Home Email this page Print this page Bookmark this page Decrease font size Default font size Increase font size
Noise & Health  
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Email Alert *
Add to My List *
* Registration required (free)  

   Efferents to the...
   Lateral Olivococ...
   Medial Olivococh...
   Intracellular St...
   Antioxidant Syst...
   Heat Shock Prote...
   Protection from ...
   Neurotrophic Fac...
   Article Figures

 Article Access Statistics
    PDF Downloaded388    
    Comments [Add]    
    Cited by others 23    

Recommend this journal


ARTICLES Table of Contents   
Year : 2003  |  Volume : 5  |  Issue : 20  |  Page : 1-17
Pathways for protection from noise induced hearing loss

Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI 48109, USA

Click here for correspondence address and email

There is increasing evidence that at least one function of both the medial and the lateral olivocochlear efferent systems is to provide adjustment of the set point of activity in their post­synaptic target, the outer hair cells and afferent processes, respectively. New results, summarized in this review, suggest that both efferent systems can provide protection from noise through this mechanism. There are also intracellular pathways that can provide protection from noise-induced cellular damage in the cochlea. This review also summarizes new results on the pathways that regulate and react to levels of reactive oxygen species in the cochlea as well as the role of stress pathways for the heat shock proteins and for neurotrophic factors in protection, recovery and repair.

Keywords: olivocochlear efferents, reactive oxygen species (ROS), heat shock protein (Hsp), neurotrophic factors, cochlea

How to cite this article:
Le Prell C G, Dolan D F, Schacht J, Miller J M, Lomax M I, Altschuler R A. Pathways for protection from noise induced hearing loss. Noise Health 2003;5:1-17

How to cite this URL:
Le Prell C G, Dolan D F, Schacht J, Miller J M, Lomax M I, Altschuler R A. Pathways for protection from noise induced hearing loss. Noise Health [serial online] 2003 [cited 2023 Dec 6];5:1-17. Available from: https://www.noiseandhealth.org/text.asp?2003/5/20/1/31693

  Introduction Top

Acoustic overstimulation has the potential for damaging the cells of the cochlea and producing a permanent loss of hearing (permanent threshold shift - PTS). There are, however, several mechanisms that can provide for protection as well as repair and recovery from the cellular trauma. In this case there can be no loss of hearing or only a temporary loss of hearing (temporary threshold shift - TTS). Some of these mechanisms, such as the reflex pathway for contraction of middle ear muscles, have developed specifically for protection from noise­induced trauma. Other pathways, such as the olivocochlear efferents, have developed to modulate cochlear function and their influence on the effects of noise might be considered a by­product of their "normal" function. Finally there are intracellular stress pathways, which have developed in all cells as a response to multiple stresses, with noise to cells of the cochlea being one such stress. In this review we will first discuss the olivocochlear pathways and how they might function for protection and then describe three types of intracellular stress pathways that can play a role in protection from noise-induced hearing loss in the cochlea.

  Efferents to the Cochlea Top

The current differentiation of the olivocochlear pathways is based on terminology developed by Warr and Guinan (for reviews, see Warr, 1992, Warr et al., 1986). The organization of the two efferent pathways has recently been reviewed by Brown (2001) and Le Prell et al., (2001a). Briefly, there is a medial system of olivocochlear (MOC) efferents, which has its origin in medially located superior olivary complex (SOC) nuclei. The MOC pathway has both crossed and uncrossed projections, ending on the bases of cochlear outer hair cells (OHCs). There is also a lateral system of olivocochlear (LOC) efferents, with an origin in the lateral superior olive (LSO) and a predominantly or entirely uncrossed projection (depending on species) that ends on type I auditory nerve peripheral processes under inner hair cells (IHCs). While these systems presumably have quite different functions, both use set point adjustment of their post-synaptic target as one of the mechanisms for achieving their function. Both appear to provide protection from hearing loss through this function.

  Lateral Olivocochlear (LOC) Efferents Top

The lateral olivocochlear (LOC) efferents have their origin in or near the LSO and project entirely or predominantly to the ipsilateral cochlea. They end on the peripheral processes of type I auditory neurons in the region under IHCs. While LOC fibres make synaptic connection with IHCs during cochlear development (for review, see Simmons, 2002), this is only rarely observed in the mature cochlea. LOC neurons contain multiple neuroactive substances, including acetylcholine (ACh), y-aminobutyric acid (GABA), dopamine (DA), dynorphin (dyn), enkaphalin (enk), and calcitonin-gene-related­peptide (CGRP: for reviews, see Eybalin, 1993, Altschuler and Fex, 1986, Le Prell et al., 2001a, Puel, 1995). There is evidence that many of these substances are co-contained within single LSO neurons (Abou-Madi et al., 1987, Altschuler et al., 1984, Altschuler et al., 1986, Altschuler et al., 1983, Altschuler et al., 1988, Safieddine et al., 1997) or LOC terminals (Altschuler et al., 1985, Safieddine and Eybalin, 1992). Thus, a large body of evidence suggests the LOC transmitters are perhaps co-released, and the potential remains for differential release even with co-containment.

Because the LOC and MOC efferents both use ACh as a transmitter and they travel together throughout much of their course, it has therefore been a challenge to differentiate and determine MOC and LOC function. Three techniques have been commonly used: electrical stimulation, pharmacological manipulation, and surgical cuts. Electrical stimulation at the floor of the fourth ventricle (e.g., Rajan, 1988, Liberman, 1991) activates crossed MOC fibres. A more lateral placement may activate all MOC and LOC fibres, allowing one to define LOC function by first stimulating both MOC and LOC neurons together and using various methods to "subtract" the MOC function. However, because the MOC efferents are myelinated whereas the LOC efferents are not, it is generally believed that LOC neurons are probably not stimulated by the application of electrical current. This prediction has not been directly tested, as to date, no one has recorded from LOC neurons. Pharmacological manipulations using strychnine, a potent antagonist at the a9 receptor, disrupt MOC function (e.g., Bobbin and Konishi, 1974, Desmedt and Monaco, 1961, Sridhar et al., 1995, Dolan et al., 1999). However, strychnine is also a potent antagonist at cholinergic a7 receptors which are present at the LOC - type I auditory nerve synapse (Morley et al., 1998). Thus, strychnine probably does not selectively block MOC efferents. Surgical transection of MOC and LOC efferents has perhaps been the most productive manipulation. MOC surgical cuts, at the floor of the fourth ventricle disrupt only the crossed portion of the MOC pathway, and more lateral cuts disrupt the MOC and LOC pathways in their entirety (e.g., Liberman, 1990, Kujawa and Liberman, 1997). Surgical transection of the efferent pathways provided the first observations of LOC function. Liberman (1990) found that efferent transection compressed spontaneous rates of firing among auditory nerve fibres in cats. This finding has more recently been confirmed in chinchillas by Zheng et al. (1999). In addition to changes in spontaneous rate distribution, transection studies have been used to show that animals in which the entire OCB is cut are much more vulnerable to sound-induced damage than are animals in which only the crossed OCB projections were cut (Kujawa and Liberman, 1997).

We recently described a novel approach for studying the functional role of LOC innervation (Le Prell et al., 2003). We selectively destroyed LOC neurons in guinea pigs by injecting melittin (a cytotoxic extract of bee venom, see Bechinger, 1997, Kourie and Shorthouse, 2000) into the LSO. The LSO is the predominant nucleus of origin for the LOC pathway in the guinea pig (Strutz and Bielenberg, 1984, Robertson, 1985, Stopp, 1990, Aschoff and Ostwald, 1987). Demonstration of reduced labelling of synaptic vesicles in cochlear tissues immuno-labelled with antibodies to synaptophysin confirmed that lesioning the LSO resulted in selective degeneration of LOC neurons. The primary functional effect of lesioning the LSO was a reduction in the amplitude of the sound-evoked whole-nerve compound action potential (CAP) response of the auditory nerve. An equivalent CAP amplitude depression has recently been demonstrated in guinea pigs in which LOC innervation was disrupted via injection of a DA­neurotoxin into the cochlear perilymph (Le Prell and Bledsoe, 2003). These results are consistent with the observation that electrically stimulating LSO neurons enhances CAP amplitude (Groff and Liberman, 2002). Taken together, the results from the whole-nerve functional assays support and extend previous suggestions that LOC neurons modulate single-unit auditory nerve activity (i.e., Liberman, 1990, Zheng et al., 1999).

The growing body of evidence that LOC neurons modulate auditory nerve activity has led us to propose a model in which LOC neurons set the sensitivity of the auditory neurons via manipulation of a "set point." [Figure - 1] Specifically, we propose that delivering putative LOC transmitter substances such as ACh and/or dyn selectively lowers the cochlear set point, thereby enhancing neural activity. In the absence of these putative transmitter substances, auditory nerve activity would be depressed. Evidence that de-efferentation depresses spontaneous auditory nerve activity has been provided in single-unit studies (Liberman, 1990, Zheng et al., 1999). Evaluations of whole-nerve evoked potentials similarly reveal depressed CAP amplitude (consistent with either a smaller number of responsive neurons or a breakdown in response synchrony, see Le Prell et al., 2003). Further evidence that ACh and dyn would enhance auditory nerve activity if released by LOC neurons is provided by pharmacological manipulation of the cochlear fluid. Specifically, iontophoresis of ACh (0.5 M) into the vicinity of the auditory nerve dendrites increases subsynaptic spiking and enhances glutamate­induced auditory nerve activity (Felix and Ehrenberger, 1992). Evaluation of the effects of dyn on cochlear potentials is limited to intra­venous (i.e., systemic) drug applications. Chinchillas treated intravenously with a dynorphin-like substance, (-)pentazocine, showed an enhancement of CAP amplitude and improvement in threshold sensitivity (Sahley et al., 1991, Sahley and Nodar, 1994); excitatory effects that were antagonized by intravenous naloxone (Sahley et al., 1996a) and norbinaltorphimine applied to the round window membrane of the cochlea (Sahley et al., 1996b). The effects of dyn agonists on whole-nerve potentials and single-unit activity have not yet been evaluated when dyn receptor agonists are infused directly into the cochlea; such manipulations are essential for the validation of this model.

The LOC neurons contain inhibitory transmitter substances as well as the excitatory substances described above. Thus, a second prediction of our model is that substances such as DA and enk selectively raise the set point of the cochlea, thereby decreasing cochlear activity. During infusion of DA agonists, auditory-nerve single­unit driven rates (Ruel et al., 2001, Oestreicher et al., 1997), the whole-nerve response (d'Aldin et al., 1995a, 1995b, Ruel et al., 2001), and spontaneous firing rates (according to Ruel et al. 2001, but not Oestreicher et al. 1997) are decreased. Similar, but more limited, results have been reported with enk and GABA agonists (for review, see Le Prell et al., 2001a). Specifically, microiontophoresis of enk onto the afferent dendrites strongly depressed auditory nerve firing induced by a-amino-3-hydroxy-5­methyl-4-isoxazole propionic acid (AMPA), kainate (KA), and, to a lesser extent, N-methyl­D-aspartate (NMDA, see Burki et al., 1993). Microiontophoresis of GABA had little effect on spontaneous firing rate of auditory neurons, but could inhibit glutamate-induced activity (Felix and Ehrenberger, 1992). Further evidence that GABA modulates afferent firing was provided by Arnold et al. (1998), who demonstrated that the GABA A agonist muscimol (but not the GABA B agonist baclofen) reduced NMDA- and AMPA-induced neural activity.

There is an alternate mechanism by which different LOC transmitters could influence set point that is termed "receptor trafficking". Glutamate receptors have cytoplasmic pools as well as the functional pools placed into the synaptic active zone of the cell membrane. The trafficking between the cytoplasmic pools and the functional pools in the afferent synapse is regulated and could be influenced by different LOC transmitters in different fashions. Differences in the placement of functional glutamate receptors (different total numbers and/or different receptor subunit composition) would influence the sensitivity of the specific afferent synapses and the effect of the IHC transmitter at that synapse.

If LOC transmitters influence cochlear activity through either mechanism, based on the diverse array of chemical transmitter substances present in LOC terminals, one prediction is that transmitter substances that enhance cochlear activity would be "turned up" in periods of low stimulation, and that substances that inhibit neural activity would be "turned up" during periods of excess stimulation, thereby providing some protection to auditory nerve fibres. Consistent with this prediction, perfusing the dopaminergic D2/D3 receptor agonist piribedil into the cochlea provides protection against neural swelling induced by acoustic over­stimulation (6 kHz, 130 dB-SPL, 15 minutes, see d'Aldin et al., 1995b) or ischemia (10-minutes, see d'Aldin et al., 1995a, 1995b, Pujol et al., 1993). Of particular importance, piribedil treatment also preserved threshold sensitivity after trauma (d'Aldin et al., 1995b). These results suggest that LOC neurons play a critical role in protecting glutamatergic afferent nerve fibres.

In addition to the pharmacological studies, there is other less-direct evidence that LOC neurons protect auditory function. For example, the consequences of acoustic over-stimulation are more severe in animals in which both the MOC and LOC pathways have been cut than in intact animals or animals in which only the crossed portion of the MOC pathway has been cut (Kujawa and Liberman, 1997). This result has typically been interpreted as a reflection that animals with intact MOC innervation are best protected against deficits associated with acoustic over-stimulation, animals with partial MOC innervation (i.e., the uncrossed MOC neurons are intact) have less protection, and animals in which the entire MOC innervation is disrupted are not protected. An alternative, but previously difficult to assess, interpretation is that loss of LOC neurons contributes to the decrease in protection. Using the recently described model of selective LOC disruption (Le Prell et al., 2003), we assessed the prediction that LOC neurons provide protection against deficits associated with acoustic overstimulation in a small number of animals.

Preliminary data from intact animals and animals with LSO lesions indicate that selective loss of LOC neurons does not influence deficits in threshold sensitivity induced by exposure to loud sound (10-kHz tone, 110-dB SPL, 20 min, presented binaurally, see Le Prell et al., 2001b). Threshold deficits assessed immediately and 90­minutes post-exposure in LSO-lesioned and intact control guinea pigs are depicted in [Figure - 2]. In addition to inducing threshold deficits, exposure to traumatizing acoustic stimulation depresses CAP amplitude. In contrast to the lack of effect of LSO integrity on trauma-induced threshold deficits, we observed a greater trauma­induced depression of CAP amplitude in animals in which the LSO was lesioned. Differences in CAP amplitude depression were limited to the lowest test frequencies immediately post­exposure (i.e., 2, 4, and 6 kHz; see [Figure - 3],[Figure - 4], left panels). At the 90-min post-exposure time point, differences were observed at frequencies up to 14 kHz (see [Figure - 3],[Figure - 4], right panels). Future studies are essential for establishing the relationship between the strength of the MOC reflex in intact and LOC-lesioned animals and the extent of deficits in evoked potentials as well as morphological trauma (e.g., neural swelling). In addition, the long-term implications of LOC disruption on recovery of function after acoustic overstimulation remain an important question for future investigations.

  Medial Olivocochlear Efferents Top

Medial olivocochlear (MOC) efferents have their origin in the ventral nucleus of the trapezoid body (VNTB) and other medially located SOC nuclei, including the superior paraolivary nucleus (SPN) which makes a contribution in some species but not others (for reviews, see Warr et al., 1986, Warr, 1992). Close to two/thirds of the MOC processes cross the auditory brain stem at the floor of the fourth ventricle and innervate the contralateral cochlea, while the rest project to the ipsilateral cochlea. MOC fibres terminate at the bases of OHCs. This innervation has a basal bias in most species, with more terminals on OHCs of the more basal turn and more terminals on first row OHCs. There is considerable evidence for ACh as the transmitter of MOC efferents (for reviews, see Altschuler and Fex, 1986, Eybalin, 1993, Le Prell et al., 2001a, Puel, 1995). ACh released by the MOC efferents acts at ACh receptors on OHCs, including a nicotinic receptor with a unique composition including a9 and 010 subunits (e.g., Luo et al., 1998, Jagger et al., 2000, Luebke and Foster, 2002, Simmons and Morley, 1998, Elgoyhen et al., 2001, Morley et al., 1998, Zuo et al., 1999). ACh release from MOC efferents changes the set point (resting potential) of the OHC (e.g., Bobbin and Konishi, 1971, Bobbin and Konishi, 1974, Dallos et al., 1997, Evans et al., 2000, Galley et al., 1972, Klinke, 1986, Sziklai et al., 2001) by changing the gain of the cochlear amplifier and modulating the motile response of individual OHCs. ACh also acts on OHCs through a second messenger system, with a "slow effect", that may influence intracellular Ca 2+ pools (Sridhar et al., 1995, Sridhar et al., 1997, Evans et al., 2000, Chen et al., 1998), and calcium-dependent potassium channels (Fuchs, 2002, Yuhas and Fuchs, 1999, van Den Abbeele et al., 1999). The intracellular response to ACh may be through intracellular pathways involving the GTPases RhoA, Rac1 and Cdc42, substances that may regulate OHC motility (Kalinec et al., 2000). The MOC pathway can act in a "reflex" fashion by changing the cochlear amplifier as a consequence of the amount of auditory pathway activity and may also act to provide protection under noise overstimulation conditions (e.g., Maison and Liberman, 2000).

Activation of the efferent system, in particular the medial system, has been shown to protect the ear from acoustic trauma. Reduction of threshold shifts is mediated via the "slow" efferent effect (Reiter and Liberman, 1995, Sridhar et al., 1995, Sridhar et al., 1997). The slow efferent effect causes an increase in intracellular calcium concentration likely through calcium-induced release of calcium from the subsurface cisternae. There is a large degree of variability in threshold shifts to noise trauma. Varying vulnerabilities to noise has led to terms such as "tough" versus "tender" ears. The source of this variability is unclear but recent studies indicate that level of MOC activity may be involved. Liberman et al. (1996) first described the ipsilaterally evoked MOC­ mediated adaptation of the 2f1-f2 distortion product otoacoustic emission (DPOAE). The strength of this reflex is correlated with the vulnerability to acoustic trauma. Animals with strong reflexes show less threshold shift after acoustic overstimulation than those with weak reflexes (Maison and Liberman, 2000).

With a correlation between a strong MOC reflex and reduced susceptibility to acoustic trauma, there is the potential to enhance the reflex to produce a toughened ear. Sound conditioning an animal prior to exposure to a traumatizing acoustic stimulus is known to reduce the animal's threshold shift to the noise (Canlon et al., 1988, Campo et al., 1991, Canlon and Fransson, 1995, Kujawa and Liberman, 1996, Ryan et al., 1994, Yamasoba and Dolan, 1998). This raises the possibility that sound conditioning increases the activity in MOC fibres and results in a protected ear. Brown et al. (1998) showed a small but significant increase in MOC fibre driven rates after sound conditioning. They stated that, although the increase in MOC fibre activity may contribute to the increased resistance to acoustic trauma, it likely does not account for all of it. In contrast to the suggestion that MOC neurons mediate conditioning-related protection from subsequent overstimulation, Yamasoba and Dolan (1998) reported that blocking medial efferent function via the infusion of strychnine into the cochlea did not influence the protection induced by pre-exposure to moderate-level acoustic signals.

It is possible that variability of MOC reflex strength has a genetic basis. It was recently shown that the German waltzing guinea pig is resistant to acoustic trauma. This new strain of German waltzing guinea pig expresses recessive hereditary inner ear degeneration in which the homozygotes are deaf at birth. The heterozygotes, or carriers, show no evidence of hearing loss but do show a resistance to acoustic trauma (Skjonsberg, 2002). Comparison of the MOC reflex in the German waltzing heterozygotes and the strain (Sahlin) crossed to the German waltzers revealed significantly larger reflexes (Skjonsberg et al., 2003). The exact reason for the resistance is unknown but does suggest the possibility of a genetic basis.

In addition to ACh, GABA has been found in MOC neurons (for reviews, see Eybalin, 1993, Altschuler and Fex, 1986, Le Prell et al., 2001a, Puel, 1995). GABA receptors have been localized to OHCs (Drescher et al., 1993) and GABA has been shown to hyperpolarize OHCs and thus GABA may function to modulate the set point (Sziklai et al., 1996, Oliver et al., 2000, Gitter and Zenner, 1992). There is also evidence for the presence of CGRP in MOC efferents (for reviews, see Eybalin, 1993, Le Prell et al., 2001a), however, the action of CGRP in the cochlea remains unknown. We note that in the lateral line hair cell system, CGRP increases spontaneous activity while having an opposite effect on driven activity (e.g., Adams et al., 1987, Bailey and Sewell, 2000a, 2000b, Sewell and Starr, 1991).

  Intracellular Stress Pathways Top

Multiple intracellular pathways can come into play in the response to noise overstimulation [Figure - 5]. The specific stress pathways initiated would depend on the severity of the noise exposure.

Many of these pathways are homeostatic, leading to protection, repair and recovery. Others will lead to cell death. These pathways interact and modulate each other to the point where protective pathways inhibit cell death pathways and cell death pathways inhibit protective ones. The pathways that are most heavily evoked become dominant, determining the fate of the cell.

  Antioxidant Systems and ROS activated pathways Top

One of the early events in noise trauma, as indicated in [Figure - 5], may be the formation of reactive oxygen species (ROS; 'free radicals') to a level that varies with the intensity of exposure. Evidence for oxidant stress as a consequence of noise trauma is compelling. For example, both superoxide anion (Yamane et al., 1995) and hydroxyl radical levels significantly increase in the cochlea following sound exposure (Ohlemiller et al., 1999). Indirect evidence for an involvement of ROS includes the demonstration that lowering the level of the endogenous antioxidant, glutathione, increases threshold shifts (Yamasoba et al., 1998). We have recently demonstrated the emergence of lipid peroxidation products (8-isoprostanes) in the guinea pig cochlea in a time-dependent and transient manner in response to noise exposure. Immunoreactivity to 8-isoprostane was seen in most tissues of the cochlea but OHCs were more heavily immunostained than IHCs while Hensen's cells showed still less staining. The localization of the heaviest hair cell stain coincided with the region that later showed the greatest loss of hair cells (Ohinata et al., 2000a).

Despite the clear evidence for a relationship between ROS formation and tissue damage, the details of the ensuing events are complex and less understood. ROS by themselves are highly reactive and can directly damage cellular constituents such as lipids, proteins and nucleic acid. However, they also trigger cellular events that may lead to cell death: uncontrolled influx of calcium and the activation of apoptotic signals, for example the activation of caspases or transcription factors such as AP-1 (Ogita et al., 2000). On the other hand, lower ROS levels generated by a lesser exposures (or in cells with stronger endogenous antioxidant capacity) may preferably invoke homeostatic and compensatory mechanisms that are geared towards rescue or repair. For example, in other tissues, enzymes of antioxidant pathways are consistently upregulated under oxidant stress including superoxide dismutase, catalase, glutathione S-transferase , glutathione reductase, and glutathione peroxidase (Nakamura et al., 2000, Maggirwar et al., 1994). The levels of some of these enzymes are indeed increased after conditioning noise, which affords protection from subsequent trauma (Jacono et al., 1998). Furthermore, R-phenylisopropyl adenosine, which is known to upregulate antioxidant enzymes, attenuates noise-induced hearing loss (Hu et al., 1997). Other homeostatic reactions include heat shock protein pathways and the upregulation of neurotrophic factors that will be discussed later. Therefore, it should be possible to shift the balance of downstream reactions towards cell survival by intervening in the initial formation of ROS or by scavenging ROS once they have been formed.

Threshold shifts and morphological damage are indeed attenuated by a variety of antioxidants: superoxide dismutase, a scavenger of ROS, and allopurinol, a blocker of ROS production and potential scavenger of ROS (Seidman et al., 1993); lazaroids, lipid peroxidation inhibitors and ROS scavengers (Quirk et al., 1994); the iron chelator deferoxamine mesylate and the antioxidants mannitol (Yamasoba et al., 1999) and glutathione (Ohinata et al., 2000b). We have recently established a significant correlation between noise-induced threshold shifts and hair cell loss and the level of lipid peroxidation in the organ of Corti under different conditions of antioxidant protection (Ohinata et al., 2003). Such a correlation suggests antioxidant therapy as a rational clinical preventive therapy in which the cause of noise trauma would be suppressed. This is a particularly interesting approach since clinically established drugs can be used in this intervention (Kopke et al., 2000). As one example, N-acetyl cysteine attenuated noise­induced threshold shifts from approximately 40 dB to about 15 dB with a concomitant preservation of hair cells (Ohinata et al., 2003).

  Heat Shock Protein Pathways Top

Samali et al. (1999) examined heat shock versus apoptotic pathways in cell culture using heat as a stress and found selective activations along the continuum of stress. They found differences in Hsf1 versus caspase 3 activation. Hsp70 expression occurred in only a small portion of the continuum. Small (2 degree C) increments moved cells from survival to death by apoptosis and then death by necrosis. We believe that a similar balance among many stress pathways takes place following noise overstimulation in the cochlea. Understanding all these pathways and their components may provide the tools to shift the balance in the pathways towards recovery, even under conditions of higher stress, and help prevent acquired deafness.

The Heat shock proteins (Hsps) were first described after hyperthermic stimulation in the fruit fly and have since been found to be expressed in a wide variety of cells in almost all species after various stresses (for review, see Welch, 1993). There are many families of heat shock proteins, differentiated based on their molecular weight including Hsp8, Hsp20, Hsp60, Hsp70, Hsp90, and Hsp110. Each of these Hsp families are conserved across many species and produced in response to stress in a wide variety of cells. The Hsp70s represent the most highly induced and most studied group (Welch, 1992). One major function of Hsps is induction by moderate stresses in order to protect cells from even more severe stresses. A common result of stress to a cell is damage of the three­dimensional structure of proteins resulting in protein dysfunction, followed by aggregation and denaturation. Hsps also promote the renaturation of proteins following the cessation of stress (e.g., Welch, 1992, Welch, 1993). Many other functions for Hsps have been proposed, however, including nonlysosomal protein degradation (Hsp8), regulation of protein folding and prevention of protein aggregation (Hsp10, Hsp27, Hsp40, Hsp47, Hsp60, Hsp70, Hsp90, Hsp105/110, TriC), free radical scavenging (Hsp32/HO1), regulation of the actin cytoskeleton (Hsp27, (x(3-crystallin), inhibition of apoptosis (Hsp27, Hsp70), regulation of cell growth and differentiation (Hsp27, (x(3­crystallin), and signal transduction (Hsp90) (Kubota et al., 1999, Morimoto et al., 1997, Oh et al., 1997).

Dechesne et al. (1992) and more recently Yoshida et al. (1999) have demonstrated hyperthermia-induced Hsp70 (Hsp72) expression in the cochlea. We found up­regulation of Hsp70 in the rat cochlea following heat and hypoxia (Myers et al., 1992) and exposure to a noise level that produces a TTS (Lim et al., 1993). Our immunocytochemical studies showed that both hypoxia and noise induced Hsp70 in OHCs. Oh et al. (2000) recently showed increased Hsp70 in hair cells following systemic cisplatin administration. The expression of Hsps is regulated by a family of transcription factors termed Hsfs. Under normal conditions Hsf1 exists as an inactive monomer that is maintained in its inactive state through the binding of molecular chaperones, such as Hsc70 and Hsp90. Stress-induced denaturation of protein causes a shift in equilibrium so these are no longer bound (Morimoto et al., 1997). Hsf1 then undergoes trimerization, serine hyperphos­phorylation and binds to the heat shock elements of its target genes inducing their expression. When induced levels of targets such as Hsp70 become in excess, they promote the inactivation of Hsf1 resulting in a cessation of the heat shock response (Morimoto et al., 1997). We find constitutive expression of Hsf1 in the rat and mouse cochlea with localization in IHCs and OHCs, spiral ganglion cells, stria vascularis and fibrocytes of the lateral wall. We find that heat exposure results in Hsf1 activation in the cochlea (Fairfield et al., 2002).

  Protection from noise Top

The evidence of a protective role for the Hsp pathway in the cochlea is indirect. For example, Yoshida et al. (1999) tested the protective effects of a heat stress prior to acoustic overstimulation in the mouse ear. The effect of an octave band of noise (8-16 kHz) at 100-dB SPL for 2 hours was compared between untreated mice and mice pre­treated with heat stress. Six hours following heat stress, when Hsp70 levels are high, they found significantly less noise-induced threshold shift in the pre-treated animals. When tested 24 hours following stress, after Hsp70 levels return to normal, the protection was no longer observed. Our studies used the TTS-producing noise exposure we had shown to upregulate Hsp70 as the prior stress. We also found a significant protection (of comparable magnitude) at 5.5 hours following the beginning of our 90-min noise exposure (Mitchell et al., 2003). Interestingly we not only found a lack of protection at 19.5 h following the noise, but a potentiation of the threshold shift, which we interpreted as a rebound effect. We have also examined noise exposures in mice in which the Hsf1 gene has been knocked out. KO mice and wild-type littermates were simultaneously exposed for two hours to a 98-dB SPL broadband noise in a rotating holder. ABR measurements were taken 3 hours, three days, and two weeks after noise exposure. Hsf1 KO mice exhibit less recovery than wild-type littermates at three days and two weeks after the noise. This suggests that the Hsf1 pathway may play a role in cochlear recovery from noise stress.

  Neurotrophic Factors and Growth Factors Top

There is constitutive GDNF expression in OHCs (Ylikoski et al., 1998) and expression of the two components of its receptor (GNDFR(x-1 & Ret) in modiolar (Stover et al., 2001) and sensorineural epithelial fractions (unpublished observations) of the rat cochlea. We also find expression of other GDNF family members and their receptors in the cochlea (Stover et al., 2000). GDNF expression has been shown to be upregulated in the nervous system following stresses such as peripheral nerve axotomy, injection of kainic acid, or inflammatory stimuli (e.g., Appel et al., 1997, Trupp et al., 1997, Hammarberg et al., 1996). Our studies showed that a noise overstimulation that results in a TTS (i.e., the same exposure level as we used to upregulate Hsp70) increased expression of GDNF in the inner ear (Nam et al, 2000). Our group (Altschuler et al., 1999, Shoji et al., 2000b, Ylikoski et al., 1998, Miller et al., 1998a, 1998b) and others (Keithley et al., 1998, Yagi et al., 1999, Yagi et al., 2000, Suzuki et al., 2000) have shown that hair cells and spiral ganglion cells are protected from drug and noise-induced trauma in guinea pig cochlea by prior delivery of the GDNF protein. We also find that prior administration of NT-3 provides protection from noise trauma, while BDNF did not provide for such protection under our experimental conditions (Shoji et al., 2000a).

  Conclusion Top

Different types of protective mechanisms have been discussed in this review. We have proposed a model of LOC efferent function where differential actions of putative LOC neuroactive substances provide for set point adjustment of their post-synaptic target, the peripheral processes of type-I SGCs. We propose that in addition to this modulation of normal function there can be LOC-mediated adjustment of function during acoustic overstimulation that provides protection against the excitotoxic swelling caused by over-release of glutamate from the IHC. We further propose that MOC efferents adjust the set point of their postsynaptic target, the OHCs, to regulate OHC motility during normal cochlear function and protect OHCs under conditions of acoustic overstimulation. Thus, both efferent systems can provide protection against noise-induced hearing loss and damage to the cochlea.

Another type of protective mechanism in the cochlea described in this review involves the intracellular stress pathways. A model was proposed of multiple pathways, some leading to protection, recovery and repair and others to cell death, with a delicate balance among these pathways which varies depending on the intensity of noise. Enhancement of protective pathways and/or blocking of those leading to cell death provides the potential for treatments that can prevent or reduce acquired deafness from acoustic overstimulation.

Taken together, it is clear that several mechanisms protect cochlear function from damage associated with exposure to loud sounds. Such protection appears to be mediated via a combination of set point adjustment and mechanisms that induce repair and recovery from cellular trauma. A major goal of the studies reviewed here has been to gain insight into biological mechanisms of protection, repair, and recovery. As such, all of these experiments have been conducted using animal models. Before these findings can be applied clinically, to help patients suffering from permanent noise-induced hearing loss, it will be necessary to further distinguish cellular and molecular changes resulting in temporary threshold shifts from those that produce permanent hearing loss. Are different pathways involved? Can drug-induced activation of selective stress pathways induce repair and recovery, compensating for activation of pathways that would otherwise result in PTS? Can we modulate activity in pathways with protective function to prevent cellular trauma in the first place? Answering these questions and others represents a significant challenge for future research.[129]

  References Top

1.Abou-Madi, L., Pontarotti, P., Tramu, G., Cupo, A. and Eybalin, M. (1987) Coexistence of putative neuroactive substances in lateral olivocochlear neurons of rat and guinea pig. Hear. Res. 30: 135-46  Back to cited text no. 1    
2.Adams, J. C., Mroz, E. A. and Sewell, W. F. (1987) A possible neurotransmitter role for CGRP in a hair-cell sensory organ. Brain Res. 419: 347-51  Back to cited text no. 2    
3.Altschuler, R. A., Cho, Y., Ylikoski, J., Pirvola, U., Magal, E. and Miller, J. M. (1999) Rescue and regrowth of sensory nerves following deafferentation by neurotrophic factors. Ann. N. Y. Acad. Sci. 884: 305-11  Back to cited text no. 3    
4.Altschuler, R. A. and Fex, J. (1986) Efferent neurotransmitters. In Neurobiology of Hearing:The Cochlea. Altschuler, R. A., Bobbin, R. P. and Hoffman, D. W., eds. Raven Press, New York, pp 383-396  Back to cited text no. 4    
5.Altschuler, R. A., Fex, J., Parakkal, M. H. and Eckenstein, F. (1984) Colocalization of enkephalin-like and choline acetyltransferase-like immunoreactivities in olivocochlear neurons of the guinea pig. J. Histochem. Cytochem. 32: 839-43  Back to cited text no. 5    
6.Altschuler, R. A., Hoffman, D. W., Reeks, K. A. and Fex, J. (1985) Localization of dynorphin B-like and alpha­neoendorphin-like immunoreactivities in the guinea pig organ of Corti. Hear. Res. 17: 249-58  Back to cited text no. 6    
7.Altschuler, R. A., Hoffman, D. W. and Wenthold, R. J. (1986) Neurotransmitters of the cochlea and cochlear nucleus: immunocytochemical evidence. Am. J. Otolaryngol. 7: 100-6  Back to cited text no. 7    
8.Altschuler, R. A., Parakkal, M. H. and Fex, J. (1983) Localization of enkephalin-like immunoreactivity in acetylcholinesterase-positive cells in the guinea-pig lateral superior olivary complex that project to the cochlea. Neuroscience 9: 621-30  Back to cited text no. 8    
9.Altschuler, R. A., Reeks, K. A., Fex, J. and Hoffman, D. W. (1988) Lateral olivocochlear neurons contain both enkephalin and dynorphin immunoreactivities: immunocytochemical co-localization studies. J. Histochem. Cytochem. 36: 797-801  Back to cited text no. 9    
10.Appel, E., Kolman, O., Kazimirsky, G., Blumberg, P. M. and Brodie, C. (1997) Regulation of GDNF expression in cultured astrocytes by inflammatory stimuli. Neuroreport 8: 3309-12  Back to cited text no. 10    
11.Arnold, T., Oestreicher, E., Ehrenberger, K. and Felix, D. (1998) GABA(A) receptor modulates the activity of inner hair cell afferents in guinea pig cochlea. Hear. Res. 125: 147-53  Back to cited text no. 11    
12.Aschoff, A. and Ostwald, J. (1987) Different origins of cochlear efferents in some bat species, rats, and guinea pigs. J. Comp. Neurol. 264: 56-72  Back to cited text no. 12    
13.Bailey, G. P. and Sewell, W. F. (2000a) Calcitonin gene­related peptide suppresses hair cell responses to mechanical stimulation in the Xenopus lateral line organ. J. Neurosci. 20: 5163-9  Back to cited text no. 13    
14.Bailey, G. P. and Sewell, W. F. (2000b) Pharmacological characterization of the CGRP receptor in the lateral line organ of Xenopus laevis. J. Assoc. Res. Otolaryngol. 1: 82-8  Back to cited text no. 14    
15.Bechinger, B. (1997) Structure and functions of channel­forming peptides: magainins, cecropins, melittin and alamethicin. J. Membr. Biol. 156: 197-211  Back to cited text no. 15    
16.Bobbin, R. P. and Konishi, T. (1971) Acetylcholine mimics crossed olivocochlear bundle stimulation. Nature. New Biol. 231: 222-3  Back to cited text no. 16    
17.Bobbin, R. P. and Konishi, T. (1974) Action of cholinergic and anticholinergic drugs at the crossed olivocochlear bundle-hair cell junction. Acta Otolaryngol. (Stockh). 77: 56-65  Back to cited text no. 17    
18.Brown, M. C. (2001) Functional neuroanatomy of the cochlea. In Physiology of the Ear. Jahn, A. F. and Santos­Sacchi, J., eds. Singular Publishing, New York, pp 529-548  Back to cited text no. 18    
19.Brown, M. C., Kujawa, S. G. and Liberman, M. C. (1998) Single olivocochlear neurons in the guinea pig. II. Response plasticity due to noise conditioning. J. Neurophysiol. 79: 3088-97  Back to cited text no. 19    
20.Burki, C., Felix, D. and Ehrenberger, K. (1993) Enkephalin suppresses afferent cochlear neurotransmission. ORL. J. Otorhinolaryngol. Relat. Spec. 55: 3-6  Back to cited text no. 20    
21.Campo, P., Subramaniam, M. and Henderson, D. (1991) The effect of 'conditioning' exposures on hearing loss from traumatic exposure. Hear. Res. 55: 195-200  Back to cited text no. 21    
22.Canlon, B., Borg, E. and Flock, A. (1988) Protection against noise trauma by pre-exposure to a low level acoustic stimulus. Hear. Res. 34: 197-200  Back to cited text no. 22    
23.Canlon, B. and Fransson, A. (1995) Morphological and functional preservation of the outer hair cells from noise trauma by sound conditioning. Hear. Res. 84: 112-24  Back to cited text no. 23    
24.Chen, C., Skellett, R. A., Fallon, M. and Bobbin, R. P. (1998) Additional pharmacological evidence that endogenous ATP modulates cochlear mechanics. Hear. Res. 118: 47-61  Back to cited text no. 24    
25.d'Aldin, C., Eybalin, M., Puel, J. L., Charachon, G., Ladrech, S., Renard, N. and Pujol, R. (1995a) Synaptic connections and putative functions of the dopaminergic innervation of the guinea pig cochlea. Eur. Arch. Otorhinolaryngol. 252: 270-4  Back to cited text no. 25    
26.d'Aldin, C., Puel, J. L., Leducq, R., Crambes, O., Eybalin, M. and Pujol, R. (1995b) Effects of a dopaminergic agonist in the guinea pig cochlea. Hear. Res. 90: 202-11  Back to cited text no. 26    
27.Dallos, P., He, D. Z., Lin, X., Sziklai, I., Mehta, S. and Evans, B. N. (1997) Acetylcholine, outer hair cell electromotility, and the cochlear amplifier. J. Neurosci. 17: 2212-26  Back to cited text no. 27    
28.Dechesne, C. J., Kim, H. N., Nowak, T. S., Jr. and Wenthold, R. J. (1992) Expression of heat shock protein, HSP72, in the guinea pig and rat cochlea after hyperthermia: immunochemical and in situ hybridization analysis. Hear. Res. 59: 195-204.  Back to cited text no. 28    
29.Desmedt, J. E. and Monaco, P. (1961) Mode of action of the efferent olivo-cochlear bundle on the inner ear. Nature 192: 1263-1265  Back to cited text no. 29    
30.Dolan, D. F., Yamasoba, T., Leonova, E., Beyer, L. A. and Raphael, Y. (1999) Morphological and physiological effects of long duration infusion of strychnine into the organ of Corti. J. Neurocytol. 28: 197-206  Back to cited text no. 30    
31.Drescher, D. G., Green, G. E., Khan, K. M., Hajela, K., Beisel, K. W., Morley, B. J. and Gupta, A. K. (1993) Analysis of gamma-aminobutyric acidA receptor subunits in the mouse cochlea by means of the polymerase chain reaction. J. Neurochem. 61: 1167-70  Back to cited text no. 31    
32.Elgoyhen, A. B., Vetter, D. E., Katz, E., Rothlin, C. V., Heinemann, S. F. and Boulter, J. (2001) alpha10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells. Proc. Natl. Acad. Sci. U. S. A. 98: 3501-6  Back to cited text no. 32    
33.Evans, M. G., Lagostena, L., Darbon, P. and Mammano, F. (2000) Cholinergic control of membrane conductance and intracellular free Ca2+ in outer hair cells of the guinea pig cochlea. Cell Calcium 28: 195-203  Back to cited text no. 33    
34.Eybalin, M. (1993) Neurotransmitters and neuromodulators of the mammalian cochlea. Physiol. Rev. 73: 309-73  Back to cited text no. 34    
35.Fairfield, D. A., Kanicki, A., Lomax, M. I. and Altschuler, R. A. (2002) Expression and localization of heat shock factor (Hsf) 1 in the rodent cochlea. Hear. Res. 173: 109­118  Back to cited text no. 35    
36.Felix, D. and Ehrenberger, K. (1992) The efferent modulation of mammalian inner hair cell afferents. Hear. Res. 64: 1-5  Back to cited text no. 36    
37.Fuchs, P. (2002) The synaptic physiology of cochlear hair cells. Audiol. Neurootol. 7: 40-4  Back to cited text no. 37    
38.Galley, N., Klinke, R., Pause, M. and Storch, W. H. (1972) Blocking of the efferent endings in the cat's cochlea. Pflugers Arch. 332:Suppl: R99  Back to cited text no. 38    
39.Gitter, A. H. and Zenner, H. P. (1992) gamma­Aminobutyric acid receptor activation of outer hair cells in the guinea pig cochlea. Eur. Arch. Otorhinolaryngol. 249: 62-5  Back to cited text no. 39    
40.Groff, J. A. and Liberman, M. C. (2002) Brainstem stimulation causes long-lasting enhancement of cochlear neural activity. Assoc. Res. Otolaryngol. Abs. 25: 239  Back to cited text no. 40    
41.Hammarberg, H., Piehl, F., Cullheim, S., Fjell, J., Hokfelt, T. and Fried, K. (1996) GDNF mRNA in Schwann cells and DRG satellite cells after chronic sciatic nerve injury. Neuroreport 7: 857-60  Back to cited text no. 41    
42.Hu, B. H., Zheng, X. Y., McFadden, S. L., Kopke, R. D. and Henderson, D. (1997) R-phenylisopropyladenosine attenuates noise-induced hearing loss in the chinchilla. Hear. Res. 113: 198-206  Back to cited text no. 42    
43.Jacono, A. A., Hu, B., Kopke, R. D., Henderson, D., Van De Water, T. R. and Steinman, H. M. (1998) Changes in cochlear antioxidant enzyme activity after sound conditioning and noise exposure in the chinchilla. Hear. Res. 117: 31-8  Back to cited text no. 43    
44.Jagger, D. J., Griesinger, C. B., Rivolta, M. N., Holley, M. C. and Ashmore, J. F. (2000) Calcium signalling mediated by the 0 9 acetylcholine receptor in a cochlear cell line from the immortomouse. J. Physiol. (Lond). 527: 49-54  Back to cited text no. 44    
45.Kalinec, F., Zhang, M., Urrutia, R. and Kalinec, G. (2000) Rho GTPases mediate the regulation of cochlear outer hair cell motility by acetylcholine. J. Biol. Chem. 275: 28000­5  Back to cited text no. 45    
46.Keithley, E. M., Ma, C. L., Ryan, A. F., Louis, J. C. and Magal, E. (1998) GDNF protects the cochlea against noise damage. Neuroreport 9: 2183-7  Back to cited text no. 46    
47.Klinke, R. (1986) Neurotransmission in the inner ear. Hear. Res. 22: 235-43  Back to cited text no. 47    
48.Kopke, R. D., Weisskopf, P. A., Boone, J. L., Jackson, R. L., Wester, D. C., Hoffer, M. E., Lambert, D. C., Charon, C. C., Ding, D. L. and McBride, D. (2000) Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla. Hear. Res. 149: 138-46  Back to cited text no. 48    
49.Kourie, J. I. and Shorthouse, A. A. (2000) Properties of cytotoxic peptide-formed ion channels. Am. J. Physiol.­Cell Ph. 278: C1063-87  Back to cited text no. 49    
50.Kubota, H., Matsumoto, S., Yokota, S., Yanagi, H. and Yura, T. (1999) Transcriptional activation of mouse cytosolic chaperonin CCT subunit genes by heat shock factors HSF1 and HSF2. FEBS Lett. 461: 125-129  Back to cited text no. 50    
51.Kujawa, S. G. and Liberman, M. C. (1996) Sound conditioning enhances cochlear responses in guinea pig. Assoc. Res. Otolaryngol. Abs. 19: 34  Back to cited text no. 51    
52.Kujawa, S. G. and Liberman, M. C. (1997) Conditioning­related protection from acoustic injury: effects of chronic deefferentation and sham surgery. J. Neurophysiol. 78: 3095-106  Back to cited text no. 52    
53.Le Prell, C. G. and Bledsoe, S. C., Jr. (2003) Disruption of lateral olivocochlear neurons depresses compound action potential amplitude. Assoc. Res. Otolaryngol. Abs. 26: 250  Back to cited text no. 53    
54.Le Prell, C. G., Bledsoe, S. C., Jr., Bobbin, R. P. and Puel, J. L. (2001a) Neurotransmission in the inner ear: Functional and molecular analyses. In Physiology of the Ear. Jahn, A. F. and Santos-Sacchi, J., eds. Singular Publishing, New York, pp 575-611  Back to cited text no. 54    
55.Le Prell, C. G., Shore, S. E. and Bledsoe, S. C., Jr. (2001b) Lesioning the lateral superior olive alters compound action potential dynamic range prior to and following traumatizing sound exposure. Assoc. Res. Otolaryngol. Abs. 24: 46  Back to cited text no. 55    
56.Le Prell, C. G., Shore, S. E., Hughes, L. F. and Bledsoe, S. C., Jr. (2003) Disruption of lateral efferent pathways: Functional changes in auditory evoked responses. J. Assoc. Res. Otolaryngol. 4: 276-290  Back to cited text no. 56    
57.Liberman, M. C. (1990) Effects of chronic cochlear de­efferentation on auditory-nerve response. Hear. Res. 49: 209-23  Back to cited text no. 57    
58.Liberman, M. C. (1991) The olivocochlear efferent bundle and susceptibility of the inner ear to acoustic injury. J. Neurophysiol. 65: 123-32  Back to cited text no. 58    
59.Liberman, M. C., Puria, S. and Guinan, J. J., Jr. (1996) The ipsilaterally evoked olivocochlear reflex causes rapid adaptation of the 2f1-f2 distortion product otoacoustic emission. J. Acoust. Soc. Am. 99: 3572-84  Back to cited text no. 59    
60.Lim, H. H., Jenkins, O. H., Myers, M. W., Miller, J. M. and Altschuler, R. A. (1993) Detection of HSP 72 synthesis after acoustic overstimulation in rat cochlea. Hear. Res. 69: 146-50  Back to cited text no. 60    
61.Luebke, A. E. and Foster, P. K. (2002) Variation in inter­animal susceptibility to noise damage is associated with alpha 9 acetylcholine receptor subunit expression level. J. Neurosci. 22: 4241-7  Back to cited text no. 61    
62.Luo, L., Bennett, T., Jung, H. H. and Ryan, A. F. (1998) Developmental expression of alpha 9 acetylcholine receptor mRNA in the rat cochlea and vestibular inner ear. J. Comp. Neurol. 393: 320-31  Back to cited text no. 62    
63.Maggirwar, S. B., Dhanraj, D. N., Somani, S. M. and Ramkumar, V. (1994) Adenosine acts as an endogenous activator of the cellular antioxidant defense system. Biochem. Biophys. Res. Commun. 201: 508-15  Back to cited text no. 63    
64.Maison, S. F. and Liberman, M. C. (2000) Predicting vulnerability to acoustic injury with a noninvasive assay of olivocochlear reflex strength. J. Neurosci. 20: 4701-7  Back to cited text no. 64    
65.Miller, A. L., Yamasoba, T. and Altschuler, R. A. (1998a) Hair cell and spiral ganglion neuron preservation and regeneration - influence of growth factors. Curr. Opin. Otolaryngol. Head Neck Surg. 6: 301-307  Back to cited text no. 65    
66.Miller, J. M., Yamasoba, T., Shoji, F. and Altschuler, R. A. (1998b) Neurotrophin and antioxidant protection of the inner ear from noise induced damage. In Recent Advances in Inner Ear Research. eds. Kanehara and Co., Tokyo  Back to cited text no. 66    
67.Mitchell, A., Miller, J. M. and Altschuler, R. A. (2003) Protection from noise-induced hearing loss following induction of the stress response. Hear. Res.: In press  Back to cited text no. 67    
68.Morimoto, R. I., Kline, M. P., Bimston, D. N. and Cotto, J. J. (1997) The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones. Essays Biochem. 32: 17-29  Back to cited text no. 68    
69.Morley, B. J., Li, H. S., Hiel, H., Drescher, D. G. and Elgoyhen, A. B. (1998) Identification of the subunits of the nicotinic cholinergic receptors in the rat cochlea using RT­PCR and in situ hybridization. Brain Res. Mol. Brain Res. 53: 78-87  Back to cited text no. 69    
70.Myers, M. W., Quirk, W. S., Rizk, S. S., Miller, J. M. and Altschuler, R. A. (1992) Expression of the major mammalian stress protein in the cochlea following transient ischemia. Laryngoscope 102: 981-987  Back to cited text no. 70    
71.Nakamura, Y., Ohigashi, H., Masuda, S., Murakami, A., Morimitsu, Y., Kawamoto, Y., Osawa, T., Imagawa, M. and Uchida, K. (2000) Redox regulation of glutathione S­transferase induction by benzyl isothiocyanate: correlation of enzyme induction with the formation of reactive oxygen intermediates. Cancer Res. 60: 219-25  Back to cited text no. 71    
72.Oestreicher, E., Arnold, W., Ehrenberger, K. and Felix, D. (1997) Dopamine regulates the glutamatergic inner hair cell activity in guinea pigs. Hear. Res. 107: 46-52  Back to cited text no. 72    
73.Ogita, K., Matsunobu, T. and Schacht, J. (2000) Acoustic trauma enhances DNA binding of transcription factor AP­1 in the guinea pig inner ear. Neuroreport 11: 859-62  Back to cited text no. 73    
74.Oh, H. J., Chen, X. and Subjeck, J. R. (1997) Hsp110 protects heat-denatured proteins and confers cellular thermoresistance. J. Biol. Chem. 272: 31636-31640  Back to cited text no. 74    
75.Oh, S. H., Yu, W. S., Song, B. H., Lim, D., Koo, J. W., Chang, S. O. and Kim, C. S. (2000) Expression of heat shock protein 72 in rat cochlea with cisplatin-induced acute ototoxicity. Acta Otolaryngol. (Stockh). 120: 146-50  Back to cited text no. 75    
76.Ohinata, Y., Miller, J. M., Altschuler, R. A. and Schacht, J. (2000a) Intense noise induces formation of vasoactive lipid peroxidation products in the cochlea. Brain Res. 878: 163-73  Back to cited text no. 76    
77.Ohinata, Y., Miller, J. M. and Schacht, J. (2003) Protection from noise-induced lipid peroxidation and hair cell loss in the cochlea. Brain Res.: 966:265-273  Back to cited text no. 77    
78.Ohinata, Y., Yamasoba, T., Schacht, J. and Miller, J. M. (2000b) Glutathione limits noise-induced hearing loss. Hear. Res. 146: 28-34  Back to cited text no. 78    
79.Ohlemiller, K. K., Wright, J. S. and Dugan, L. L. (1999) Early elevation of cochlear reactive oxygen species following noise exposure. Audiol. Neurootol. 4: 229-36  Back to cited text no. 79    
80.Oliver, D., Klocker, N., Schuck, J., Baukrowitz, T., Ruppersberg, J. P. and Fakler, B. (2000) Gating of Ca2+­activated K+ channels controls fast inhibitory synaptic transmission at auditory outer hair cells. Neuron 26: 595­601  Back to cited text no. 80    
81.Puel, J. L. (1995) Chemical synaptic transmission in the cochlea. Prog. Neurobiol. 47: 449-76  Back to cited text no. 81    
82.Pujol, R., Puel, J. L., Gervais d'Aldin, C. and Eybalin, M. (1993) Pathophysiology of the glutamatergic synapses in the cochlea. Acta Otolaryngol. (Stockh). 113: 330-4  Back to cited text no. 82    
83.Quirk, W. S., Shivapuja, B. G., Schwimmer, C. L. and Seidman, M. D. (1994) Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts. Hear. Res. 74: 217-20  Back to cited text no. 83    
84.Rajan, R. (1988) Effect of electrical stimulation of the crossed olivocochlear bundle on temporary threshold shifts in auditory sensitivity. I. Dependence on electrical stimulation parameters. J. Neurophysiol. 60: 549-68  Back to cited text no. 84    
85.Reiter, E. R. and Liberman, M. C. (1995) Efferent­mediated protection from acoustic overexposure: relation to slow effects of olivocochlear stimulation. J. Neurophysiol. 73: 506-14  Back to cited text no. 85    
86.Robertson, D. (1985) Brainstem location of efferent neurones projecting to the guinea pig cochlea. Hear. Res. 20: 79-84  Back to cited text no. 86    
87.Ruel, J., Nouvian, R., Gervais d'Aldin, C., Pujol, R., Eybalin, M. and Puel, J. L. (2001) Dopamine inhibition of auditory nerve activity in the adult mammalian cochlea. Eur. J. Neurosci. 14: 977-86  Back to cited text no. 87    
88.Ryan, A. F., Bennett, T. M., Woolf, N. K. and Axelsson, A. (1994) Protection from noise-induced hearing loss by prior exposure to a nontraumatic stimulus: role of the middle ear muscles. Hear. Res. 72: 23-8  Back to cited text no. 88    
89.Safieddine, S. and Eybalin, M. (1992) Triple immunoflourescence evidence for coexistence of acetylcholine, enkephalins, and calcitonin-gene related peptide within efferent (olivocochlear) neurons of rats and guinea pigs. Eur. J. Neurosci. 4: 981-992  Back to cited text no. 89    
90.Safieddine, S., Prior, A. M. and Eybalin, M. (1997) Choline acetyltransferase, glutamate decarboxylase, tyrosine hydroxylase, calcitonin gene-related peptide and opioid peptides coexist in lateral efferent neurons of rat and guinea-pig. Eur. J. Neurosci. 9: 356-67  Back to cited text no. 90    
91.Sahley, T. L., Kalish, R. B., Musiek, F. E. and Hoffman, D. W. (1991) Effects of opioid be drugs on auditory evoked potentials suggest a role of lateral olivocochlear dynorphins in auditory function. Hear. Res. 55: 133-42  Back to cited text no. 91    
92.Sahley, T. L., Musiek, F. E. and Nodar, R. H. (1996a) Naloxone blockade of (-)pentazocine-induced changes in auditory function. Ear Hear. 17: 341-53  Back to cited text no. 92    
93.Sahley, T. L. and Nodar, R. H. (1994) Improvement in auditory function following pentazocine suggests a role for dynorphins in auditory sensitivity. Ear Hear. 15: 422-31  Back to cited text no. 93    
94.Sahley, T. L., Nodar, R. H. and Musiek, F. E. (1996b) Blockade of opioid-induced changes in auditory function at the level of the cochlea. Ear Hear. 17: 552-8  Back to cited text no. 94    
95.Samali, A., Holmberg, C. I., Sistonen, L. and Orrenius, S. (1999) Thermotolerance and cell death are distinct cellular responses to stress: dependence on heat shock proteins. FEBS Lett. 461: 306-310  Back to cited text no. 95    
96.Seidman, M. D., Shivapuja, B. G. and Quirk, W. S. (1993) The protective effects of allopurinol and superoxide dismutase on noise-induced cochlear damage. Otolaryngol. Head Neck Surg. 109: 1052-6  Back to cited text no. 96    
97.Sewell, W. F. and Starr, P. A. (1991) Effects of calcitonin gene-related peptide and efferent nerve stimulation on afferent transmission in the lateral line organ. J. Neurophysiol. 65: 1158-69  Back to cited text no. 97    
98.Shoji, F., Miller, A. L., Mitchell, A., Yamasoba, T., Altschuler, R. A. and Miller, J. M. (2000a) Differential protective effects of neurotrophins in the attenuation of noise-induced hair cell loss. Hear. Res. 146: 134-42  Back to cited text no. 98    
99.Shoji, F., Yamasoba, T., Magal, E., Dolan, D. F., Altschuler, R. A. and Miller, J. M. (2000b) Glial cell line­derived neurotrophic factor has a dose dependent influence on noise-induced hearing loss in the guinea pig cochlea. Hear. Res. 142: 41-55  Back to cited text no. 99    
100.Simmons, D. D. (2002) Development of the inner ear efferent system across vertebrate species. J. Neurobiol. 53: 228-250  Back to cited text no. 100    
101.Simmons, D. D. and Morley, B. J. (1998) Differential expression of the alpha 9 nicotinic acetylcholine receptor subunit in neonatal and adult cochlear hair cells. Brain Res. Mol. Brain Res. 56: 287-92  Back to cited text no. 101    
102.Skjonsberg, A. (2002) In Nordic Symposium on Noise and HealthStockholm.  Back to cited text no. 102    
103. Skjonsberg, A., Halsey, K. E., Ulfendahl, M. and Dolan, D. F. (2003) Post-onset adaptation before noise exposure in animals shown to be resistant to noise trauma. Assoc. Res. Otolaryngol. Abs. 26: 102  Back to cited text no. 103    
104.Sridhar, T. S., Brown, M. C. and Sewell, W. F. (1997) Unique postsynaptic signaling at the hair cell efferent synapse permits calcium to evoke changes on two time scales. J. Neurosci. 17: 428-37  Back to cited text no. 104    
105.Sridhar, T. S., Liberman, M. C., Brown, M. C. and Sewell, W. F. (1995) A novel cholinergic "slow effect" of efferent stimulation on cochlear potentials in the guinea pig. J. Neurosci. 15: 3667-78  Back to cited text no. 105    
106.Stopp, P. E. (1990) The problem of obtaining reproducible quantitative data of the olivocochlear pathway as exemplified in the guinea pig. Eur. Arch. Otorhinolaryngol. 247: 29-32  Back to cited text no. 106    
107.Stover, T., Gong, T. L., Cho, Y., Altschuler, R. A. and Lomax, M. I. (2000) Expression of the GDNF family members and their receptors in the mature rat cochlea. Brain Res. Mol. Brain Res. 76: 25-35  Back to cited text no. 107    
108.Stover, T., Nam, Y., Gong, T. L., Lomax, M. I. and Altschuler, R. A. (2001) Glial cell line-derived neurotrophic factor (GDNF) and its receptor complex are expressed in the auditory nerve of the mature rat cochlea. Hear. Res. 155: 143-51  Back to cited text no. 108    
109.Strutz, J. and Bielenberg, K. (1984) Efferent acoustic neurons within the lateral superior olivary nucleus of the guinea pig. Brain Res. 299: 174-7  Back to cited text no. 109    
110.Suzuki, M., Yagi, M., Brown, J. N., Miller, A. L., Miller, J. M. and Raphael, Y. (2000) Effect of transgenic GDNF expression on gentamicin-induced cochlear and vestibular toxicity. Gene Ther. 7: 1046-54  Back to cited text no. 110    
111.Sziklai, I., He, D. Z. and Dallos, P. (1996) Effect of acetylcholine and GABA on the transfer function of electromotility in isolated outer hair cells. Hear. Res. 95: 87-99  Back to cited text no. 111    
112.Sziklai, I., Szonyi, M. and Dallos, P. (2001) Phosphorylation mediates the influence of acetylcholine upon outer hair cell electromotility. Acta Otolaryngol. (Stockh). 121: 153-6  Back to cited text no. 112    
113.Trupp, M., Belluardo, N., Funakoshi, H. and Ibanez, C. F. (1997) Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J. Neurosci. 17: 3554-67  Back to cited text no. 113    
114.van Den Abbeele, T., Teulon, J. and Huy, P. T. (1999) Two types of voltage-dependent potassium channels in outer hair cells from the guinea pig cochlea. Am. J. Physiol. 277: C913-25  Back to cited text no. 114    
115.Warr, W. B. (1992) Organization of olivocochlear efferent systems in mammals. In Mammalian Auditory Pathway: Neuroanatomy. Webster, D. B., Popper, A. N. and Fay, R. R., eds. Little, Brown, and Co., Boston, pp 410-448  Back to cited text no. 115    
116.Warr, W. B., Guinan, J. J. and White, J. S. (1986) Organization of efferent fibres: The lateral and medial olivocochlear systems. In Neurobiology of Hearing: The Cochlea. Altschuler, R. A., Hoffman, D. W. and Bobbin, R. P., eds. Raven Press, New York, pp 333-348  Back to cited text no. 116    
117.Welch, W. J. (1992) Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease. Physiol. Rev. 72: 1063-1081  Back to cited text no. 117    
118.Welch, W. J. (1993) How cells respond to stress. Sci. Am. 268: 56-64  Back to cited text no. 118    
119.Yagi, M., Kanzaki, S., Kawamoto, K., Shin, B., Shah, P. P., Magal, E., Sheng, J. and Raphael, Y. (2000) Spiral ganglion neurons are protected from degeneration by GDNF gene therapy. J. Assoc. Res. Otolaryngol. 1: 315-25  Back to cited text no. 119    
120.Yagi, M., Magal, E., Sheng, Z., Ang, K. A. and Raphael, Y. (1999) Hair cell protection from aminoglycoside ototoxicity by adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor. Hum. Gene Ther. 10: 813-23  Back to cited text no. 120    
121.Yamane, H., Nakai, Y., Takayama, M., Iguchi, H., Nakagawa, T. and Kojima, A. (1995) Appearance of free radicals in the guinea pig inner ear after noise-induced acoustic trauma. Eur. Arch. Otorhinolaryngol. 252: 504-8  Back to cited text no. 121    
122.Yamasoba, T. and Dolan, D. F. (1998) The medial cochlear efferent system does not appear to contribute to the development of acquired resistance to acoustic trauma. Hear. Res. 120: 143-51  Back to cited text no. 122    
123.Yamasoba, T., Nuttall, A. L., Harris, C., Raphael, Y. and Miller, J. M. (1998) Role of glutathione in protection against noise-induced hearing loss. Brain Res. 784: 82-90  Back to cited text no. 123    
124.Yamasoba, T., Schacht, J., Shoji, F. and Miller, J. M. (1999) Attenuation of cochlear damage from noise trauma by an iron chelator, a free radical scavenger and glial cell line-derived neurotrophic factor in vivo. Brain Res. 815: 317-25  Back to cited text no. 124    
125.Ylikoski, J., Pirvola, U., Virkkala, J., Suvanto, P., Liang, X. Q., Magal, E., Altschuler, R. A., Miller, J. M. and Saarma, M. (1998) Guinea pig auditory neurons are protected by glial cell line-derived growth factor from degeneration after noise trauma. Hear. Res. 124: 17-26  Back to cited text no. 125    
126.Yoshida, N., Kristiansen, A. and Liberman, M. C. (1999) Heat stress and protection from permanent acoustic injury in mice. J. Neurosci. 19: 10116-24  Back to cited text no. 126    
127.Yuhas, W. A. and Fuchs, P. A. (1999) Apamin-sensitive, small-conductance, calcium-activated potassium channels mediate cholinergic inhibition of chick auditory hair cells. J. Comp. Physiol. [A]. 185: 455-62  Back to cited text no. 127    
128.Zheng, X. Y., Henderson, D., McFadden, S. L., Ding, D. L. and Salvi, R. J. (1999) Auditory nerve fibre responses following chronic cochlear de-efferentation. J. Comp. Neurol. 406: 72-86  Back to cited text no. 128    
129.Zuo, J., Treadaway, J., Buckner, T. W. and Fritzsch, B. (1999) Visualization of alpha9 acetylcholine receptor expression in hair cells of transgenic mice containing a modified bacterial artificial chromosome. Proc. Natl. Acad. Sci. U. S. A. 96: 14100-5  Back to cited text no. 129    

Correspondence Address:
R A Altschuler
KHRI, University of Michigan, 1301 East Ann, Ann Arbor, MI 48109-0506
Login to access the Email id

Source of Support: None, Conflict of Interest: None

PMID: 14558888

Rights and PermissionsRights and Permissions


  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]

This article has been cited by
1 Prophylactic and therapeutic functions of drug combinations against noise-induced hearing loss
Bao, J. and Hungerford, M. and Luxmore, R. and Ding, D. and Qiu, Z. and Lei, D. and Yang, A. and Liang, R. and Ohlemiller, K.K.
Hearing Research. 2013; 304: 33-40
2 Exposure to industrial wideband noise increases connective tissue in the rat liver
Oliveira, M.J.R. and Freitas, D. and Carvalho, A.P.O. and Guimarães, L. and Pinto, A. and Águas, A.P.
Noise and Health. 2012; 14(60): 227-229
3 Effects of expectations on loudness and loudness difference
Parker, S. and Moore, J.M. and Bahraini, S. and Gunthert, K. and Zellner, D.A.
Attention, Perception, and Psychophysics. 2012; 74(6): 1334-1342
4 Audiological findings in Williams syndrome: A study of 69 patients
Barozzi, S. and Soi, D. and Comiotto, E. and Borghi, A. and Gavioli, C. and Spreafico, E. and Gagliardi, C. and Selicorni, A. and Forti, S. and Ambrosetti, U. and Cesarani, A. and Brambilla, D.
American Journal of Medical Genetics, Part A. 2012; 158 A(4): 759-771
5 Developmental expression of plasma glutathione peroxidase during mouse organogenesis
Jung, K.Y. and Baek, I.-J. and Yon, J.-M. and Lee, S.-R. and Kim, M.-R. and Lee, B.J. and Yun, Y.W. and Nam, S.-Y.
Journal of Molecular Histology. 2011; 42(6): 545-556
6 Association of polymorphisms of heat shock protein 70 with susceptibility to noise-induced hearing loss in the taiwanese population
Chang, N.-C., Ho, C.-K., Lin, H.-Y., Yu, M.-L., Chien, C.-Y., Ho, K.-Y.
Audiology and Neurotology. 2011; 16(3): 168-174
7 The efferent system or olivocochlear function bundle - fine regulator and protector of hearing perception
Ciuman, R.R.
International Journal of Biomedical Science. 2010; 6(4): 276-288
8 Static magnetic field affects oxidative stress in mouse cochlea
Politański, P., Rajkowska, E., Pawlaczyk-ŁUszczyńska, M., Dudarewicz, A., Wiktorek-Smagur, A., Śliwińska-Kowalska, M., Zmyślony, M.
International Journal of Occupational Medicine and Environmental Health. 2010; 23(4): 377-384
9 Effects of sex, gonadal hormones, and augmented acoustic environments on sensorineural hearing loss and the central auditory system: Insights from research on C57BL/6J mice
Willott, J.F.
Hearing Research. 2009; 252(1-2): 89-99
10 Inner ear protection and regeneration: A æhistoricalæ perspective
Diaz, R.C.
Current Opinion in Otolaryngology and Head and Neck Surgery. 2009; 17(5): 363-372
11 From cochlear cell death pathways to new pharmacological therapies
Wang, J., Puel, J.-L.
Mini-Reviews in Medicinal Chemistry. 2008; 8(10): 1006-1019
12 Hyperactive auditory efferent system and lack of acoustic reflexes in Williams syndrome
Attias, J., Raveh, E., Ben-Naftali, N.F., Zarchi, O., Gothelf, D.
Journal of Basic and Clinical Physiology and Pharmacology. 2008; 19(3-4): 193-207
13 Advances in molecular and cellular therapies for hearing loss
Hildebrand, M.S., Newton, S.S., Gubbels, S.P., Sheffield, A.M., Kochhar, A., de Silva, M.G., Dahl, H.-H.M., (...), Smith, R.J.H.
Molecular Therapy. 2008; 16(2): 224-236
14 A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma
Wang, J., Pignol, B., Chabrier, P.-E., Saido, T., Lloyd, R., Tang, Y., Lenoir, M., Puel, J.-L.
Neuropharmacology. 2007; 52(6): 1426-1437
15 Role for the lateral olivocochlear neurons in auditory function. Focus on "Selective removal of lateral olivocochlear efferents increases vulnerability to acute acoustic injury"
Le Prell, C.G.
Journal of Neurophysiology. 2007; 97(2): 963-965
16 Bandwidth dependency of cochlear centrifugal pathways in modulating hearing desensitization caused by loud sound
Rajan, R.
Neuroscience. 2007; 147(4): 1103-1113
17 Genetic aspects of hearing loss
Dahl, H.-H., Manji, S., De Silva, M., Peverelli, M., Hildebrand, M.
Acoustics Australia. 2006; 34(1): 25-29
18 Bandwidth determines modulatory effects of centrifugal pathways on cochlear hearing desensitization caused by loud sound
Rajan, R.
European Journal of Neuroscience. 2006; 24(12): 3589-3600
19 Noise-induced hypoacusia: Present state [Hipoacusia inducida por ruido: Estado actual]
Sánchez, H.H. and Carrera, M.G.
Revista Cubana de Medicina Militar. 2006; 35(4)
20 Noise-induced hypoacusia: Present state | [Hipoacusia inducida por ruido: Estado actual]
Sánchez, H.H., Carrera, M.G.
Revista Cubana de Medicina Militar. 2006; 35(4)
21 Post-exposure treatment attenuates noise-induced hearing loss
Yamashita, D., Jiang, H.-Y., Le Prell, C.G., Schacht, J., Miller, J.M.
Neuroscience. 2005; 134(2): 633-642
22 Disruption of lateral olivocochlear neurons via a dopaminergic neurotoxin depresses sound-evoked auditory nerve activity
Le Prell, C.G., Halsey, K., Hughes, L.F., Dolan, D.F., Bledsoe Jr., S.C.
JARO - Journal of the Association for Research in Otolaryngology. 2005; 6(1): 48-62
23 Contextual modulation of olivocochlear pathway effects on loud sound-induced cochlear hearing desensitization
Rajan, R.
Journal of Neurophysiology. 2005; 93(4): 1977-1988