Age-related decline of auditory function in the chinchilla (Chinchilla laniger)

Hearing Research 111 (1997) 114^126

Age-related decline of auditory function in the chinchilla (Chinchilla laniger) Sandra L. McFadden a *, Pierre Campo b , Nicola Quaranta c , Donald Henderson ;

a

a

Center for Hearing and Deafness, Hearing Research Laboratories, Department of Communicative Disorders, 215 Parker Hall, SUNY at Bu¡alo, Bu¡alo, NY 14214, USA

b

INRS, Service de Physiologie de l'Environnement, Avenue de Bourgogne, 54501 Vandoeuvre, France

c

Department of Audiology and Otology, University of Bari, Bari, Italy

Received 14 January 1997; revised 28 May 1997; accepted 30 May 1997

Abstract

The aim of this study was to examine the functional consequences of aging in the chinchilla, a rodent with a relatively long life span and a range of hearing similar to that of humans. Subjects were 21 chinchillas aged 10^15 years, and 23 young controls. Thresholds were determined from auditory evoked potentials (EVPs), and outer hair cell (OHC) functioning was assessed by measuring 2f1 f2 distortion product otoacoustic emissions (DPOAEs). Six cochleas from 11^12-year-old animals were examined for hair cell loss and gross strial pathology. The results show that the chinchilla exhibits a small but significant decline of auditory sensitivity and OHC functioning between 3 and 15 years of age, with high-frequency losses exceeding and growing more rapidly than low-frequency losses. Compared to rodents with shorter life spans, the chinchilla has a rate of loss that is more similar to that of humans, which could make it a valuable model for understanding the etiology of human presbycusis.

3

Presbycusis; Age-related hearing loss; Auditory evoked potential; Distortion product otoacoustic emission; Cochlear pathology Keywords :

1. Introduction

Presbycusis refers to a constellation of age-related auditory de¢cits that include a loss of hearing sensitivity and a decreased ability to understand speech, particularly in the presence of background noise (Working Group on Speech Understanding and Aging, 1988). Once hearing loss begins to occur in adulthood, it tends to become more pronounced and accelerated with each passing decade, with high-frequency losses exceeding low-frequency losses at all ages (Corso, 1963; Glorig and Nixon, 1962; Jerger, 1973; Hinchcli¡e, 1959; Pearson et al., 1995 ; Spoor, 1967). Data from large populations screened for noise exposure and otologic disease (e.g., International Organization for Standardization; Pearson et al., 1995) show small ( 5 dB) but statisti-

6

* Corresponding author. Tel.: +1 (716) 829-2001; Fax: +1 (716) 829-2980; E-mail: [email protected]

cally signi¢cant losses of sensitivity as early as age 20^ 30 in males. However, losses are likely to become clinically signi¢cant, i.e. to exceed 20 dB hearing level (HL), only after age 50. Beginning around age 70^75, clinically signi¢cant losses can be seen in males at low frequencies ( 4 kHz) as well as high frequencies (4^8 kHz), with losses at 8 kHz exceeding 50 dB HL. Age-related hearing de¢cits in humans have commonly been attributed to histopathological changes in the cochlea, including a loss of sensory cells, atrophy of the stria vascularis, and a loss of spiral ganglion cells (Bredberg, 1968; Johnsson and Hawkins, 1972; Nadol, 1980 ; Schuknecht, 1989 ; Schuknecht and Gacek, 1993). However, presbycusis also involves changes in the central auditory system that may be either independent of cochlear pathology or secondary to it, as shown by numerous studies with animals (e.g. Boettcher et al., 1993, 1995, 1996; Caspary et al., 1995 ; McFadden and Willott, 1994a,b; Walton et al., 1995 ; Willott,

0378-5955 / 97 / $17.00 ß 1997 Elsevier Science B.V. All rights reserved PII S 0 3 7 8 - 5 9 5 5 ( 9 7 ) 0 0 0 9 9 - 3

HEARES 2854 11-11-97

6

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

115

1984, 1996a,b ; Willott et al., 1988, 1991, 1992, 1993).

olds can decline signi¢cantly (Mills et al., 1990). The

The etiological mechanisms and functional consequen-

C57 mouse is essentially deaf long before reaching the

ces of age-related changes throughout the auditory sys-

end of its 2-year life expectancy (Willott, 1991), with

tem are beginning to be elucidated as a result of re-

thresholds

search

exceeding

80

dB

SPL

by

15^18

months

and

(Henry, 1983 ; Hunter and Willott, 1987). In contrast,

complexity of changes that can and do occur with aging

the average gerbil, whose life expectancy is approxi-

(see Willott, 1991 for a review), no one animal is likely

mately 36 months (Adams and Schulte, 1997 ; Schmiedt

to serve as an ideal model of human presbycusis. In-

et al., 1990), is likely to have relatively minor losses

stead, a full understanding of presbycusis will require

(typically

research using a wide variety of animal models and

(Boettcher et al., 1993, 1995, 1996 ; Mills et al., 1990 ;

diverse experimental approaches.

Schmiedt et al., 1990).

using

animal

models.

Given

the

range

Two of the best characterized models of human pres-

less

than

30

dB)

even

at

36^38

months

Potentially important di¡erences in pattern, magni-

and

tude, and rate of age-related hearing loss can be ob-

Schulte, 1997 ; Boettcher et al., 1993, 1995, 1996 ; Grat-

served among humans, C57 mice, and Mongolian ger-

ton et al., 1995, 1996 ; Hellstrom and Schmiedt, 1990 ;

bils. To facilitate comparisons among the three species,

Mills et al., 1990, 1997 ; Schmiedt et al., 1990, 1996 ;

Fig. 1 shows average hearing loss of 12-month-old C57

Schulte and Schmiedt, 1992 ; Tarnowski et al., 1991)

mice, 36-month-old gerbils, and human males aged 50^

and the C57 mouse (e.g. Henry, 1983 ; Hunter and Wil-

80 years. It is important to note for these comparisons

lott, 1987 ; McFadden and Willott, 1994a,b ; Mikaelian,

that the current life expectancy of the human male liv-

1979 ; Walton et al., 1995 ; Willott, 1984, 1991, 1996a,b ;

ing in the USA is 72 years (National Center for Health

Willott et al., 1988, 1991, 1992, 1993, 1994, 1995).

Statistics), compared to 24 months for the C57 mouse

These two rodent species have speci¢c features that

and 36 months for the Mongolian gerbil. Thus, in terms

make them valuable as models of human presbycusis

of percent of life span achieved (the usual metric for

(see Mills et al., 1990 ; Willott, 1991), and most previous

comparing hearing loss over time between animals and

research has focused on the similarities between them

humans ; see Willott, 1991), 12-month-old C57 mice can

and humans. However, di¡erences may be instructive to

be considered to correspond to 36-year-old males, and

consider as well, as they could provide important clues

36-month-old gerbils to 72-year-old males.

bycusis

are

the

Mongolian

gerbil

(e.g.

Adams

regarding the etiology of presbycusis in humans.

As shown in Fig. 1, hearing loss in human males is

The gerbil has an audibility curve similar to that of

typically characterized by high-frequency loss that ex-

humans, with greatest sensitivity around 4 kHz (Mills et

ceeds and grows more rapidly than low-frequency loss.

al., 1990 ; Ryan, 1976). The C57 mouse has an audibil-

The C57 mouse exhibits an audiometric pattern similar

ity curve that is shifted upward by several octaves, with

to this, although the a¡ected frequencies are shifted

greatest sensitivity around 16 kHz (Henry and Chole,

upward by several octaves. In contrast, the gerbil ex-

1980 ;

Willott,

hibits a £at loss of hearing from 1 to 16 kHz. At 12

Walton et al., 1995). The

months of age, the average C57 mouse has developed

Mongolian gerbil is an outbred strain, and is therefore

losses ranging from 20 dB at 2 and 4 kHz, to 45 dB at

genetically diverse, like the human. As a result, varia-

32 kHz. At 36 months of age, the average gerbil has lost

bility in the magnitude of hearing loss that gerbils de-

approximately 20 dB of sensitivity at octave frequencies

velop over their life span is extremely high, with some

from 1 to 16 kHz. Thus, if the hearing curve for the

animals exhibiting no signi¢cant loss between 16^18

C57 mouse is shifted downward by two octaves, then

months (the age at which hearing loss is likely to begin)

12-month-old

C57

and 36 months, and others exhibiting losses that exceed

quantitatively

similar

the limits of measurement (Mills et al., 1990, 1996a,b).

(Fig. 1). Gerbils at 36 months of age are most like

In contrast to gerbils and humans, all individuals of the

70^80-year-old males in the magnitude of their low-fre-

C57 strain are genetically identical. As a result, any

quency loss, but most like 50-year-old males in the

di¡erences that are observed among individuals can

magnitude

be attributed to environmental factors and/or interac-

points in their life span, i.e. near the end of the life

tions between environmental factors and speci¢c, ho-

expectancy, gerbils have approximately 20^40 dB less

mogeneous genetic backgrounds (Erway et al., 1993 ;

high-frequency loss than 70-year-old males. The di¡er-

Erway and Willott, 1996 ; Erway and Willott, 1996 ;

ences will become even larger in humans and gerbils

Willott et al., 1995).

that live beyond their average life expectancy.

1994a ;

Li

and

Borg,

1991 ;

Mikaelian, 1979 ;

McFadden

and

of

mice to

are

both

human

high-frequency

qualitatively

males

loss.

At

in

their

and 60s

comparable

Hearing loss in C57 mice typically begins in young

The di¡erences in magnitude of loss between the ro-

adulthood, around 1^2 months of age (Henry, 1983 ;

dent models and humans are not simply due to di¡er-

Hunter and Willott, 1987 ; Li and Borg, 1991). In con-

ences in chronological age. Rather, they result from

trast, the gerbil typically maintains normal hearing sen-

fundamental di¡erences in the rate of decline among

sitivity until 16^18 months of age, after which thresh-

the species, that may be relevant for understanding

HEARES 2854 11-11-97

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

116

The di¡erences in onset, pattern, magnitude, and rate of hearing loss among humans, gerbils and C57 mice imply di¡erences in underlying etiological mechanisms. Cochlear pathology and hearing loss in the C57 mouse are hypothesized to result from a single gene (Erway et al., 1993 ; Erway and Willott, 1996). It is likely that genetic factors also contribute to age-related pathology

and

hearing

loss

in

gerbils

(Adams

and

Schulte, 1997 ; Mills et al., 1996b) and humans (Schuknecht, 1974 ; Willott, 1996a), with the genes either acting directly (e.g. by triggering degenerative processes at particular periods in the life span), or indirectly (e.g. by a¡ecting susceptibility to environmental in£uences, the most obvious ones being ototoxic drugs and noise) (Erway and Willott, 1996 ;

Steel et al., 1983 ;

Willott,

1996a). The fast rate of decline in quiet-aged gerbils that are not exposed to noise or ototoxic chemicals is consistent with direct gene actions. On the other hand, the slow rate of age-related decline typically seen in humans suggests that indirect gene actions or other factors may be involved. Thus, one hypothesis to acFig. 1. Comparison of average hearing loss in 36-month-old Mon-

count for di¡erences between humans, gerbils and C57

golian gerbils, 12-month-old C57 mice, and human males aged 50^

mice in the rate of loss is that age-related threshold

80 years. Values for gerbils are based on mean age-related threshold shifts

reported

in

¢ve

recent

studies

by

Mills

and

colleagues

shifts in the gerbil and C57 mouse primarily re£ect

(Boettcher et al., 1993, 1995, 1996 ; Mills et al., 1990, 1997). Values

direct gene actions, whereas shifts in humans depend

shown for C57 mice are based on thresholds reported by Henry

on more complex interactions between genetics and a

(1983), Li and Borg (1991), McFadden and Willott (1994a), and Mi-

life time of exposure to environmental noise and vari-

kaelian (1979). Values shown for human males were derived from

ous ototoxic agents.

Spoor (1967) (open symbols) and the more recent Baltimore Longitudinal Study of Aging data from a population screened for noise

The hypothesis is consistent with the notion that

exposure and otologic disease, reported by Pearson et al. (1995)

many degenerative changes associated with aging result

(¢lled symbols).

from the accumulation of cellular damage over time (Cohen, 1988 ; Hay£ick, 1977, 1985). Cellular damage could be caused by processes such as free radical for-

the etiological mechanisms underlying their age-related

mation or waste-product accumulation, that are associ-

pathologies. The 10^60 dB of hearing loss observed in

ated both with normal cellular function and with re-

males at age 70 develops over a chronological time

sponses of the system to environmental stresses (Beal,

period of 30^50 years, depending on frequency (Pearson

1995 ; Harman, 1986). It is possible that the progression

et al., 1995). Low-frequency losses occur at rates be-

of presbycusis seen in humans re£ects time-related ac-

tween 0.2 and 0.8 dB HL/year, and high-frequency

cumulation of damage caused by normal (genetically

losses occur at rates between 0.8 and 2 dB HL/year.

determined) metabolic processes, even in the absence

The £at 20 dB of hearing loss seen in 36-month-old

of exposure to extrinsic agents such as acoustic over-

gerbils develops over a chronological time period of

stimulation and ototoxic chemicals, that increasingly

1.5^1.7 years (i.e. between 16^18 months and 36 months

compromises cellular adaptive or compensatory mech-

of age), which translates to a rate of 12^13 dB HL/year.

anisms (Cotman and Peterson, 1989).

Hearing loss occurs most rapidly in C57 mice, with

The

importance

of

time-related

accumulation

of

losses shown in Fig. 1 developing over a chronological

damage versus time-independent, genetically triggered

period of 0.8^0.9 years (i.e. from 1^2 months to 12

degenerative processes or other factors in the etiology

months), which translates to rates ranging from 22^56

of presbycusis is di¤cult, if not impossible, to evaluate

dB HL/year, depending on frequency. Thus, when the

with current rodent models. One species that might be

rate of hearing loss is referenced to chronological aging,

able to provide insight into the importance of chrono-

it is seen to occur slowly (up to 2 dB HL/year) in hu-

logical aging is the chinchilla (Chinchilla

mans, rapidly (12^13 dB HL/year) in Mongolian ger-

outbred rodent species that, like the Mongolian gerbil

bils, and very rapidly (22^56 dB HL/year) in C57 mice.

(Mills et al., 1990), has a range of hearing similar to

With respect to the chronological rate of age-related

that of humans (He¡ner and He¡ner, 1991 ; Miller,

decline in auditory sensitivity, neither the C57 mouse

1970). Although the average life expectancy of the chin-

nor the gerbil is an adequate model for the human.

chilla has not been clearly established, as it has for

HEARES 2854 11-11-97

laniger),

an

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

117

short-lived laboratory rodents such as mice and gerbils,

cated next to a cemetery in a rural area of Rochester,

there is no question that it exceeds 8 years. Literature

MN. The noise history of the animals was not docu-

from

Chinchilla

mented by the breeder, but it is unlikely that they were

Ranch) states that the average life span of the chinchilla

exposed to unusually loud or damaging levels of noise

is 8^12 years, with some animals living to 22 years.

during their life times. Nevertheless, it is possible that

Bohne and colleagues (Bohne et al., 1990 ; Sun et al.,

some, or even all, of the decrements observed in the

1994) have reported that the life span of the chinchilla

aged animals were related to their noise exposure his-

is 15^20 years, and Clark (1984) lists the life span as

tory, even if noise levels were not particularly high

12^20 years. Thus, the chinchilla provides an unusual

(Schmiedt and Schulte, 1992). We do not consider this

opportunity to examine the in£uence of endogenous

a problem for two reasons. First, exposure to environ-

and exogenous factors linked to chronological aging.

mental noises may be one trigger of the cellular meta-

one

commercial

breeder

(Moulton

We are unaware of any published studies describing

bolic processes that produce age-related hearing loss in

the hearing sensitivity of aged chinchillas. However,

humans and some animals. Second, based on the ob-

histological data obtained by Bohne et al. (1990) sug-

servation by Bohne et al. (1990) that cochlear histopa-

gest that chinchillas may exhibit a slow progression of

thology of commercially bred aged chinchillas was not

age-related hearing loss that parallels that of the hu-

di¡erent from that of colony-raised aged chinchillas, it

man. Bohne et al. observed morphological changes in

is unlikely that di¡erent results would have been ob-

21 cochleas from chinchillas aged 8^19.2 years that

tained using colony-reared animals. The aged animals we obtained were 10 (n = 2), 11

were qualitatively similar to those seen in the temporal bones of aging humans. Beginning after approximately

(n = 12), 12 (n = 4), 14 (n = 2), and 15 (n = 1) years old,

3 years of age, chinchillas manifest sensory, neural and

with a mean age of 11.6 years (S.D. = 1.3). The precise

strial cochlear pathology that becomes progressively

ages of the young animals were not known. However,

worse with age. At the same time, the histological

as none of the 23 young animals was older than 3 years,

changes observed by Bohne were relatively minor. If

cochlear pathology was assumed to be minimal or ab-

the histological changes are associated with signi¢cant

sent in this group (Bohne et al., 1990 ; Bhattacharyya

functional de¢cits, then the chinchilla may provide an

and Dayal, 1985).

important perspective on the importance of time-related

Each animal was deeply anesthetized with ketamine

accumulation of damage in the etiology of presbycusis.

(0.56 mg/kg) and acepromazine (36 mg/kg), and chronic

This study describes EVP thresholds and input/out-

recording electrodes were surgically implanted in the

32

f ) distortion product

left and/or right inferior colliculus (IC). A small hole

otoacoustic emissions (DPOAEs) for 21 aged chinchil-

was drilled in the dorsal cranium overlying the IC, and

las (10^15 years) and 23 young controls (

a

put (I/O) functions of cubic (2f1

9

3 years).

tungsten

electrode

was

stereotaxically

lowered

The cubic DPOAE is the largest and most commonly

through the hole while the surgeon monitored sound-

measured distortion product generated by the cochlea

evoked electrical activity on audio and video monitors.

in response to stimulation by two primary tones, f1 and

When the electrode had been advanced to a depth that

f2 . Cubic DPOAEs appear to depend on outer hair cell

produced clear, large-amplitude EVPs, it was cemented

(OHC) functioning (Brownell, 1990 ; Trautwein et al.,

to the skull with cyanoacrylic adhesive and dental ce-

1996), and have been used to assess the condition of the

ment. A second electrode was implanted in the rostral

OHC system in both aged (Lonsbury-Martin et al.,

cranium just below the dura mater to serve as the

1991) and noise-damaged (Avan et al., 1996 ; Hamernik

ground lead for EVP recording. Ten young and six

et al., 1996) ears. In addition to the two physiological

aged animals were implanted with a single electrode

measures,

animals

in the left IC ; the rest were implanted bilaterally. Fol-

were examined for evidence of hair cell loss and gross

lowing surgery, animals were allowed to recover in the

stria

cochleas

from

six

11^12-year-old

de-

quiet animal colony for 1^3 weeks before testing. All

scribes the results of suprathreshold tests of auditory

procedures regarding the use and care of the animals

function performed on a subset of these young and

were reviewed and approved by the University at Buf-

aged animals.

falo Institutional Animal Care and Use Committee and

vascularis

pathology.

A

companion

paper

conformed to state and federal guidelines for the humane treatment of animals. 2. Methods

2.2. Stimuli and procedures for measuring evoked potential thresholds

2.1. Subjects aged chinchillas

All testing was conducted in a sound-attenuating

from a commercial breeder

booth (Industrial Acoustics Corp.) lined with sound-

(Moulton Chinchilla Ranch), whose facilities are lo-

absorbing foam panels. An animal was placed in a

Subjects were 23 young and 21 (Chinchilla

laniger) obtained

HEARES 2854 11-11-97

118

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

padded restraining yoke that held its head at a constant orientation within a calibrated sound ¢eld. All animals were tested while awake. Test stimuli were 10 ms tones (5 ms cosine rise/fall ramps, 10/s rate) at 0.5, 1, 2, 4, 8 and 16 kHz, generated digitally by a signal processing board (Spectrum Signal Processing TMS320C25) housed in an IBM-compatible personal computer (PC). Signals were converted to analog voltages by a 16-bit D/A converter on the board, and routed through computer-controlled attenuators and impedance matching transformers to a loudspeaker (Realistic 401197) located at a distance of approximately 38 cm in front of the animal's head. Output from the recording electrode was ampli¢ed (U20 000), ¢ltered (10^3000 Hz), and routed to an A/D converter on a separate board in the computer. Tone bursts were presented in ascending order of frequency and intensity (5 dB steps) until clearly de¢ned suprathreshold responses were obtained. Each animal was tested on three separate occasions, and the three threshold estimates were averaged for a stable estimate of sensitivity as a function of frequency. To determine thresholds, stored waveforms were visually analyzed by three independent raters, each of whom was blind as to the age of the animal. Threshold at each frequency was de¢ned as the mid-point between the lowest level at which a clear response was elicited and the next lower level, in a 5 dB step, at which no response could be discerned. The average of estimates made by the three raters was used as the threshold measure for each animal. 2.3. Stimuli and procedures for obtaining DPOAE input/output functions

DPOAEs were measured in a sound-attenuating booth (Industrial Acoustics Corp.) lined with soundabsorbing foam panels, using a low noise microphone (Etymotic ER10B). Animals were placed in a customdesigned restraining device and tested while awake. The two tones used to elicit the DPOAE were generated by separate digital signal processing boards (Spectrum Signal Processing TMS320C25) in a PC, low-pass ¢ltered (TDK HFL0030, roll-o¡ 90 dB between 20 and 24 kHz), attenuated by custom-designed computer-controlled attenuators, ampli¢ed, and delivered from sound sources (Etymotic ER2) coupled to the microphone through a narrow tube. Output of the microphone was processed by a third signal processing board in the PC. Microphone output was digitized by a 16-bit A/D converter and sampled for 500 ms at a sampling rate of 31 kHz. Measurements made in a hard-walled cavity indicated that the distortion in the measurement system was less than 2 dB SPL for primary tone levels of 80 dB SPL. I/O functions for f2 primaries of 1.2, 2.4, 3.6, 4.8, 7.2,

9.6, and 12 kHz were recorded in 5 dB steps from 0 to 70^80 dB SPL, using an f2/f1 ratio of 1.2, and a level di¡erence of 15 dB (L1 s L2). Parameters for the primary tones were selected on the basis of a parametric study (unpublished data) conducted with young normal-hearing animals, showing that the largest amplitude responses are typically elicited using a f2 /f1 ratio of 1.2 and a level di¡erence of 10^15 dB. Three I/O functions were obtained from each ear of each animal and averaged. 2.4. Histology

Two young and six 11^12-year-old animals were deeply anesthetized with sodium pentobarbital (100 mg/kg i.p.) and decapitated. The rest of the animals were subsequently used in another experiment, and their cochleas were therefore unavailable for histological examination. The cochleas were quickly removed from the temporal bone, the ossicles were removed, and the round window membranes were perforated. The cochleas were gently perfused through the round window membranes with 2.5% glutaraldehyde in veronal acetate bu¡er (pH 7.3^7.4), stored in cold ¢xative for a minimum of 12 h, post-¢xed with 1% osmium tetroxide bu¡er for 1 h, then rinsed in veronal acetate bu¡er. The cochleas were dissected in 70% EtOH, beginning at the apex and proceeding toward the base. After the bony capsule had been removed, the stria vascularis and spiral ligament were carefully separated from the rest of the cochlea using a 31-gauge syringe needle as a knife. The three sections of strial tissue were either mounted in glycerin on glass microscope slides and coverslipped as a surface preparation, or embedded in resin and sectioned in 4^5 Wm sections for comparisons of tissue thickness. Dissection of the organ of Corti was completed by removing Reissner's membrane and the tectorial membrane, and then dissecting the tissue away in three turns. The organ of Corti sections were mounted in glycerin on glass microscope slides and coverslipped. Strial tissue samples from young and aged cochleas were observed with a light microscope (Zeiss Axioskop). Specimens were evaluated for qualitative di¡erences in stria vascularis thickness, extent of vascularization, diameter of blood vessels, and accumulation of pigmented granules. No attempt was made to quantify the di¡erences in stria vascularis between young and aged specimens in the small sample available. Surface preparations of the organ of Corti from the aged animals were evaluated using a Nomarski di¡erential interference contrast microscope (Zeiss). The number of missing inner hair cells (IHCs) and OHCs in each 0.24 mm segment of the organ of Corti was determined for each subject, and individual cochleograms were constructed to show the percentage of

HEARES 2854 11-11-97

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

hair cells missing as a function of distance from the apex. Then, an average cochleogram was constructed to show percent loss within each 10% section of the cochlea for the 6 aged ears. The standard reference values for cochleograms in our lab are averages of hair cell counts obtained from cochleas of 9 young (approximately 6-month-old) chinchillas.

119

2.5. Data analyses

Table 1 Summary of results from linear regression analyses of threshold as a function of age Frequency (kHz) R Slope Intercept P 0.5 0.4106 0.84 15.75 0.0005 1 0.4500 1.10 7.55 0.0001 2 0.4160 1.09 4.27 0.0004 4 0.4490 0.96 33.13 0.0001 8 0.6429 2.00 36.48 6 0.0001 16 0.6150 2.10 30.20 6 0.0001

Data analyses were geared toward answering the following questions: (1) Are EVP thresholds of aged animals elevated relative to those of young animals? (2) If so, what is the rate of sensitivity loss in older animals? (3) Are DPOAE I/O functions of aged animals depressed relative to those of young animals? Mean thresholds of the young and aged groups were compared using one-way ANOVAs at each frequency. Linear regression analyses were used to determine the rate of threshold elevation as a function of age at each frequency. For the linear regression analyses, all young animals were assumed to be 3 years of age. Thus, the regressions spanned a 12-year range, from 3 to 15 years of age. DPOAE data were compared by computing the 95% con¢dence interval for the young animals. All statistical tests were evaluated using a 0.05 criterion of signi¢cance.

variability, one-way ANOVAs indicated that thresholds of aged (mean = 11.6 years; S.D. = 1.3) chinchillas were signi¢cantly higher than those of young controls at all frequencies (all P values 6 0.001). Elevations were greater at high frequencies (8 and 16 kHz) than at lower frequencies. Linear regression analyses were performed to quantify the relationship between age and loss of sensitivity in our sample. The results are summarized in Table 1. Age accounted for a signi¢cant proportion (up to 41% at 8 kHz) of the variance in threshold data at every frequency. Loss of sensitivity at low frequencies (0.5^4 kHz) occurred at rates between 0.84 and 1.1 dB HL/ year, whereas losses at 8 and 16 kHz occurred at rates of 2.0 and 2.1 dB HL/year, respectively. 3.2. DPOAE input/output functions

3. Results

3.1. Evoked potential thresholds

Mean EVP thresholds of aged chinchillas (n = 21) and young controls (n = 23) are shown in Fig. 2. The shaded regions, representing the 95% con¢dence interval for each group, show that variability was greater among the older group of animals. Despite considerable

Fig. 2. Mean evoked potential thresholds (dB SPL) of young (n =23) and aged (n = 21) animals as a function of frequency. Shaded regions represent 95% con¢dence intervals for each group.

Mean DPOAE input/output functions for f2 frequencies of 1.2, 2.4, 3.6, 4.8, 7.2, 9.6 and 12 kHz are shown in Fig. 3. The thin line represents the mean values for 17 young normal-hearing chinchillas, and the hatched area shows the 95% con¢dence interval. The thick solid line represents the mean values for 15 aged (mean = 12.2 years) animals. The noise £oor, represented by the lowlevel (0^20 dB input levels) portion of the I/O function, was approximately 38 dB at the lowest frequency (f2 = 1.2 kHz), and 312 dB or less at all higher frequencies. DPOAE threshold was de¢ned as the input level at which the amplitude of the DPOAE exceeded the noise £oor by at least 3 dB. DPOAE thresholds of young animals ranged from 35 dB at f2 = 1.2 kHz to 20 dB at f2 = 12 kHz. Thresholds of aged animals were 5^10 dB higher than thresholds of young animals at most frequencies. DPOAE amplitudes of aged animals were signi¢cantly lower than amplitudes of young animals at all frequencies tested. This was true both for mean data (shown in Fig. 3) and for functions from individual aged animals, i.e. every aged animal tested had decreased DPOAE amplitudes relative to young controls. Furthermore, amplitudes of DPOAEs from aged animals were reduced at all input levels above threshold.

HEARES 2854 11-11-97

120

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

Fig. 3. Input/output functions for 2f1 3f2 DPOAE at seven frequencies. The thin solid line represents the mean amplitude for young animals (n=17), and the hatched region around the mean represents the 95% con¢dence interval. The thick solid line represents means for the aged animals (n = 15).

For example, at an input level of 60 dB SPL, mean amplitudes of DPOAEs of young animals were between 7 and 11 dB higher than amplitudes of aged animals.

3.3. Cochlear histopathology

Mean cytocochleograms for six cochleas from ani-

HEARES 2854 11-11-97

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

Fig. 4. Mean cytocochleograms of six aged (11-12-year-old) chinchillas, showing percent hair cell loss as a function of distance along the basilar membrane (10% segments, measured from the apex of the cochlea). A: Outer hair cell losses shown separately for each row. B: Inner hair cell losses.

mals aged 11^12 years are shown in Fig. 4. OHC loss (A) and IHC loss (B) are expressed in percent loss for each 10% segment of the organ of Corti from apex to

121

base, relative to nine cochleas from young animals (see Section 2). The average length of the six aged cochleas was 19.85 ( þ 0.9) mm, compared to our mean reference length of 19.45 ( þ 0.7) mm for young ears. For the six aged cochleas, OHC losses in rows 2 and 3 exceeded losses in row 1 (Fig. 4A), particularly in the apical half of the cochlea, where di¡erences were in the order of 5^10%. OHC losses exceeded 15% only for rows 2 and 3 in the extreme apex (0^10% distance from apex) and for all three rows in the base (90^ 100% distance from apex). The largest OHC lesions were observed in the base, with OHC losses (averaged across rows) ranging from 6% to 39% for individual animals (mean = 28.5%). IHC losses did not exceed 6% in any region of the cochlea. Losses in the apical half of the cochlea ranged from 0 to 2.5%, whereas losses in the base ranged from 0.3% to 5.3%. As with OHCs, IHC losses were greatest in the extreme base and apex of the cochlea. The greatest loss of IHCs (5.3%) occurred at a location 90^100% distance from the apex, followed by losses of 1.8^2.5% in the apical 20% of the cochlea. Fig. 5 illustrates the appearance of the organ of Corti in the basal turn of an 11-year-old cochlea. Phalangeal scars have formed in areas of missing OHCs in all three rows and pigmented granules, which may be lipofuscin or melanin, have accumulated throughout the organ of Corti. In stria vascularis of aged animals, the most obvious di¡erence from young animals was increased size and incidence of pigmented granules, as illustrated in Fig. 6. Other qualitative di¡erences between young and aged animals included reduced vascularization and decreased diameter of blood vessels, and thinning of the strial tissue.

Fig. 5. Surface preparation of organ of Corti from the basal turn of an 11-year-old cochlea. Several OHC are missing in rows 1 and 2 (4 and 3, respectively), and phalangeal scars have formed in their place. Note the widespread distribution of pigmented granules, which may be lipofuscin or melanin, throughout the organ of Corti.

HEARES 2854 11-11-97

122

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

Fig. 6. Surface preparations of the stria vascularis from a young chinchilla (A, top) and an 11-year-old chinchilla (B, bottom). Darkly stained inclusions are larger and much more numerous in the older specimens.

HEARES 2854 11-11-97

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

123

4.2. Hair cell loss

4. Discussion

4.1. Age-related loss of auditory sensitivity: comparisons with gerbils and C57 mice

Pure tone thresholds of aged chinchillas were signi¢cantly elevated at all frequencies between 0.5 and 16 kHz, with threshold elevations at 8 and 16 kHz exceeding those at lower frequencies. Thus, age-related loss of sensitivity in the chinchilla is characterized by an audiometric pattern that resembles the pattern exhibited most frequently by humans with presbycusis, i.e. greater losses for high frequencies than for low frequencies (Corso, 1963; Glorig and Nixon, 1962; Hinchcli¡e, 1959; Pearson et al., 1995; Working Group on Speech Understanding and Aging, 1988). In this regard, the chinchilla appears to be more similar to the C57 mouse than to the gerbil (see Fig. 1) and other rodent models of presbycusis that exhibit greater apical pathology and low-frequency hearing loss than basal pathology and high-frequency loss (Adams and Schulte, 1997; Willott, 1991). Compared to the C57 mouse, however, the chinchilla has a range of hearing that is more similar to that of humans (He¡ner and He¡ner, 1991; Miller, 1970), which may enhance its usefulness as a model for understanding some functional consequences of age-related cochlear pathology. Mean threshold shifts in our group of animals aged 10^15 years (mean = 11.6 years, S.D. = 1.3) were relatively small, ranging from 6.3 to 15.3 dB HL, depending on frequency (Fig. 2). Based on the rates shown in Table 1, chinchillas at the upper end of their life span estimate at 20 years would be expected to have losses of 13^17 dB at low frequencies (0.5^4 kHz), and 31^32 dB at high frequencies (8 and 16 kHz). Neither the measured values for 12-year-old chinchillas nor the projected values for 20-year-old chinchillas are much di¡erent from losses measured in 36-month-old gerbils or 12month-old C57 mice. However, unlike these short-lived rodents, the chinchilla has a rate of loss that approximates the rate seen in human males. Regression analyses indicated that auditory sensitivity declined at rates of 0.8^2 dB HL/year in chinchillas, versus 0.2^2 dB HL/ year for human males. Similarities in the pattern and rate of hearing loss between chinchillas and humans could re£ect similar etiological mechanisms. Thus, the chinchilla may be an excellent model for exploring the etiology, as well as the functional consequences, of agerelated hearing loss in humans. Obviously, given the time and expense involved in raising chinchillas to `old age,' they are not a practical substitute for shortlived species such as mice and gerbils for most studies of aging. However, our data suggest that despite their practical limitations, the chinchilla may be the most appropriate rodent model for elucidating the etiology of human presbycusis.

The inner and outer hair cell losses we observed in chinchillas aged 11^12 years (Fig. 3) were slightly less than would be expected from losses reported by Bohne et al. (1990). OHC losses reported by Bohne for 12 animals aged 8^11.5 years were approximately 13% in the apex (1^22% distance from apex), 7% in the 3 kHz region (51^72% distance from apex), 7% in the 6 kHz region (64^85% distance from apex), and 8% in the base (80^100% distance from apex). In Bohne's oldest age group, which consisted of nine animals aged 11.5^19.2 years, OHC losses had increased to 18%, 12%, 15% and 25%, respectively. Outer hair cell losses of our 11^12year-old animals would be expected to fall between these two sets of values. However, OHC losses in roughly equivalent regions (0^20%, 50^70%, 60^80%, and 80^100% distances) amounted to 12%, 4%, 4% and 17%, respectively. IHC losses were also slightly smaller in our sample. However, these di¡erences are minor, as both studies observed less than 7% IHC loss in all four regions of the cochlea, irrespective of age group. Despite relatively minor di¡erences in the magnitude of hair cell loss, the present study and the study by Bohne et al. (1990) provide a consistent picture of the pattern of age-related hair cell degeneration in the chinchilla. Between young adulthood (approximately 3 years) and 8^10 years, IHC and OHC losses are minor, not exceeding 6% in any region of the cochlea. At this time, losses are slightly greater in the apex than in the base. After 8^10 years, however, OHC losses begin to accelerate, particularly in the base of the cochlea. In our sample of 11^12-year-old chinchillas, OHC losses in the basal half exceeded losses in the apical half by nearly 10%. 4.3. Relationship between anatomical and physiological measures

The present data indicate that aging in the chinchilla is associated with a general decline of auditory function. Presumably, these functional de¢cits result from progressive cochlear pathology, such as hair cell loss. However, the magnitude of the age-related loss of sensitivity we observed was greater than would be expected on the basis of hair cell losses alone. Poor correlations between hair cell loss and degree of hearing loss have been noted in noise-exposed animals as well (Arehole et al., 1989; Boettcher et al., 1992; Shone et al., 1991). One possibility to account for the discrepancy is that threshold sensitivity is being a¡ected by other degenerative changes in the cochlea, such as neural degeneration and/or strial pathology (Adams and Schulte, 1997; Gratton et al., 1995; Schulte and Schmiedt, 1992). Our qualitative impressions of the stria vascularis in aged

HEARES 2854 11-11-97

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

124

chinchillas

support

this

notion.

A

second

possibility,

then one obvious implication for humans is that adher-

though

ing to good hearing conservation practices which min-

present, may be functionally abnormal. A third possi-

imize exposure to noise and ototoxic chemicals can re-

bility is that the central auditory system has undergone

duce the magnitude of age-related hearing loss.

not

mutually

exclusive,

is

that

hair

cells,

changes with age that are largely independent of peripheral pathology. Our DPOAE results (Fig. 2) are consistent with the hypothesis DPOAE

that

aging

thresholds

a¡ects

were

slightly

OHC elevated

Acknowledgments

functioning. (5^10

dB),

Supported in part by the Center for Hearing and

and amplitudes were signi¢cantly decreased at all fre-

Deafness

quencies tested despite relatively minor losses of OHCs.

grant

University

of

Bu¡alo,

5RO10H0115214

at

to

D.H.

and

Our data do not permit a determination of the source

like to thank Kimin Kim for assistance in data collec-

of the DPOAE de¢cits. However, several possibilities

tion and DPOAE analysis, Marty Howard for assist-

can be considered. First, DPOAE de¢cits could be re-

ance in data collection, and Vincenzo Sallustio and Da-

lated to decreased endolymphatic potential (EP) associ-

lian Ding for preparation of histological specimens.

The

by

NIDCD

authors

would

ated with strial pathology. Studies with the Mongolian gerbil have shown a strong relationship between pathologic

changes

threshold

in

the

elevations

lateral

wall,

(Boettcher

et

decreased al.,

1995 ;

EP,

and

Gratton

et al., 1995 ; Schulte and Schmiedt, 1992 ; Schmiedt et al., 1990). Second, it may be that many surviving OHCs in aged animals are functionally abnormal. Third, it is possible that the DPOAE de¢cits are related to agerelated

changes

in

the

olivocochlear

e¡erent

system,

References Adams, J.C., Schulte, B.A., 1997. Histopathologic observations of the aging gerbil cochlea. Hear. Res. 104, 101^111. Arehole, S., Salvi, R.J., Saunders, S.S., Gratton, M.A., 1989. Evokedresponse forward-masking functions in chinchillas with noise-induced permanent hearing loss. Audiology 28, 92^110. Avan, P., Bon¢ls, P., Loth, D., 1996. E¡ects of acoustic overstimula-

which has been shown to in£uence OHC electromotility

tion on distortion-product and transient-evoked otoacoustic emis-

and otoacoustic emissions (Mountain, 1980 ; Siegel and

sions. In : Axelsson, A. et al. (Eds.), Scienti¢c Basis of Noise-In-

Kim, 1982), rather than changes in the OHCs them-

duced Hearing Loss. Thieme, New York, pp. 65^81. Beal, M.F., 1995. Aging, energy, and

selves.

oxidative

stress in neurode-

generative diseases. Ann. Neurol. 38, 357^366.

4.4. Implications for understanding human presbycusis

Bhattacharyya, T.K., Dayal, V.S., 1985. Age-related cochlear hair cell loss in the chinchilla. Ann. Otol. Rhinol. Laryngol. 94, 75^80. Boettcher,

The results of the present study show that the aging chinchilla loses auditory sensitivity at rates very similar to those seen in humans. The similarities between chinchillas and humans in the rate of loss suggest that sim-

F.A.,

Mills,

J.H.,

Dubno,

J.R.,

Schmiedt,

R.A.,

1995.

Masking of auditory brainstem response in young and aged Mongolian gerbils. Hear. Res. 89, 1^13. Boettcher, F.A., Mills, J.H., Norton, B.L., 1993. Age-related changes in auditory evoked potentials of gerbils. I. Response amplitudes. Hear. Res. 71, 137145.

ilar etiological mechanisms may be contributing to age-

Boettcher, F.A., Mills, J.H., Swerdlo¡, J.L., Holley, B.L., 1996. Audi-

related hearing loss in the two species. Thus, the chin-

tory evoked potentials in aged gerbils : responses elicited by noises

chilla could o¡er insights into human presbycusis that are not possible with other rodent models such as gerbils and C57 mice.

separated by a silent gap. Hear. Res. 102, 167^178. Boettcher, F.A., Sprongr, V.P., Salvi, R.J., 1992. Physiological and histological

changes

associated

with

the

reduction

in

threshold

shift during interrupted noise exposure. Hear. Res. 62, 217^236.

Because the chinchillas used in our study were not raised in a low-noise environment, the possibility that age-related changes were due to exposure to environmental noises cannot be ruled out. However, exposure to similar levels of noise could be an important factor

Bohne, B.A., Gruner, M.M., Harding, G.W., 1990. Morphological correlates of aging in the chinchilla cochlea. Hear. Res. 48, 79^92. Bredberg, G., 1968. Cellular pattern and nerve supply of the human organ of Corti. Acta Otolaryngol. Suppl. 236, 1^135. Brownell, W.E., 1990. Outer hair cell electromotility and otoacoustic emissions. Ears Hear. 11, 82^92.

contributing to hearing loss in humans as well (Kryter,

Caspary, D.M., Milbrandt, J.C., Helfert, R.H., 1995. Central auditory

1983, 1985 ; Mills and Going, 1982). The chinchilla of-

aging : GABA changes in the inferior colliculus. Exp. Gerontol.

fers a means for assessing the importance of chronic exposure to noise and other ototoxic agents in the etiology of age-related hearing loss. For example, if hear-

30, 349^360. Clark, J.D., 1984. Biology and diseases of other rodents. In : Fox, J.G., Cohen, R.J., Loew, F.M. (Eds.), Laboratory Anim.l Medicine, Academic Press, New York.

ing losses are greater in chinchillas raised in noise than

Cohen, G.D., 1988. The Brain in Human Aging. Springer, New York.

in chinchillas raised in quiet, this would suggest that a

Corso, J.F., 1963. Age and sex di¡erences in pure-tone thresholds.

signi¢cant proportion of human presbycusis might be due to chronic exposure to environmental noise. If age-

Arch. Otolaryngol. 77, 385^405. Cotman, C.W., Peterson, C., 1989. Aging in the nervous system. In : Siegel, G.J. et al. (Eds.), Basic Neurochemistry : Molecular, Cellu-

related hearing loss is associated with exposure to noise

lar, and Medical Aspects (4th edn.). Raven, New York, pp. 523^

and other ototoxic agents over an individual's life time,

540.

HEARES 2854 11-11-97

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

125

Erway, L.C., Willott, J.F., 1996. Genetic susceptibility to noise-in-

loss : E¡ects of changing the azimuthal location of a continuous

duced hearing loss in mice. In : Axelsson, A. et al. (Eds.), Scienti¢c

noise masker on responses to contralateral tones. Hear. Res. 78,

Basis of Noise-Induced Hearing Loss. Thieme, New York, pp. 56^ 64.

132^148. Mikaelian, D.O., 1979. Development and degeneration of hearing in

Erway, L.C., Willott, J.F., Archer, J.R., Harrison, D.E., 1993. Genet-

the C57/bl6 mouse : Relation of electrophysiologic responses from

ics of age-related hearing loss in mice. I. Inbred and F1 hybrid

the round window and cochlear nucleus to cochlear anatomy and

strains. Hear. Res. 65, 125^132.

behavioral responses. Laryngoscope 34, 1^15.

Glorig, A., Nixon, J., 1962. Hearing loss as a function of age. Laryngoscope 72, 1596^1610.

Miller, J.D., 1970. Audibility curve of the chinchilla. J. Acoust. Soc. Am. 48, 513^523.

Gratton, M.A., Smyth, B.J., Schulte, B.A., Vincent, D.A., Jr., 1995. Na,K-ATPase activity declines in the cochlear lateral wall of quietaged gerbils. Hear. Res. 83, 33^40.

Mills, J.H., Going, J.A., 1982. Review of environmental factors a¡ecting hearing. Environ. Health Perspect. 44, 119^127. Mills, J.H., Boettcher, F.A., Dubno, J.R., 1997. Interaction of noise-

Gratton, M.A., Schmiedt, R.A., Schulte, B.A., 1996. Age-related decreases in endocochlear potential are associated with vascular abnormalities in the stria vascularis. Hear. Res. 102, 181^190.

induced permanent threshold shift and age-related threshold shift. J. Acoust. Soc. Am. 101, 1681^1686. Mills, J.H., Boettcher, F.A., Dubno, J.R., Schmiedt, R.A., 1996a.

Hamernik, R.P., Ahroon, W.A., Lei, S.-F., 1996. The cubic distortion

Psychophysical and evoked response studies of aged subjects :

product otoacoustic emissions from the normal and noise-dam-

Masking by low-pass noise. In : Axelsson, A. et al. (Eds.), Scien-

aged chinchilla cochlea. J. Acoust. Soc. Am. 100, 1003^1012.

ti¢c Basis of Noise-Induced Hearing Loss. Thieme, New York,

Harman, D., 1986. Free radical theory of aging : role of free radicals

pp. 181^192.

in the origination and evolution of life, aging, and disease proc-

Mills, J.H., Lee, F.-S., Dubno, J.R., Boettcher, F.A., 1996b. Interac-

esses. In : Johnson, J.E. Jr., Walford, R., Harman, D., Miquel, J.

tions between age-related and noise-induced hearing loss. In : Ax-

(Eds.), Free Radicals, Aging, and Degenerative Diseases. Liss,

elsson, A. et al. (Eds.), Scienti¢c Basis of Noise-Induced Hearing

New York.

Loss. Thieme, New York, pp. 193^212.

Hay£ick, L., 1977. The cellular basis for biological aging. In : Finch,

Mills, J.H., Schmiedt, R.A., Kulish, L.F., 1990. Age-related changes

C.E., Hay£ick, L. (Eds.), Handbook of the Biology of Aging. Van

in auditory potentials of Mongolian gerbil. Hear. Res. 46, 201^

Nostrand Reinhold, New York.

210.

Hay£ick, L., 1985. Theories of biological aging. In : Maddox, G.L. (Ed.), The Encyclopedia of Aging. Springer, New York.

Mountain,

D.C.,

1980.

Changes

in

endolymphatic

potential

and

crossed olivocochlear bundle stimulation alters cochlear mechan-

He¡ner, R.S., He¡ner, H.E., 1991. Behavioral hearing range of the chinchilla. Hear. Res. 52, 13^16.

ics. Science 210, 71^72. Nadol, J.B. Jr., 1980. The aging peripheral hearing mechanism. In :

Hellstrom, L.I., Schmiedt, R.A., 1990. Compound action potential input/output functions in young and quiet-aged gerbils. Hear. Res. 50, 163^174.

Beasley, D.S., Davis, G.A. (Eds.), Aging Communication Processes and Disorders. Grune and Stratton, Orlando, FL, pp. 63^85. Pearson, J.D., Morrell, C.H., Gordon-Salant, S., Brant, L.J., Metter,

Henry, K.R., 1983. Aging and audition. In : Willott, J.F. (Ed.), Audi-

E.J., Klein, L.L., Fozard, J.L., 1995. Gender di¡erences in a lon-

tory Psychobiology of the Mouse. CC Thomas, Spring¢eld, IL,

gitudinal study of age-associated hearing loss. J. Acoust. Soc. Am.

pp. 470^493.

97, 1196^1205.

Henry, K.R., Chole, R.A., 1980. Genotypic di¡erences in behavioral, physiological and anatomical expressions of age-related hearing loss on the laboratory mouse. Audiology 19, 369^383.

Ryan, A., 1976. Hearing sensitivity of the Mongolian gerbil,

unguiculatus.

Meriones

J. Acoust. Soc. Am. 59, 1222^1226.

Schmiedt, R.A., Mills, J.H., Adams, J.C., 1990. Tuning and suppres-

Hinchcli¡e, R., 1959. The threshold of hearing as a function of age. Acoustica 9, 303^308.

sion in auditory nerve ¢bers of aged gerbils raised in quiet or noise. Hear. Res. 45, 221^236.

Hunter, K.P., Willott, J.F., 1987. Aging and the auditory brainstem

Schmiedt, R.A., Schulte, B.A., 1992. Physiologic and histopathologic

response in mice with severe or minimal presbycusis. Hear. Res.

changes in quiet- and noise-aged gerbil cochleas. In : Dancer, A.L.,

30, 207^218.

Henderson, D., Salvi, R.J., Hamernik, R.P. (Eds.), Noise-Induced

International Organization for Standardization, 1990. Acoustic-determination of occupational noise exposure and estimation of noiseinduced hearing impairment, ISO 1999. ISO, Geneva.

Hearing Loss. Mosby Year Book, St. Louis, MO, pp. 246^256. Schmiedt, R.A., Mills, J.H., Boettcher, F.A., 1996. Age-related loss of activity of auditory-nerve ¢bers. J. Neurophysiol. 76, 2799^2803.

Jerger, J., 1973. Audiological ¢ndings in aging. Adv. Oto-Rhino-Laryngol. 20, 115^124.

Schuknecht, H., 1974. Pathology of the Ear. Harvard Press, Cambridge, MA.

Johnsson, L.-G., Hawkins, J.E., 1972. Sensory and neural degenera-

Schuknecht, H., 1989. Pathology of presbycusis. In : Goldstein, J.C.,

tion with aging, as seen in microdissections of the human inner

Kashima, H.K., Koopmann, C.F. (Eds.), Geriatric Otolaryngol-

ear. Ann. Otol. Rhinol. Laryngol. 81, 193^197.

ogy. B.C. Decker, Toronto, Ont., pp. 40^44.

Kryter, K.D., 1983. Presbycusis, sociocusis and nosocusis. J. Acoust. Soc. Am. 73, 1897^1916.

Schuknecht, H., Gacek, M., 1993. Cochlear pathology in presbycusis. Ann. Otol. Rhinol. Laryngol. Suppl. 158, 1^16.

Kryter, K.D., 1985. The E¡ects of Noise on Man. Academic Press, New York.

Schulte, B.A., Schmiedt, R.A., 1992. Lateral wall Na,K-ATPase and endocochlear potential decline with age in quiet-reared gerbils.

Li, H.S., Borg, E., 1991. Age-related loss of auditory sensitivity in two mouse genotypes. Acta Otolaryngol. 111, 827^834.

Hear. Res. 62, 46^56. Shone, G., Altschuler, R.A., Miller, J.M., Nuttall, A.L., 1991. The

Lonsbury-Martin, B.L., Cutler, W.M., Martin, G.K., 1991. Evidence

e¡ect of noise exposure on the aging ear. Hear. Res. 56, 173^178.

for the in£uence of aging on distortion-product otoacoustic emis-

Siegel, J.H., Kim, D.O., 1982. E¡erent neural control of cochlear

sions in humans. J. Acoust. Soc. Am. 89, 1749^1759.

mechanics ? Olivocochlear bundle stimulation a¡ects cochlear bio-

McFadden, S.L., Willott, J.F., 1994a. Responses of inferior colliculus neurons in C57BL/6J mice with and without sensorineural hearing loss : E¡ects of changing the azimuthal location of an unmasked pure-tone stimulus. Hear. Res. 78, 115^131.

mechanical nonlinearity. Hear. Res. 6, 245^248. Spoor, A., 1967. Presbycusis values in relation to noise induced hearing loss. Int. Audiol. 6, 48^57. Steel, K., Niaussat, M.M., Bock, G.R., 1983. The genetics of hearing.

McFadden, S.L., Willott, J.F., 1994b. Responses of inferior colliculus neurons in C57BL/6J mice with and without sensorineural hearing

In : Willott, J.F. (Ed.), Auditory Psychobiology of the Mouse. CC Thomas, Spring¢eld, IL, pp. 341^394.

HEARES 2854 11-11-97

S.L. McFadden et al. / Hearing Research 111 (1997) 114^126

126

Sun, J.C., Bohne, B.A., Harding, G.W., 1994. Is the older ear more susceptible to noise damage ? Laryngoscope 104, 1251^1258.

tory cortex associated with sensorineural hearing loss in adult

Tarnowski, B.I., Schmiedt, R.A., Hellstrom, L.I., Lee, F.S., Adams, J.C., 1991. Age-related changes in cochleas of Mongolian gerbils. Hear. Res. 54, 123^134. Selective inner hair cell loss does not alter distortion product otoacoustic emissions. Hear. Res. 96, 71^82.

mice. J. Comp. Neurol. 321, 666^678. Willott, J.F., Erway, L.C., Archer, J.R., Harrison, D.E., 1995. Genetics of age-related hearing loss in mice. II. Strain di¡erences and

Walton, J.P., Frisina, R.D., Meierhans, L.R., 1995. Sensorineural hearing loss alters recovery from short-term adaptation in the C57BL/6 mouse. Hear. Res. 88, 19^26.

e¡ects of caloric restriction on cochlear pathology and evoked response thresholds. Hear. Res. 88, 143^155. Willott, J.F., Parham, K., Hunter, K.P., 1988. Response properties of

Willott, J.F., 1984. Changes in frequency representation in the auditory system of mice with age-related hearing impairment. Brain Res. 309, 159^162.

inferior colliculus neurons in middle-aged C57 mice with presbycusis. Hear. Res. 37, 15^28. Willott, J.F., Parham, K., Hunter, K.P., 1991. Comparison of the

Willott, J.F., 1991. Aging and the Auditory System : Anatomy, Physiology, and Psychophysics. Singular, San Diego, CA. neuroscience perspective. J. Am. Acad. Audiol. 7, 141^151. mouse. In : Salvi, R., Henderson, D., Coletti, V., Fiorino, F. York, pp. 297^316.

and

Regeneration.

Thieme,

Hear. Res. 53, 78^94. Willott, J.F., Bross, L.S., McFadden, S.L., 1994. Morphology of the

Willott, J.F., 1996b. Auditory system plasticity in the adult C57BL/6J Plasticity

auditory sensitivity of neurons in the cochlear nucleus and inferior colliculus neurons of young and aging C57BL/6J and CBA/J mice.

Willott, J.F., 1996a. Anatomic and physiologic aging : A behavioral

Auditory

C57BL/6J mice. J. Comp. Neurol. 329, 402^411. Willott, J.F., Bross, L.S., McFadden, S.L., 1992. Morphology of the dorsal cochlear nucleus in young and aging C57BL/6J and CBA/J

Trautwein, P., Hofstetter, P., Wang, J., Salvi, R., Nostrant, A., 1996.

(Eds.),

Willott, J.F., Aitkin, L.M., McFadden, S.L., 1993. Plasticity of audi-

New

inferior colliculus in C57BL/6J and CBA/J mice across the lifespan. Neurobiol. Aging 15, 175^183. Working Group on Speech Understanding and Aging, 1988. Speech understanding and aging. J. Acoust. Soc. Am. 83, 859^895.

HEARES 2854 11-11-97