Functional Recovery After Hair Cell Regeneration in Birds

Book_Salvi etal_9780387733630_Proof1_December 20, 2007 02 03 04 05 4 Functional Recovery After Hair Cell Regeneration in Birds PR OO F 01 06 07 08 09 Robert J. Dooling, Micheal L. Dent, Amanda M. Lauer, and Brenda M. Ryals 10 11 12 13 14 15 1. Introduction 16 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 ED 21 CT 20 RE 19 In response to either acoustic trauma or insult from ototoxic drugs, both young and adult birds show a temporary period of hair cell loss and regeneration, usually culminating in considerable anatomical, physiological, and even behavioral recovery within several weeks (Corwin and Cotanche 1988; Ryals and Rubel 1988; Tucci and Rubel 1990; Girod et al. 1991; Hashino et al. 1991; Lippe et al. 1991; Saunders et al. 1992, 1996; Ryals et al. 1999b). Recent reviews of the recovery of auditory function after hair cell regeneration have focused on physiological measures of the auditory nerve and brainstem (compound action potential [CAP], auditory brainstem response [ABR], or changes in hair cell responses using distortion product emissions (e.g., Smolders 1999; see Saunders and Salvi, Chapter 3). All of these measures are highly correlated with the return of hearing, but behavioral measures of hearing address, most directly, the actual recovery of auditory perception. This chapter emphasizes studies that address the behavioral recovery of hearing after hair cell loss and regeneration in birds. As far as we know, birds provide the only animal model in which it is possible to restore hearing through renewed sensory cell input and then examine the effect of this hearing recovery on the learning and production of vocalizations. We review several studies that have addressed the effects of hair cell loss and regeneration on complex vocal production. As one can imagine, the issue of whether a “new” auditory periphery results in sufficient functional recovery so that an adult bird can perceive, learn, and produce complex acoustic communication signals has considerable health relevance, as current research efforts are focused on triggering hair cell regeneration in the mammalian auditory system (e.g., Izumikawa et al. 2005). Understanding the fine detail of hearing recovery in birds may tell us something about how bird ears function, add to our knowledge of plasticity in both peripheral and central auditory nervous system structures, and expose the common features of sensorimotor interfaces across vertebrates. CO R 18 UN 17 117 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 118 01 R.J. Dooling et al. 2. Changes in Absolute Sensitivity 02 04 05 06 07 08 09 10 There have been principally two ways to damage auditory sensory cells with resulting changes in sensory function: acoustic trauma and administration of ototoxic drugs. The two approaches typically lead to different patterns of hair cell damage and loss and different patterns of hair cell regeneration and functional recovery (Saunders et al. 1995; Salvi et al. 1998; Cotanche 1999; Smolders 1999). Here, we discuss the extents and time courses of hearing loss and functional recovery to these two types of peripheral auditory system trauma in birds. PR OO F 03 11 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 ED 16 Morphological assessment of hair cell loss and regeneration after acoustic trauma has shown that acoustic overstimulation generally results in the loss of some, but not all, hair cells in a specific location on the basilar papilla, depending on the type, intensity, and duration of the acoustic trauma (reviewed in Cotanche 1999). Temporary hearing loss in birds after acoustic overexposure, first described in budgerigars (Melopsittacus undulatus), revealed some differences between birds and mammals (Saunders and Dooling 1974; Dooling 1980). Budgerigars exposed to 1/3 octave bands of noise centered at 2 kHz for 72 hours at levels of 76–106 dB sound pressure level (SPL) showed maximum hearing losses at 2 kHz, and the threshold shift ranged from 10 to 40 dB depending on the level of the exposure. A permanent threshold shift was observed only with the 106-dB exposure, suggesting that birds, compared to mammals, are more resistant to damage from noise (Dooling 1980). Temporary threshold shifts in these birds were also of a shorter duration than typically seen in mammals and were also restricted to a narrower range of frequencies (e.g., Luz and Hodge 1971; Price 1979; Dooling 1980; Henderson and Hamernik 1986). In addition to showing little spread across frequencies, in budgerigars the maximum threshold shift occurred at higher frequencies than the exposure frequency. Hashino and colleagues (1988) extended these bird–mammal differences to impulse noise exposures. Two 169-dB SPL impulse noises produced by pistols caused more low-frequency than high-frequency hearing loss with the return to preexposure hearing levels occurring at a faster rate for high than for low frequencies. These results are unique and intriguing, and their confirmation could provide insight into the functioning of the avian ear. Japanese quail (Coturnix coturnix) exposed to a 1.5-kHz octave band noise at 116 dB SPL for 4 hours showed elevated thresholds for pure tones up to 50 dB immediately after exposure (Niemiec et al. 1994). Thresholds were most severely affected at frequencies of 1.0 kHz and above, although there was considerable variation among subjects. Thresholds improved rapidly within the first week after exposure, recovering to preexposure levels by 8–10 days. Damaged hair cells were still observed up to 2 weeks postexposure but not by 5 weeks postexposure. Similar patterns of threshold shifts and recoveries were seen after repeated CT 15 RE 14 2.1 Acoustic Overexposure CO R 13 UN 12 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 PR OO F 06 ED 05 CT 04 RE 03 exposures to noise, although recovery times increased with increasing numbers of exposures. Interestingly, Niemiec et al. (1994) found that structural abnormalities (elongated stereocilia, supporting cell expansion, and stress links between hair cells) remained for at least 4 weeks after pure tone sensitivity had recovered. They suggested that while these abnormalities may not influence absolute threshold sensitivity, they may be involved in other aspects of functional hearing. Other investigators have suggested that lingering structural abnormalities within the tectorial membrane (lack of upper fibrous layer) may be related to incomplete recovery of other aspects of auditory function such as frequency resolution (Salvi et al. 1998; Lifshitz et al. 2004). While neural correlates of frequency resolution tend to corroborate poorer frequency resolving capacity after acoustic trauma and hair cell regeneration, corresponding behavioral studies are still lacking. Behavioral studies of frequency resolution after hair cell regeneration following ototoxic insult have been performed and are described later in this chapter. Ryals and colleagues (1999b) found that the amount of hearing loss and the time course of recovery varied considerably among different species of adult (sexually mature) birds even when exposure conditions and test conditions were identical. In their study, quail and budgerigars were exposed to intense pure tones centered in their region of best hearing at 112–118 dB SPL for 12 hours. Quail showed much greater susceptibility to acoustic trauma than did budgerigars, with significantly larger threshold shifts and hair cell loss. Quail showed a threshold shift of 70 dB at 2.86 kHz 1 day after overexposure. Thresholds for the quail remained virtually unchanged for 8–9 days postexposure, and then began to improve by about 2 dB/day until day 30. Quail experienced a permanent threshold shift of approximately 20 dB, which remained even when tested 1 year after exposure. Budgerigars exhibited a threshold shift of about 35–40 dB at 0.5 days after exposure, but showed a much faster recovery than quail. By 3 days postexposure, budgerigars’ thresholds had improved to within 10 dB of normal. Chickens exposed to a 120-dB pure tone at 525 Hz for 48 hours (Saunders et al. 1995) showed similar initial threshold shifts and rates of recovery as the budgerigars. CAP measurements in pigeons exposed to a 142-dB pure tone at 700 Hz for 1 hour (Ding-Pfennigdorff et al. 1998) showed intermediate threshold shifts between the quail and the budgerigars and chickens. In a more comprehensive study, budgerigars, canaries (Serinus canaria), and zebra finches (Taeniopygia guttata) were exposed to a bandpass noise (2–6 kHz) at 120 dB SPL for 24 hours. These birds showed thresholds at 1.0 kHz that were elevated by 10–30 dB and that improved to within normal limits by about 10 days postexposure in all three species. At 2.86 kHz, the center of the exposure band, budgerigars, canaries, and zebra finches showed a 50-dB threshold shift. Recovery began immediately afterward for canaries and finches, and threshold improved to within 10 dB of normal by about 30 days postexposure. In budgerigars, threshold recovery did not begin until 10 days postexposure. By 50 days postexposure, thresholds recovered to about 20 dB above normal, and no CO R 02 UN 01 119 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 120 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 PR OO F 06 ED 05 CT 04 RE 03 further improvement occurred by 70 days, at which point the loss was assumed to be permanent. Overall, results showed a significantly more rapid recovery in canaries and zebra finches than in budgerigars. Histological analysis in all of these birds quantified hair cell loss and recovery in the region of damage before, during, and after threshold recovery. In general, the more severe the initial degree of hair cell loss (width of damage and decrease in hair cell number) was, the more severe the initial threshold shift. Ryals et al. (1995), Salvi et al. (1998), and Cotanche (1999) have shown that structures such as the tegmentum vasculosum, which provides the endolymphatic potential in birds, the tectorial membrane, and neural synapses may also be damaged immediately after acoustic trauma There are two important conclusions from these studies. One is that even when exposure and test conditions are identical, the amount of damage and the time course of loss and recovery from acoustic trauma are quite different among species. The second conclusion is that determination of the direct role of regenerated hair cells in the recovery of hearing after acoustic overstimulation is confounded by the continuing presence of nonregenerated hair cells on the papilla after initial acoustic trauma, the initial and continuing damage to other structures within the inner ear such as the tectorial membrane, and the fact that a considerable amount of hearing can return before a full complement of hair cells is replaced through regeneration. These behavioral results are paralleled by a wealth of physiological data. Measures of compound action potential (CAP) and evoked potential (EP) thresholds, for instance, have also shown a recovery from acoustic trauma in birds. In pigeons, CAP thresholds increased immediately after exposure to a 0.7-kHz tone at 136–142 dB SPL for 1 hour, but showed some recovery in most subjects (Müller et al. 1996, 1997). The time course of recovery varied somewhat among individual subjects, and some animals showed no recovery. A residual threshold shift of 26.3 dB remained at 2.0 kHz for some of the animals that recovered, while other showed normal thresholds within 3 weeks after exposure. Newborn chicks and adult chickens also show increased CAP and EP thresholds immediately after acoustic trauma, but animals with longer survival times showed near-normal thresholds (McFadden and Saunders 1989; Adler et al. 1992, 1993; Pugliano et al. 1993). Interestingly, less recovery occurred when chicks were exposed a second time (Adler et al. 1993). Threshold shifts to a pure tone overexposure (Fig. 4.1A) and to narrowband noise overexposure (Fig. 4.1B) are shown across several species of birds. Although the exposure durations, intensities, and frequencies differed across species, these recovery curves represent virtually all of the existing data available on experiments that tested the same subjects repeatedly. Given the large differences in susceptibility to acoustic trauma both within and across species, these types of experiments are important for understanding the nature of the time course of recovery in individual subjects. These figures highlight the similarities in recovery times across species, even when the extent of the initial hearing loss is quite different. CO R 02 UN 01 R.J. Dooling et al. Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 121 01 02 03 PR OO F 04 05 06 07 08 09 10 11 12 13 14 15 16 ED 17 18 19 20 21 CT 22 23 24 25 26 RE 27 28 29 30 33 34 35 36 37 38 39 40 41 42 43 44 45 Figure 4.1. (A) Behaviorally measured threshold shifts after acoustic overexposure to a 2.86-kHz pure tone for Japanese quail (n = 3) and budgerigars (n = 2 at 112 dB and n = 3 at 118 dB) (replotted from Ryals et al. 1999b) and to a 525-Hz pure tone for chickens (n = 4) (replotted from Saunders et al. 1995). Shown for comparison are threshold shifts after a 700-Hz pure tone exposure as measured by the compound action potential (CAP) in pigeons (replotted from Ding-Pfennigdorff et al. 1998). (B) Threshold shifts after continuous narrowband noise overexposures for canaries (n = 2), budgerigars (n = 5), zebra finches (ZF, n = 3), and Japanese quail (n = 3; canaries, budgerigars, zebra finches replotted from Ryals et al. 1999b and Japanese quail replotted from Niemiec et al. 1994). For comparison with these continuous exposures, results from budgerigars exposed to 4 gunshot impulses (n = 2) are also shown (replotted from Hashino et al. 1988). UN 32 CO R 31 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 122 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 PR OO F 06 ED 05 CT 04 Previous work has shown that considerable variation exists in the response of the auditory system to acoustic overexposure and that structures other than hair cells are damaged if the exposure is intense or prolonged enough (reviewed in Cotanche 1999). Moreover, the apparently paradoxical finding that a considerable amount of functional recovery occurs before hair cell regeneration is complete further complicates interpretation. In part for this reason, more recent studies of behavioral recovery after hair cell regeneration have used ototoxic drug administration to cause hair cell loss. Typically in birds, hair cells in the basal end of the papilla are damaged and are lost first, with the loss proceeding toward the apical region with increased dose and time (Cotanche 1999). Studies of recovery from insult with ototoxic drugs have the advantage of being able to attribute the recovery of hearing more completely to the regeneration of new auditory hair cells with less of a confounding influence of surviving hair cells or mechanical damage to other structures such as the basilar papillae or tectorial membrane. In budgerigars given 100 mg/kg or 200 mg/kg of kanamycin (KM) for 10 days, threshold shifts of about 20–60 dB occurred for frequencies of 2.0 kHz and above, depending on the dosage of KM (Hashino and Sokabe 1989). Threshold shifts reached maximal values 3–5 days after the end of the KM treatment. Slightly larger threshold shifts occurred at 0.5 kHz, reaching nearly 80 dB at day 3 for the higher dose condition. Recovery of thresholds reached asymptotic levels around 15 days posttreatment. Residual hearing losses of less than 20 dB occurred for frequencies of 2.0 kHz and above in birds given the higher dosage, but returned to normal levels in birds given the lower dosage. Permanent threshold shifts of about 10 dB and 40 dB at 0.5 kHz occurred in birds given the lower and higher KM dosage, respectively. Because aminoglycosides induce hair cell loss primarily in the basal region of the basilar papilla (Hashino et al. 1992; Dooling et al. 1997), a permanent low-frequency hearing loss would not be expected and this pattern of low-frequency hearing loss remains a curious one. Other studies have reported returns to near-normal absolute sensitivity for pure tones after ototoxic drug-induced hair cell loss and regeneration in European starlings (Sturnus vulgaris; Marean et al. 1993) and budgerigars (Dooling et al. 1997). Experiments on budgerigars show that by about the fifth day of injections, absolute thresholds began to increase dramatically, and the threshold shift at 2.86 kHz by the time injections were completed (10 days) was greater than 60 dB. Immediately after KM treatment, the greatest shift occurred for frequencies above 2.0 kHz (Dooling et al. 1997). Recovery of hearing began immediately after cessation of injections. By 8 weeks postinjection, absolute thresholds improved to within 5–15 dB of normal for frequencies below 2.0 kHz and to within 20–30 dB of normal above 2.0 kHz. Recovery of threshold shift eventually reached an asymptote with a permanent threshold shift on average of 23 dB. In a more recent study on budgerigars, Dooling et al. (2006) measured thresholds at six frequencies and found them to be differentially affected by the RE 03 2.2 Ototoxic Drug Administration CO R 02 UN 01 R.J. Dooling et al. Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 PR OO F 06 ED 05 CT 04 RE 03 KM injections. Initial threshold shift was greater at high frequencies (50–60 dB above 2 kHz) than it was at low frequencies (10–30 dB below 2 kHz). Thresholds gradually recovered to within about 15–25 dB of preinjection thresholds by 8 weeks after injections, with the most rapid recovery occurring at the lowest frequencies. Absolute thresholds for all frequencies reached asymptote by 8 weeks after cessation of KM injections with a return to within 5–15 dB of normal for frequencies below 2 kHz and within 20–30 dB of normal above 2 kHz (Dooling et al. 2006). Marean and colleagues (1995) compared behavioral detection thresholds from starlings before, during, and after 11 days of subcutaneous injections of KM. The starlings were given 100 mg/kg injections for 2 days and then 200 mg/kg injections for 9 days. The birds showed large threshold shifts initially at high frequencies and then at progressively lower frequencies. These shifts were in excess of 60 dB at 4–7 kHz but none of the birds showed any change in auditory thresholds for frequencies below 3 kHz. The recovery of hearing began within a few days of the end of the KM injections, and lasted for approximately 50 days. After a second course of KM injections, the starlings showed less of a threshold shift than after the first injection. Subsequent studies showed that the smaller threshold shift after the second course of injections was likely due to metabolic changes sustained after the first course of antibiotics and not to a resistance to antibiotic damage by regenerated hair cells (Marean et al. 1995). The time course of recovery and the amount of permanent threshold shift in starlings, compared to budgerigars, suggest that they may be less sensitive to damage from aminoglycoside antibiotics, similar to Bengalese finches (Lonchura domestica; Marean et al. 1993, 1998; Woolley et al. 2001). As is the case with acoustic overexposure, there are a number of physiological estimates of threshold recovery after ototoxic drug administration that in general parallel behavioral findings. Tucci and Rubel (1990) used frequencyspecific auditory evoked potentials and tested 16- to 20-week-old chicks (Gallus gallus domesticus) after gentamicin injections. EPs were increased immediately after injections ceased, and continued to increase for up to 5 weeks afterward. This is in contrast to behavioral thresholds that generally show a decrease in thresholds following termination of injections. They suggested that the increase in EP threshold during the early stage of recovery was due to a lack of neural synchrony. Partial recovery of thresholds was seen by 16–20 weeks, predominantly at low and mid frequencies. Residual hearing loss was greatest at the highest frequencies. Interestingly, recovery of thresholds lagged hair cell regeneration by 14–18 weeks. Administration of KM also results in temporarily increased CAP and EP thresholds, primarily at higher frequencies in chickens and quail (Chen et al. 1993; Lou et al. 1994; Trautwein et al. 1998). Some residual loss persists at the highest frequencies tested, however. In a more recent study, Woolley et al. (2001) measured hair cell regeneration and the recovery of auditory thresholds in Bengalese finches using the aminoglycoside amikacin (alternating doses of 150 mg/kg and 300 mg/kg daily for 7 days). EP thresholds were measured for frequencies ranging from 0.25 to CO R 02 UN 01 123 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 124 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 PR OO F 06 ED 05 CT 04 RE 03 6 kHz. Heavy hair cell losses on the basal end of the basilar papilla correlated with hearing losses above 2 kHz. Recovery of auditory thresholds began at about 1 week after treatments and ceased approximately 4 weeks later. Thresholds at high frequencies remained elevated at 8–12 weeks. One conclusion is that the temporal course of hearing recovery is more similar among closely related species because the pattern in finches is more similar to that of the starling (Marean et al. 1993) than that of either the budgerigar (Dooling et al. 1997) or the chick (Tucci and Rubel 1990). In aggregate, these comparative results are similar in some respects to the comparative results on recovery of hearing after noise exposures, where canaries and zebra finches were similar to each other but different from budgerigars and quail (Ryals et al. 1999b). It is also important to realize the difficulties inherent in comparisons between behavioral and EP measures of hearing. Hearing is a behavior whereas EPs are a measure of neural synchrony due to stimulus onset, and usually correlate well with stimulus intensity. However, the minimum stimulus intensity required to produce a measurable evoked potential is typically 10–30 dB higher than behavioral detection thresholds. Thus, behavioral measures of hearing remain the gold standard for determining the effect of ototoxicity or acoustic overstimulation on hearing. Figure 4.2 shows behavioral audiograms from several species of birds measured behaviorally (A-budgerigars and B-starlings) compared with ABR (C-pigeons and D-Bengalese finches), and CAP (E-chickens) threshold curves. These functions show the preinjection thresholds for each species, along with data from several time periods after the ototoxic drug administration. In general, the findings are quite similar across species. Hearing losses are greatest at the high frequencies, minimal at the lowest frequencies, and recovery generally proceeds from the lowest frequencies first to the higher frequencies at later time periods. These findings from several species of birds shows that hair cell damage from ototoxic drug administration proceeds from the base to the apex of the basilar papilla, that hearing loss is greatest at high frequencies, and that functional recovery of hearing follows the hair cell replacement that one might expect from a place representation of frequency on the basilar membrane. The only exception from this general pattern is an unusual report that budgerigars experienced a low-frequency hearing loss to KM-induced hair cell destruction (Hashino and Sokabe 1989). The exact reasons for the anomalous results are still unknown. An unusual bird, the Belgian Waterslager (BWS) canary, also shows an interesting response to hair cell loss and regeneration. These birds have been bred for a distinctive low-frequency song and have an inherited auditory pathology resulting in, on average, 30% fewer hair cells on their basilar papilla, a 12% reduction in the number of auditory nerve fibers, and abnormal cochlear nuclei cell volumes compared to non-BWS canaries (Gleich et al. 1994, 2001; Kubke et al. 2002). Hair cells on the abneural edge of the papilla, which are primarily innervated by efferent fibers, appear to be most affected, and this pathology develops after hatching and extends the length of the papilla (Gleich et al. 1994; CO R 02 UN 01 R.J. Dooling et al. Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 125 01 02 03 PR OO F 04 05 06 07 08 09 10 11 12 13 14 15 16 ED 17 18 19 20 21 CT 22 23 24 25 26 RE 27 28 29 30 33 34 35 36 37 38 39 40 41 42 43 44 45 UN 32 CO R 31 Figure 4.2. Behavioral data are shown for (A) budgerigars (Dooling et al. 2006) and (B) European starlings (Marean et al. 1993). ABRs are shown for (C) pigeons (Muller and Smolders 1998, 1999) and (D) Bengalese finches (Woolley et al. 2001), and (E) CAPs are shown for chickens (Chen et al. 1993). Book_Salvi etal_9780387733630_Proof1_December 20, 2007 126 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 PR OO F 03 Weisleder et al. 1996; Ryals et al. 2001; Ryals and Dooling 2002). Even though the loss of hair cells is evident throughout the papilla, the hereditary hearing loss in BWS is clearly greatest at frequencies above 2.0 kHz (Okanoya and Dooling 1985, 1987; Okanoya et al. 1990; Gleich et al. 1995; Wright et al. 2004). Absolute thresholds are elevated by 20–40 dB and critical ratios are larger than normal at high frequencies, while normal at low frequencies (Lauer and Dooling 2002), indicating that auditory filters are broadened and frequency selectivity is reduced in BWS in the area of greatest hearing loss. Despite an ongoing rate of spontaneous hair cell regeneration in the BWS canary, new hair cells never completely repair the basilar papilla, which would potentially lead to more normal hearing. Interestingly, both noise overexposure and aminoglycoside-induced damage cause a further increase in supporting cell proliferation and differentiation (Dooling et al. 1997; Gleich et al. 1997). In BWS canaries, absolute thresholds for high frequencies increase after systemic administration of KM in BWS, but during recovery they return to slightly below (better than) preinjection levels by 13 weeks after injections of the drug cease (Dooling and Dent 2001; unpublished data). Figure 4.3 shows these results in greater detail for 4.0 kHz. Although both BWS and non-BWS canaries show a threshold shift following the KM injections, the amounts of both the threshold shifts and the recover patterns differ between the two groups. Interestingly, the final thresholds for BWS canaries at 4 kHz are about 5 dB lower than the preinjection thresholds, showing a permanent improvement rather than a permanent loss as in normal canaries. There was no improvement in hair cell number and morphology in these BWS canaries with improved thresholds (Ryals et al. 1999a). Thus, the cause of this threshold improvement in BWS is still not clear. ED 02 CT 01 R.J. Dooling et al. 26 RE 27 28 29 30 33 34 35 36 37 38 39 40 41 42 43 44 45 UN 32 CO R 31 Figure 4.3. Absolute thresholds at 4.0 kHz before, during, and after KM injections in BWS (black circles) and non-BWS (white squares) canaries. Normal canaries show the typical pattern of a small residual permanent threshold shift after KM treatment. BWS canaries also show a temporary threshold shift but then show a permanent improvement in hearing sensitivity at 4 kHz as a result of KM treatment. Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 01 02 127 3. Effects of Hair Cell Loss and Regeneration on Auditory Discrimination 03 05 06 07 08 Not surprisingly, almost all of the work on the effect of hair cell loss and regeneration on hearing has focused on the audiogram. However, a subject’s ability to discriminate complex features of sounds after hair cell regeneration may be equally or more important than simply assessing threshold. Several recent studies have addressed this issue. PR OO F 04 09 10 11 12 13 14 15 16 3.1 Discrimination Tests: Changes in Spectral, Intensity, and Temporal Resolution Behavioral studies of auditory masking and discrimination have now been conducted on several species of birds including starlings, budgerigars, and chickens (Saunders and Salvi 1995; Dooling et al. 1997; Marean et al. 1998). 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Saunders and Salvi (1995) examined pure tone masking patterns in chickens using a tone-on-tone paradigm before and after exposure to a 525-Hz pure tone at 120 dB SPL for 48 hours. Two months after the exposure, masking patterns were reassessed in these birds and the postexposure masking patterns were virtually identical to the preexposure masking patterns. Frequency selectivity has also been shown to decrease in birds immediately after aminoglycoside treatment. Critical ratios, a crude estimate of auditory filter bandwidth, have been shown to increase immediately after KM treatment in budgerigars (Hashino and Sokabe 1989), indicating a broadening of the auditory filters. Marean et al. (1998) measured auditory filter widths in starlings using notched noise maskers before, during, and after KM injections. Auditory filters at 5 kHz were significantly wider after hair cell regeneration while spectral resolution was virtually unchanged at the other frequencies. In budgerigars, intensity (IDLs) and frequency difference limens (FDLs) were measured before, during, and after 10 days of KM administration for pure tones at 1.0 and 2.86 kHz. In spite of mild but permanently elevated absolute thresholds 4 weeks after KM treatment, IDLs were not significantly affected by the KM injections and FDLs were only slightly elevated at both frequencies as shown in Figure 4.4 (Dooling et al. 2006). CT 21 RE 20 3.1.1 Spectral and Intensive Measures CO R 19 3.1.2 Temporal Measures UN 18 ED 17 Marean et al. (1998) also measured minimum temporal resolution in starlings over the time course of hair cell loss and regeneration using temporal modulation transfer functions (TMTFs). TMTFs were mostly unaffected after KM administration. Some decrease in temporal resolution was evident for band-limited noise centered at 5.0 kHz, but these observed effects may have been due to poor Book_Salvi etal_9780387733630_Proof1_December 20, 2007 128 R.J. Dooling et al. 01 02 03 PR OO F 04 05 06 07 08 09 10 11 12 13 14 15 16 ED 17 18 19 20 22 23 Figure 4.4. (A) FDLs and (B) IDLs for 1.0- and 2.86-kHz pure tones before and at three time periods after injections for three subjects. Error bars represent standard errors. (Replotted from Dooling et al. 2006.) CT 21 24 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 RE 27 audibility of the signal as a result of threshold shifts, rather than to disruption of temporal resolution per se. Maximum temporal integration (increasing threshold with decreasing stimulus duration) in birds, as in most vertebrates, is typically around 200–300 ms (Dooling et al. 2000). Saunders et al. (1995) showed that maximum temporal integration decreases immediately after acoustic trauma in chickens; it then returned to normal approximately 10–20 days after exposure. The slopes of threshold-duration functions decreased immediately after exposure, but recovered to near-normal levels after hair cell regeneration. Figure 4.5 shows the maximum temporal integration functions for the chicken at 1 kHz after acoustic overexposure to a 525-Hz pure tone (Saunders and Salvi, 1993; Saunders et al. 1995). CO R 26 3.2 Discrimination Tests: Vocalizations UN 25 Hearing in humans and animals is typically assessed with simple sounds. But we know from work with both normal hearing and hearing impaired listeners that auditory tests with pure tones are less than perfect predictors of how well a human listener can detect, discriminate, or understand speech. Recent tests on budgerigars recovering from KM treatment were designed with parallels to human speech perception in mind. Budgerigars have been particularly useful Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 129 01 02 03 PR OO F 04 05 06 07 08 09 10 11 12 13 14 15 16 ED 17 18 19 20 21 Figure 4.5. (A) Maximum temporal integration functions at 1 kHz for chickens from Saunders et al. (1995) and Saunders and Salvi (1993) for two subjects. Thresholds are shown relative to the subjects’ thresholds for the 512-ms stimulus condition. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 RE 25 avian models for behavioral studies of auditory perception as well as complex vocal production. These birds learn new vocalizations throughout life, especially in response to changes in their social milieu (Dooling 1986; Dooling et al. 1987; Farabaugh et al. 1994; Hile et al. 2000) and they require hearing and auditory feedback for the maintenance of their adult vocal repertoire. Deafening, by cochlear removal during development or in adulthood, results in an impoverished vocal repertoire (Dooling et al. 1987; Heaton et al. 1999). Moreover, budgerigars trained to produce particular vocalizations under controlled experimental conditions show strong evidence of the Lombard effect (increases in vocal intensity when placed in a noisy environment), suggesting a real time monitoring of vocal output (Manabe et al. 1998). In a series of tests on the abilities of budgerigars to discriminate among complex vocal signals before and after KM treatment, birds were tested on their ability to discriminate between pairs of calls in a test set of five different speciesspecific budgerigar contact calls and their synthetic analogs for a total of 10 calls in the test set (see Fig. 4.6A). Each bird was tested on the entire 10-call set both before and approximately every 4–6 weeks after injections up to about 24 weeks after cessation of KM injections. Discriminations between contact call types were relatively easy while discrimination between a natural contact call and its synthetic analog was difficult (Dooling et al. 2006). The relatively easy discriminations between contact call types as measured by percent correct response returned to pretreatment levels by only 4 weeks after cessation of KM injections while the more difficult discriminations between a CO R 24 UN 23 CT 22 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 130 R.J. Dooling et al. 01 02 03 PR OO F 04 05 06 07 08 09 10 11 12 13 14 15 16 ED 17 18 19 20 21 CT 22 23 24 25 26 RE 27 28 29 30 33 34 35 36 37 38 39 40 41 42 43 44 45 Figure 4.6. (A) Sonograms of contact calls from five different birds and their synthetic analogs plotted as frequency by time (taken from Dooling and Okanoya 1995). (B) The average percentage correct for three budgerigars discriminating among the five natural contact calls and their synthetic analogs before treatment with KM and at 4, 12, 14, and 23 weeks after injections. Asterisks represent significantly different results from the preinjection condition (∗ p = 005, ∗∗ p < 005). UN 32 CO R 31 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 02 03 04 05 06 07 08 natural call and its synthetic analogue showed prolonged disruption (Fig. 4.6B). Additional analyses of response latencies also show that the birds’ perceptual space for contact calls was still somewhat distorted four weeks into recovery. Some calls that were perceptually distinct before KM administration were being perceived as similar many weeks into the recovery process (Dooling et al. 2006). These data on the budgerigar suggest a more complicated picture of hearing recovery in these birds when the task involves the discrimination of complex vocalizations. PR OO F 01 09 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 ED 14 The previous results focused on the recovery in the detection and discrimination of simple and complex sounds after hair cell regeneration. However, a higher order task that needs to be addressed after hair cell regeneration is the ability to understand what is being said. This reminds us that it is one thing to hear speech, and even to discriminate among speech sounds but it is quite another thing to understand what is being said. A recent experiment addressed the effect of hair cell loss and regeneration on this broader question by testing whether budgerigars recognized contact calls that were previously familiar. This task is inherently more difficult than the discrimination task described in the preceding text in that the birds had to remember from trial to trial which call was the “go” call and which call was the “no go” call. Figure 4.7A shows the average percent correct for the six budgerigars on the classification task before, during, and after 10 days of KM injections. Before injections of KM, the birds’ performance was well above the 85% criterion level. However, performance fell to chance levels (50%) after several days of KM injections and remained there when assessed in a single 100-trial test session 24 and 38 days later. At 38 days (4 weeks after cessation of KM injections), the birds were retrained and tested daily on the same task in 100-trial daily sessions. The birds returned to preinjection performance levels in 4 days. Response latencies for “go” stimuli remained below 1 s and relatively unchanged throughout the experiment, attesting to the birds’ excellent health and behavioral responsiveness (Fig. 4.7B). Response latencies to the “no-go” stimuli averaged near 5 s before and during the first few days of treatment with KM. But, as testing continued and the birds began to respond by pecking the report key to both “go” and “no-go” stimuli, response latencies to the “no-go” approached the levels recorded to the “go” stimuli. The six KM-treated birds tested after 4 weeks of recovery required an average of more than four 100-trial sessions to reach criterion instead of the average of less than two 100-trial sessions to reach criterion after a 4-week pause in testing but with no KM treatment. The results of important control experiments necessary for interpretation are summarized in Figure 4.7C. The first two control conditions are for four birds that were not injected with KM but were nonetheless given either a 2-week or a 4-week pause in testing. When testing resumed, the number of trials to reach criterion was much less than the time required to learn a CT 13 RE 12 3.3 Identification Tests: Recognition of Contact Calls CO R 11 UN 10 131 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 132 R.J. Dooling et al. 01 02 03 PR OO F 04 05 06 07 08 09 10 11 12 13 14 15 16 ED 17 18 19 20 21 CT 22 23 24 25 26 RE 27 28 29 30 33 34 35 36 37 38 39 40 41 42 43 44 45 Figure 4.7. (A) Average percentage correct responses of six budgerigars on a Go/NoGo recognition task involving two contact calls before, during, and after treatment with KM. Twenty-four days after the end of treatment, classification performance had not yet returned to preinjection levels. At retesting on day 38, however, performance improved to preinjection levels within 4 days of testing. Error bars represent standard errors. (B) The average response latencies to both “go” and “no-go” stimuli for the six budgerigars before, during, and after KM treatment. Response latencies for the “go” stimuli remained low throughout the experiment, attesting to the birds’ health and attentiveness. (C) Summary of the number of trials to reach criterion in the KM experiment and various control UN 32 CO R 31 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 02 03 04 05 06 07 new classification because the calls were familiar to the birds. Birds performing above criterion on one pair of contact calls (original calls) and switched to another pair (new calls) also required slightly over four 100-trial sessions to reach criterion. These results suggest that previously familiar contact calls do not sound the same to budgerigars that have been treated with KM and subsequently regenerated new hair cells. Instead, they sound like unfamiliar calls based on the time required to relearn a classification task involving these calls. PR OO F 01 08 09 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 ED 14 One of the most devastating consequences of severe hearing impairment in humans is the loss of acoustic communication and the inevitable decline in the precision of speech production (Binnie et al. 1982; Waldstein 1990). With their dependence on hearing to develop and maintain a normal, species-specific vocal repertoire, birds provide a model for testing the effects of hearing loss and recovery on vocal production. To test this, operant conditioning with food reward was used to train birds to reliably and consistently produce species-specific contact calls with a high degree of precision (see, e.g., Manabe et al. 1998). Contact calls produced by the bird in the operant test chamber were compared online to a digitally stored template of the call. Contact calls that matched a stored template resulted in food reinforcement, while calls that did not match the template were not reinforced with food. These contingencies ensured that the birds were highly motivated to produce contact calls matching the template with the utmost precision. This precision with which birds produced contact calls under these controlled conditions was assessed during and after treatment with high doses of KM. Figure 4.8A shows template matching performance for three budgerigars, each producing two different call types under operant control before, during, and after an 8-day course of KM. All three birds showed some loss in vocal precision during KM treatment; however, the loss was variable across the three birds. All three birds recovered to pretreatment levels, even those showing the greatest loss, within 10–15 days after the injections. On average, the ability to produce a precise vocal match to a stored contact call recovered to preinjection levels long before auditory recovery reached asymptote at about 8 weeks. CT 13 RE 12 4. Vocal Production 37 38 39 40 41 42 43 44 45 ◭ CO R 11 UN 10 133 Figure 4.7. experiments indicating that KM treatment renders previously familiar calls unrecognizable. Control animals (no drug condition) take less than two sessions after 2 (black bar) or 4 (white bar) weeks of not running in any experiments to again reach criterion. Birds given a 4-week pause in running plus KM (striped bar) took an average of four sessions to reach criterion, a similar number of sessions as no-drug animals given a new set of calls to learn (gray bar). Error bars represent standard errors. Book_Salvi etal_9780387733630_Proof1_December 20, 2007 134 R.J. Dooling et al. 01 02 03 PR OO F 04 05 06 07 08 09 10 11 12 13 14 15 16 ED 17 18 19 20 21 CT 22 23 24 25 26 RE 27 28 29 30 33 34 35 36 37 38 39 40 41 42 43 44 45 Figure 4.8. (A) The relative similarity of contact calls produced by three different budgerigars to their respective templates before, during, and up to 25 days after 8 days of KM injections. Closed symbols (square, circle, and triangle) represent template 1 and open symbols represent template 2 for each bird. The line represents the best fit to the mean data from the three birds (two calls from each bird for a total of six calls). Individual data from two of the birds were published previously (Dooling et al. 1997). (B) The mean song note sequence stereotypy for eight birds that sang a degraded song before, during, and after Amikacin injections. (Data are replotted from Woolley and Rubel 2002.) CO R 32 UN 31 In another set of experiments on vocal recovery, Woolley and Rubel (2002) examined vocal memory and vocal learning in adult Bengalese finches after hair cell loss and regeneration. They used a combination of noise and the ototoxic drug amikacin to induce the extensive hair cell loss to maximize song degradation (see Woolley and Rubel 1999). The results were interesting but complicated. Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 PR OO F 03 Bengalese finches normally sing a multinote song with energy ranging from 1 to 10 kHz. After 1 week of this treatment, the stereotypy of syllable sequences was reduced and syllable structure changed in 8 of the 15 birds tested. The remaining birds maintained normal song despite treatment. Scanning electron microscopy analysis of the auditory papillae and ABR responses in these birds revealed that some had hair cells remaining in the apical region of the papillae and also had normal low-frequency hearing. Over the course of hair cell regeneration, song gradually recovered. By 4 weeks posttreatment, the stereotypy of syllable sequences returned to normal. Figure 4.8B shows this degradation and then recovery in syllable order of songs in Bengalese finches from Woolley and Rubel (2002). Though most syllables returned to their original structures by 8 weeks posttreatment, some syllables showed changes in note placement and changes in acoustic structure. The time courses of recovery are quite similar to those seen in the budgerigars, despite differences in the situation where the birds produced these songs. Three of the eight birds whose song was disrupted by hair cell loss showed additional song modifications between 4 and 8 weeks posttreatment. Approximately half of these birds’ syllables changed after the song had recovered to near normal. Changes included breaking the notes of original syllables apart, dropping some notes from the repertoire, modifying the acoustic structure of remaining notes, recombining notes to form new syllables, and creating new sequences of syllables. These changes were linked to changes in the song of the birds’ cagemates and were not spontaneous. ED 02 CT 01 24 25 26 5. Summary 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 CO R 30 These studies address recovery of hearing and auditory perception of vocalizations after hair cell damage and regeneration and the recovery in the ability to produce precise vocalizations under experimental control. Results show that both hearing and vocal production are affected when many hair cells are damaged or lost, but both behaviors return to normal or near normal over time. In humans, hearing loss as measured by pure tone detection or discrimination tasks involving simple sounds often does not predict the effect of hearing loss on the perception, understanding, or production of speech. Similarly, difficult discriminations between contact calls in budgerigars were affected for up to 20 weeks after KM treatment. At 4 weeks of recovery, perceptual maps for contact calls were distorted compared to pretreatment maps; however, the maps recovered to normal after 6 months posttreatment. So, in budgerigars, at least, results show a large recovery in vocal discrimination within a few weeks but some residual perceptual problems persist for up to 5–6 months. A common refrain of hearing impaired humans is that speech can be heard as well as before but not understood (Newby 1964). This is an intriguing phenomenon and one that is even more interesting in an organism that has the capability of auditory hair cell regeneration. When trained to recognize or UN 29 RE 27 28 135 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 136 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 PR OO F 06 ED 05 CT 04 RE 03 “label” two different contact calls, budgerigars completely lose the ability to label correctly when their hair cells have been lost to KM ototoxicity. Four weeks into recovery, these birds quickly relearn the classification of previously familiar contact calls to a high level, but they do so with a time course that suggests that the previously familiar calls now sound unfamiliar. In other words, though the ability to detect, discriminate, and classify complex acoustic sounds approaches pretreatment levels even as soon as 4 weeks into recovery, the perceptual world of complex vocalizations does not sound the same as it did before hair cells were lost. These results bear some similarity to the difficulties postlingually deafened humans have with new cochlear implants or even reprogrammed cochlear implants (e.g., Tyler et al. 1997; Hamzavi et al. 2003). If recent studies on hair cell regeneration in mammals prove someday applicable to humans, one can anticipate from these studies that a considerable period of adjustment may be necessary before a human can successfully interpret a new acoustic world. Another consequence of profound hearing loss in humans is disruption of normal auditory feedback that serves to guide the precision of vocal production leading to degraded speech quality. The broad outlines of a similar phenomenon have been known to exist in birds for some time. Budgerigars deafened as young develop extremely abnormal contact calls and songs. Birds deafened in adulthood also eventually come to produce extremely abnormal vocalizations. These results, and those from many other species, establish the importance of auditory feedback in vocal learning in birds. Budgerigars trained to produce specific contact calls under operant control show a loss of vocal precision and considerable variability at the peak of their hearing loss from ototoxicity. The effect of hearing loss on the quality of speech production in humans is also characterized by acute variability. In birds, this effect is transient, lasting no more than 2 weeks, and recovers well before absolute auditory sensitivity recovers substantially. These results suggest that even a little hearing goes a long way in guiding vocal production in these birds and that proprioceptive feedback may provide a temporary substitute for auditory feedback in this case of hearing loss. Interestingly, while the precision of vocal production is initially affected by hearing loss from hair cell damage, this precision recovers long before the papilla is repopulated with new, functional hair cells. This suggests that, even in the absence of veridical auditory feedback, budgerigars, like humans, can also rely on long-term memory combined perhaps with feedback from other sensory systems to guide vocal production. Because both young and adult budgerigars deafened by cochlear removal show permanent changes in vocal output, the questions now should focus on how long the sensorimotor interfaces can do without appropriate sensory feedback before functional recovery in vocal production is no longer possible. The answer to this question, even in a bird, should have immediate relevance for treatment of hearing loss in humans, the timing of auditory prosthetic devices such as cochlear implants, and the ultimate hope for restoration of human hearing with regenerated hair cells. CO R 02 UN 01 R.J. Dooling et al. Book_Salvi etal_9780387733630_Proof1_December 20, 2007 4. Hair Cell Regeneration in Birds 01 02 03 137 Acknowledgments. This work was supported by NIDCD grants DC-01372, DC000198, and DC-004664 to R.J.D; DC-005450 to A.M.L.; and T32-DC-00046 to M.L.D. 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 ED 09 Adler HJ, Kenealy JF, Dedio RM, Saunders JC (1992) Threshold shift, hair cell loss, and hair bundle stiffness following exposure to 120 and 125 dB pure tones in the neonatal chick. Acta Otolaryngol 112:444–454. Adler HJ, Poje CP, Saunders JC (1993) Recovery of auditory function and structure in the chick after two intense pure tone exposures. Hear Res 71:214–224. Binnie CA, Daniloff RG, Buckingham HW (1982) Phonetic disintegration in a five year old following sudden hearing loss. J Speech Hear Dis 47:181–189. Chen L, Salvi RJ, Hashino E (1993) Recovery of CAP threshold and amplitude in chickens following kanamycin ototoxicity. Hear Res 69:15–24. Corwin JT, Cotanche DA (1988) Regeneration of sensory hair cells after acoustic trauma. Science 240:1772–1774. Cotanche DA (1999) Structural recovery from sound and aminoglycoside damage in the avian cochlea. Audiol Neurootol 4:271–285. Ding-Pfennigdorff D, Smolders JWTh., Muller M, Klinke R (1998) Hair cell loss and regeneration after severe acoustic overstimulation in the adult pigeon. Hear Res 120:109–120. Dooling RJ (1980) Behavior and psychophysics of hearing in birds. In Popper AN, Fay RR (eds) Comparative Studies of Hearing in Vertebrates. New York: Springer-Verlag, pp. 261–288. Dooling RJ (1986) Perception of vocal signals by budgerigars. Exp Biol 45:195–218. Dooling RJ, Dent ML (2001) New studies on hair cell regeneration in birds. Acoust Sci Tech 22:93–100. Dooling RJ, Okanoya K (1995) The method of constant stimuli in testing auditory sensitivity in small birds. In Klump GM, Dooling RJ, Fay RR, Stebbins WC (eds) Methods in Comparative Psychoacoustics. Basel, Switzerland: Birkhauser-Verlag, pp. 161–169. Dooling RJ, Gephart BF, Price PH, McHale C, Brauth SE (1987) Effects of deafening on the contact call of the budgerigar, Melopsittacus undulatus. Anim Behav 35:1264–1266. Dooling RJ, Ryals BM, Manabe K (1997) Recovery of hearing and vocal behavior after hair cell regeneration. Proc Natl Acad Sci USA 94:14206–14210. Dooling RJ, Lohr B, Dent ML (2000) Hearing in birds and reptiles. In Dooling RJ, Fay RR, Popper AN (eds) Comparative Hearing: Birds and Reptiles. New York: Springer-Verlag, pp. 308–359. Dooling RJ, Ryals BM, Dent ML, Reid TL (2006) Perception of complex sounds in budgerigars (Melopsittacus undulatus) with temporary hearing loss. J Acoust Soc Am 119:2524–2532. Farabaugh SM, Linzenbold A, Dooling RJ (1994) Vocal plasticity in budgerigars (Melopsittacus undulatus): evidence for social factors in the learning of contact calls. J Comp Psychol 108:81–92. Girod DA, Tucci DL, Rubel EW (1991) Anatomical correlates of functional recovery in the avian inner ear following aminoglycoside ototoxicity. Laryngoscope 101:1139–1149. Gleich O, Dooling RJ, Manley GA (1994) Inner-ear abnormalities and their functional consequences in Belgian Waterslager canaries (Serinus canarius). Hear Res 79:123–136. CT 08 RE 07 References CO R 06 UN 05 PR OO F 04 Book_Salvi etal_9780387733630_Proof1_December 20, 2007 138 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 PR OO F 06 ED 05 CT 04 RE 03 CO R 02 Gleich O, Klump GM, Dooling RJ (1995) Peripheral basis for the auditory deficit in Belgian Waterslager canaries (Serinus canarius). Hear Res 82:100–108. Gleich O, Dooling RJ, Presson JC (1997) Evidence for supporting cell proliferation and hair cell differentiation in the basilar papilla of adult Belgian Waterslager canaries (Serinus canarius). J Comp Neurol 377:5–14. Gleich O, Dooling RJ, Ryals BM (2001) A quantitative analysis of the nerve fibers in the VIIIth nerve of Belgian Waterslager canaries with a hereditary sensorineural hearing loss. Hear Res 151:141–148. Hamzavi J, Baumgartner WD, Pok SM, Franz P, Gstoettner W (2003) Variables affecting speech perception in postlingually deaf adults following cochlear implantation. Acta Otolaryngol 123:493–498. Hashino E, Sokabe M (1989) Kanamycin induced low-frequency hearing loss in the budgerigar (Melopsittacus undulatus). J Acoust Soc Am 85:289–294. Hashino E, Sokabe M, Miyamoto K (1988) Frequency susceptibility to acoustic trauma in the budgerigar (Melopsittacus undulatus). J Acoust Soc Am 83:2450–2453. 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Hear Res 153:181–195. Wright T, Brittan-Powell EF, Dooling RJ, Mundinger- PC (2004) Sex-linkage of deafness and song frequency spectrum in the Waterslager strain of domestic canary. Proc R Soc Lond B (Suppl) 271:s409–s412. UN 01 R.J. Dooling et al.