the neural membrane potential, the scala media voltage needs to be threshold change resulting from loud sound exposure may tightly controlled. On the post-synaptic side, changes in be a result of individual variations in the effectiveness of afferent dendrite excitability could lead to altered the efferent protection. spontaneous firing and in addition could lead to There are twopuzzling aspects to the protective hypersensitivity to sound or to sudden deafness. Figure 5, effect. The first is to do with the mechanism. Because of the inspired in part by Patuzzi57 illustrates the ways in which saturation of the outer hair cell amplifier,the classical lateral and medial efferents could provide feedback medial efferent effect on outer hair cells should be regulation of these twoparameters of cochlear neural completely ineffective atthe sort of intensities of sound output. Both spontaneous and drivenafferent firing rates employed to produce the acoustic trauma. If efferent provide the inputs to these feedback circuits. activation does protect by reducing the basilar membrane The problem with these plausible theoretical notions vibration amplitude during the loud sound it is unclear how of a long term homeostatic role for the olivocochlear this is achieved. It is possible that the efferent protective efferents, is that there is little compelling evidence to effect is mediated not by an effect on vibration amplitude, support them. Adult animals whose cochleae have been butbytriggering some intracellular pathway in the outer completely de-efferented shownoobvious fluctuations or hair cells that leads to protection of the outer hair cell gross abnormalities of neural threshold. In cats it has been transduction current. It is known that there are a number of reported that the mean spontaneous firing rate across all other slower Ca2+-dependent processes in outer hair cells. primary afferents falls some weeks after de-efferentation,28

142 Proceedings of the Australian Physiological Society (2008) 39 D. Robertson and in mice with lesioned lateral superior olivary nuclei, In this scheme of things, the medial efferent action on outer there is a reduction in the amplitude of the auditory nerve hair cell conductance is only one of manycontrol elements. response to moderate intensity sounds.58 As argued already Despite this uncertainty about a homeostatic role for however, these effects could represent a loss of some the olivocochlear efferents we do have some quite trophic influence rather than a loss of ongoing neural compelling evidence from animal studies, that abnormal feedback control. Similarly,human patients in whom the levels of efferent activity can actually produce peripheral efferent input to the cochlea has been severed in the course hearing pathology.36,64 Some animals showapre-existing of vestibular nervesection as a treatment for intractable hearing losses of 20dB or more in a restricted frequency vertigo, shownosignificant alteration in standard measures range (assessed by measuring the thresholds of the afferent of threshold and a host of other audiometric parameters.59,60 nerveresponse to tones). Remarkably,when the medial The incidence of phantom auditory sensation (or tinnitus) in efferent axons in the brainstem are cut, the hearing such patients has also been investigated and the results are thresholds showsubstantial and immediate recovery of interesting but inconclusive.Such patients frequently suffer sensitivity,insome cases to normal levels. Such results from tinnitus before surgery.About equal numbers of clearly showthat spontaneous tonic activity of efferents can patients showanamelioration, a worsening, or no change in result in reversible hearing losses in limited regions of the their tinnitus after de-efferentation.61 cochlea. Wedonot knowwhat factors trigger such abnormal efferent firing, but these results are interesting Brainstem centres from the perspective ofspontaneous fluctuations and

MOCS sudden hearing loss in humans. Perhaps some of these cases LOCS are due to hyperactivity in efferent pathways to the cochlea and the hearing loss might be alleviated by pharmacological Outer hair cell basolateral Cochlear resistance agents that block peripheral efferent action. amplifier gain Scala media voltage Signal detection and discrimination? Basilar membrane The final postulated role for the olivocochlear vibration Inner hair cell d.c.membrane efferents is the one that on balance, I favour.Listening in potential Inner hair cell membrane the real acoustic world is a messy business as anyone trying potential change to followaconversation in a noisy restaurant knows. There Afferent Dendrite Spontaneous are manymechanisms by which the auditory system strives excitability Transmitter release to select signals of interest from the extraneous background noise, but for some years nowithas been proposed that the Primary afferent response to sound Primary afferent spontaneous medial efferent neurons are one element in this important firing rate aspect of auditory signal processing. Winslow&Sachs65 first showed the neural basis of Figure 5. Schematic illustration of the various ways in this proposed role of the medial efferents. Figure 6A shows whichMOCS and LOCS pathways could act in a homeo- atypical input-output curveofasingle primary auditory static feedbackmode to regulate afferent nerve firing. afferent showing its firing rate in response to a pure tone of different intensities. There is a spontaneous firing rate in It is perhaps not surprising that animal experiments the absence of sound and above threshold a rapid increase and clinical data have not provided compelling evidence for in firing to reach a saturation rate. When the medial ahomeostatic regulatory role for olivocochlear efferents. efferents are activated, the curveisshifted to the right There are almost certainly other homeostatic mechanisms because of the action of the medial efferents on the outer that may be operating either in tandem or as backups. For hair cell gain. example, Housleyand co-workers in Auckland have The situation in the presence of background noise is extensively studied purinergic signalling pathways in the very different (Figure 6B). Note firstly that the neuron cochlea and shown that the voltage in the scala media may increases its background firing rate in response to the noise. be controlled by P2X receptor ion channels allowing more This results in increased adaptation of the neuron and a or less current drain through the cellular boundaries of the consequent reduction in the maximum firing rate. The result scala media compartment. In addition, P2Y receptors in is that the range of output firing rates in response to the tone the ion pumping cells of the stria may help to regulate the is nowsignificantly compressed and the slope of the input voltage by directly controlling the electrogenic ion output curvedecreases. There is also a shift to the right pumping.62 O’Beirne and Patuzzi63 provide evidence that because the background noise partly “jams” the outer hair the outer hair cell is itself a complexhomeostatic machine cell amplifier and reduces cochlear sensitivity.This with multiple feedback loops in which membrane potential, interaction between background noise and a tone signal is voltage and stretch-activated ion channels, intracellular known as “masking” and it is one of the major problems calcium, slowhair cell length changes and hair bundle that we encounter in trying to listen to signals such as operating point all interact with the scala media driving speech in the presence of competing noisy backgrounds. potential to regulate overall gain and scala media voltage.

Proceedings of the Australian Physiological Society (2008) 39 143 Centrifugal control in mammalian hearing

combinations, there is still a significant effect of a cue, ABTone in quiet Tone in noise equivalent to about a 3dB improvement in probe detection 300 when cue and probe are matched.68 This is an important result because it shows that a component of the cue effect is

200 available on a trial-by-trial basis, and is not simply the result of some built up expectation of a particular frequency +MOC stim. being presented. In further studies Tan has shown that in 100 +MOC stim. subjects with a hearing loss resulting from outer hair cell

Firing rate (spikes/s) damage, remembering that the outer hair cells are the targets of the medial efferents, the enhancing effect of the 0 4 24 44 64 84 104 4 24 44 64 84 cue was absent at most frequencies studied. So we think Tone level (dB SPL) that the neurectomy data of Scharf59,60 and our own psychophysical results constitute some evidence that under Figure 6. Effects of MOC electrical stimulation on input- certain conditions, medial efferent activation can enhance output curves of single auditory afferent neuron in quiet and the detection of particular signals in background noise. Our in presence of background noise.(Adapted from Winslow & working hypothesis is that in the particular experiments Sachs, 198765). described, the cue sound activates the medial olivocochlear neurons via the brainstem circuits that were described earlier and the anti-masking effect improvesthe Now, when medial efferents are activated in the detectability of the probe tones in the noise. The effect is presence of masking noise, the effect on the input-output frequency-selective,both because of the sharply-tuned curvetotones is rather different from that in quiet. The response areas of the efferent neurons, and because of their efferents cause a suppression of the response to the projection back to the outer hair cells at the place close to relatively lowlev elbackground noise, so the background where the cue tone frequencyisrepresented. This firing rate is reduced. As explained earlier,the efferents mechanism might be optimized in certain sorts of tasks in have little or no effect on the responses of the neuron to the which excitatory descending projections from higher higher leveltones, and in addition the drop in firing to the centres such as auditory cortex, locus coeruleus and noise causes reduced adaptation, resulting in an elsewhere might act synergistically with the brainstem improvement in the maximum firing rate. The net result is a inputs to produce strong activation of the olivocochlear substantial recovery of the output dynamic range and the efferents in response to the cue. It is possible that important slope of the input-output curve, a phenomenon that has ev eryday listening tasks such as focussing on the stream of been referred to as “anti-masking”. Wehav e investigated information in speech in the presence of other competing this anti-masking effect in the inferior colliculus and sounds, or listening for repeated lowintensity signals of cochlear nucleus. Although the input-output curves of these strong significance for communication or survival, could neurons vary in shape, some being similar to those of activate these processes. Our results also suggest that the primary afferents and others showing various degrees of most common form of sensorineural deafness in which the non-monotonicity,westill found strong evidence of the outer hair cells are damaged or degenerated may be 66,67 expected anti-masking in manyneurons. accompanied by a loss of this efferent-mediated attentional What evidence is there that this anti-masking action filter mechanism. Further study is needed to determine of the efferents is translated into meaningful behavioural whether this loss of centrifugal function contributes to the performance? The vestibular neurectomy patients lacking loss of functionality in signal discrimination in noise that is olivocochlear efferents, referred to before, showed a commonly experienced by sufferers of this condition. spectacular absence of anyeffects of the de-efferentation on basic auditory function. However, theydid showachange Conclusions in performance in a particular listening task. In normal subjects, accuracyindetection of a tone in noise is much After more than 60 years of research, the anatomical better when the frequencyofthe tone is “expected”, either organization and mode of action of the olivocochlear because that frequencyispresented more often than others, efferent pathways is relatively well understood. However, or because the tone to be detected is preceded by a clearly the functional role of this centrifugal control system in audible cue of the same frequency.68 This effect has been normal and abnormal hearing, is still contentious. described as an “attentional filter”, the idea being that the Numerous roles are possible although on balance the auditory cue sets in motion some unspecified process that evidence appears to favour a role in enhancing signal directs attention to the cue frequencyand so improvesthe detection in noise. detection of matching probes. In de-efferented human Acknowledgments subjects, this attentional filter has been found to be absent, with cue and non-cue frequencies being detected with equal Supported by grants from the NHMRC, Medical probability.59,60 Health Research Infrastructure Fund and The University of We hav e recently shown that in normal subjects with Western Australia. completely randomized cue and probe frequency

144 Proceedings of the Australian Physiological Society (2008) 39 D. Robertson

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Effect of electrical stimulation of the crossed contributions of enhanced and suppressed sensitivity olivocochlear bundle on temporary threshold shifts to the auditory attentional filter. Hear.Res. 2008; in auditory sensitivity.I.Dependence on electrical 241:18-25. stimulation parameters. J. Neurophysiol. 1988; 60: 549-68. Received13October 2008, in revised form 12 December 53. Rajan R. Effect of electrical stimulation of the crossed 2008. Accepted 13 January 2009.

146 Proceedings of the Australian Physiological Society (2008) 39 D. Robertson

©D.Robertson, 2008

Author for correspondence:

Professor D. Robertson, Physiology M311, School of Biomedical Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Hwy,Crawley, WA6009, Australia.

Tel: +61 8 6488 3291 Fax: +61 8 6488 1025 E-mail: [email protected]

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