Psychology assignment
Behavioral Neuroscience Copyright 19W by the 1984, Vol 98, No 6, 107.t-10H2 American Psychological Association, lnc
Noise and the Young Mouse: Genotype Modifies the Sensitive Period for Effects
on Cochlear Physiology and Audiogenic Seizures Kenneth R. Henry
University of California, Davis
A sharply defined "critical period" has been described for the young C57BL/ 6 mouse, during which acoustic trauma will profoundly alter subsequent auditory behavior (audiogenic seizures, acoustic startle reflex). In several genotypes and species, a broader "sensitive period" exists, during which acoustic trauma is most damaging to cochlear functions in the young ear. In order to examine the correspondence of these two events, C57BL/6 and CBA inbred mice, at eight ages ranging from 12 to 54 days, were exposed to 2 min of a 124-dB (SPL) octave band noise (8-16 kHz). A noninvasive electrococh- leographic technique was used to assess cochlear microphonic (CM) and action potential (AP) thresholds in exposed mice and their nonexposed littermate controls. This allowed cochlear functional measures and behavioral tests (susceptibility to audiogenic seizures) to be made in the same animals. Noise had no observable effect on the 12-day-old CBA mouse, produced a maximal threshold elevation (47 dB for AP, 28 dB for CM) at 30-36 days, with the effect declining to nearly half of this value in 54-day-old subjects. Susceptibility to audiogenic seizures in the exposed CBA mice was greatest at the peak of this sensitive period for cochlear damage (r = .95). C57BL/6 mice also appeared unaffected when noise exposure occurred at 12 days of age; they had maximal AP (23 dB) and CM (17 dB) threshold elevations at 36 days, and 54- day-old mice had an 18-dB elevation of the AP and their CM was no longer affected. Susceptibility to audiogenic seizures was greatest in C57BL/6 mice exposed to noise at 18 days, and it did not correspond with the sensitive period for cochlear damage (r = .21). Therefore, both genotypes have a sensitive period for the effects of noise trauma on the CM and AP, the CBA has a sensitive period for acoustic priming for audiogenic seizures, and the C57BL/ 6 has a critical period for acoustic priming. Genetic differences in age-related losses of central nervous system auditory functions are postulated as being responsible for these behavioral differences. These data are compared with known auditory functions of the SJL and BALB/c mouse strains in order to explain genetically determined differences of the sensitive (or critical) period of acoustic priming, and for the length of time the mice subsequently remain susceptible to audiogenic seizures.
A circumscribed period occurs during the exposing them to a few seconds of loud life of the young rodent, during which an noise during this period (Henry, 1967; insult to the ear can result in the develop- Henry & Bowman, 1970a). The sensitive ment of pathological auditory behavior, period for this acoustic priming varies The sensitive or critical period for the somewhat as a function of genotype and C57BL/6 mouse occurs between 14 and 35 species, although it always appears to occur days postnatally, with 16-20 days being during early life (Henry & Bowman, 1970b; most effective. Pronounced susceptibility Iturrian & Fink, 1968; Iturrian & Johnson, to audiogenic seizures can be induced in 1971). these otherwise resistant mice by merely The neurological sequellae of acoustic
priming can be observed in specific audi- D , , . . , , , , , . u ., D tory structures. They can be lateralized to Requests, for reprints should be sent to Kenneth R. . . . . , :; ,, „ _, .,. o
Henry, Department of Psychology, University of Cal- t h e i p s i l a t e r a l e a r (Fu l l e r & C o l l i n s , 1968; ifomia, Davis, California 95616. H e n r y , B o w m a n , T h o m p s o n , & Lefever ,
1073
1074 KENNETH R. HENRY
1971) and the contralateral inferior colli- culus (Henry, Wallick, & Davis,' 1972; Ward, 1971). Priming also sensitizes the mouse to the acoustic startle reflex, and this, too, can be lateralized to the ipsilateral ear (Henry, 1972). Saunders, Bock, Chen, and Gates (1972) demonstrated that the brief acoustic priming exposure produced cochlear damage. It was subsequently noted that conductive hearing loss (Gates, Chen, & Bock, 1973; McGinn, Willott, & Henry, 1973), chemical damage to the cochlea (Norris, Cawthorn, & Carrol, 1977; Tepper & Schlesinger, 1980), and middle ear infec- tion (Niaussat, 1977) during early life also induce susceptibility to audiogenic seizures. Therefore, loss of peripheral auditory input during early life seems to be associated with development of susceptibility to audiogenic seizures in the rodent.
An apparent explanation of the early sensitive period for acoustic priming could be found in the increased susceptibility of the immature cochlea to noise-induced damage. Falk, Cook, Haseman, and Sand- ers (1974) showed greater cochlea hair cell damage in guinea pigs less than 10 days old, when compared with adult animals ex- posed to the same noise. A number of stud- ies (reviewed in Henry, 1983a, 1983b) have demonstrated similar results. Saunders and Hirsch (1976) reported a close correspond- ence between the effect of noise on inducing susceptibility to audiogenic seizures and its effect on causing apparent cochlear damage in C57BL/6 mice. By noting the extent of noise-induced elevation of the cochlear mi- crophonic (CM), as measured from the ex- posed round window, they concluded that cochlear losses were maximal in prewean- ling mice exposed at 18 days of age, coin- cidental with the age for maximally priming this genotype for audiogenic seizures.
But results of recent studies with the CBA mouse (Henry, 1983b) suggest a very different age of maximal sensitivity to cochlear noise damage: The CBA is most sensitive to elevation of the cochlear nerve action potential (AP) at about the time of puberty (35-45 days), and not at some pre- pubertal age. Unlike the C57BL/6 mouse, which shows auditory degeneration before puberty (Henry, in press; Henry & Chole, 1980; Henry & Lepkowski, 1978; Shnerson,
Devigne, & Pujol, 1982; Shnerson & Pujol, 1982), the CBA maintains good cochlear function for most of its lifespan (Henry, in press; Henry & Chole, 1980; Mikalean, 1979; Mikaelian, Warfield, & Norris, 1974).
These studies raise some interesting questions: Do the CM and AP differ in the ages a which they are maximally sensitive to noise damage? If so, is one of these measures more closely related than the other to the period of maximum sensitivity to priming? Is this genotype-specific, that is, is there a difference in these events in the auditorily abnormal C57BL/6 and the normal-hearing CBA mouse? In order to answer these questions, all three measures (CM, AP, and audiogenic seizures) were evaluated in C57BL/6 and CBA mice ex- posed to noise at eight ages, ranging from 12 to 54 days.
Method
Highly inbred C57BL/6 and CBA mice were used for these experiments. They were the first-to-fifth- generation offspring of C57BL/6J and CBA/J mice obtained from the Jackson Laboratory (Bar Harbor, Maine) They were bred and reared in the University of California at Davis Auditory Genetics Colony in order to provide a uniform and controlled environ- mental setting. The ambient noise level in the colony averaged less than 40 dB (SPL) over the frequency range to which the mice were most sensitive (2-80 kHz).
Subjects were maintained with ad-lib access to Si- monsen chow and tap water, under controlled temper- ature and lighting conditions (12-12 hr light/dark). All testing was performed between the fourth and ninth hour of their light cycle. The mice were culled after birth, if necessary, in order to maintain a maximum of 6 pups per litter, litters of fewer than 3 pups were discarded This procedure resulted in greater uniform- ity within a strain. At weaning, all mice were housed 6 to a cage. No more than 2 mice per litter were used for any one condition, and, whenever possible, an experimental mouse was matched with its own litter- mate for control. Subjects within a cage were given a toe punch to designate their experimental state. The code used for this punch was randomly changed from cage to cage and was not broken until after the mouse had undergone all testing conditions.
One hundred thirty-three C57BL/6 and 183 CBA mice were tested. Most of these were tested under two of the three conditions (e.g., CM and AP; AP and audiogenic seizure). No effect of the first was found on the second test (audiogenic seizure testing was never the first test, as it would have damaged the cochleas). But the confounding of different repeated measures for different groups and other inequalities (CM thresholds were determined at five frequencies, AP measures at six frequencies; audiogenic seizures
NOISE, GENOTYPE, AND THE SENSITIVE PERIOD 1075
were measured up to 54 days of age in the CBA, but only up to 42 days in the C57BL/6 which were no longer susceptible at this time) did not allow an analy- sis of variance to be performed.
The noise exposures (and sham exposures for the controls) were given to mice of eight ages This span ranged from 12 days, a time at which their external meatuses were still unopened and cochlear functioning was still rudimentary, through onset of auditory be- havior at about 14 days (Kikuchi & Hilding, 1965; Sher, 1971; Shnerson & Pujol, 1982), through weaning (21 days) and beyond puberty (35-45 days) to 54 days (for a good description of auditory development in various strains of mice over the entire lifespan, see Willott, 1983).
All experimental mice were exposed to an 8-16- kHz octave band of noise at 123 dB (re 20 MPS) for 2 min, at ages ranging from 12 to 54 days The method of exposure and patterns of acoustic frequency spread have been described in detail elsewhere (Henry, 1984). Most testing (AP, CM, audiogenic seizures) was per- formed 4.5-5.5 days later The nonexposed httermates' normative AP and CM thresholds were described in an earlier publication (Henry, in press) All measures were evaluated in terms of differences between exper- imental (primed) and control (nonprimed) mice
Cochlear threshold measures were obtained in a nontraumatic measure from the intact mouse, a situ- ation that allowed both behavioral and electrophysio- logical measures to be made from the same subjects. After the mouse was anesthetized with sodium pen- tobarbital, a thermocouple was inserted rectally, and the head of the mouse was inserted in a restrainer which maintained the ears in a uniform position throughout testing This consisted of a muzzle clamp and a stainless steel mouth bar The top incisors of the mouse were placed in holes at the appropriate position of the mouth bar This position was chosen so that the end of the mouth bar rested against the soft palate This mouth bar provided electrical com- munication with the stimulated cochlea (the nonstim- ulated ear was temporarily occluded), which lay only 2-3 mm from the soft palate, and served as one of the recording electrodes. A stainless steel needle was placed through the scalp vertex and served as the second active electrode. The impedance between these sources was typically less than 5,000 U Because sur- gery was not necessary to apply these electrodes, which were subsequently removed without any apparent damage to the mouse, the procedure was considered to be nontraumatic. The animal was placed on a dc heating pad, a thermal blanket was placed over it in order to maintain a uniform temperature throughout its body (especially the middle and inner ear, as deter- mined in pilot studies with locally applied microther- mocouples), and core temperature was actively main- tained between 37 and 39"C. Maintenance of a normal cochlear temperature was essential, because a temper- ature decrease resulted in elevated high-frequency cochlear thresholds Respiration, heart rate, and elec- troencephalographic activity were constantly moni- tored, and recordings were made only when these parameters were within normal physiological ranges.
Acoustic stimuli were produced, shaped, timed, and gated by standard acoustic and logic circuitry. They were phase-locked for CM and free-running for AP
measurements. A frequency meter was used to con- stantly measure the stimuli. The electrical sine wave stimuli (1 ms in duration, 200-jis rise and decay, 50- ms interstimulus interval) were transduced by either a TDH-49 headphone (2-16 kHz) or a Bruel and Kjaer (B & K) 0.5-in. microphone driven as a speaker. A quasi-free field delivery was used, with the transducers placed 1 cm from the pinna and directed toward the opening of the auditory canal. A 0.25-in. B & K microphone, placed adjacent to the tragus, was wired to a B & K No. 2209 SPL meter and paralleled to an oscilloscope in order to constantly monitor the stimuli.
The bioelectrical stimuli were amplified 100,000 times, bandpassed, and processed by a Nicolet 1170 signal averager. The AP recordings utilized a band pass of 300-5000 Hz, the CM, a band pass of ± 5% of the stimulus frequency. From 512 to 4,096 passes were used for each measure This technique, which has been described elsewhere in more detail (Henry, in press) resulted in reliable evaluation of the visual detection threshold to the CM and AP. The analytical power of the signal averaging technique, coupled with active filtration and amplification, allowed the visual detec- tion threshold to be less than 1 *Ar (this is far less than the noise level of the preamplifiers, but averaging allowed the random noise to cancel).
Figure 1 illustrates these values in the 23-day-old mice that had been primed (or sham primed) at 18 days of age. Because AP responses are well synchro- nized, thresholds obtained from the surface of the mouse are quite close to those that would be obtained from chronic round window electrodes. The CM is less well synchronized, so thresholds obtained from surface electrodes are approximately 20 dB less sensitive than those recorded locally (it is for this reason that differ- ence measures—primed vs. nonprimed—are used for analysis). But this disadvantage is more than compen- sated for by the observation that the remote CM recordings more closely parallel AP thresholds (Henry & Chole, 1980; Shnerson & Pujol, 1982) than those obtained from acute round window electrodes (Saun- ders & Hirsch, 1976) In the mouse whose entire auditory system is normal, they also parallel behav- ioral thresholds (Henry & Chole, 1980). Contributing to the advantages of the present technique are the facts that the sound was presented in a naturalistic way, utilizing natural resonant properties of the outer and middle ear, and that the middle and inner ears were not disturbed by foreign objects or uncontrolled temperature changes which would affect their prop- erties.
Testing for audiogenic seizures utilized a stimulus identical to that used for priming The original exper- imental design called for using a 110-dB SPL, identical to that used by Saunders and Hirsch (1976), but a pilot study revealed a very low incidence of audiogenic seizures with this low an SPL for priming and testing. Severity of the audiogenic seizures was evaluated by ascribing 25 points for the presence of each of the successive stages of the syndrome (wild running, my- oclonic seizure, myotonic seizure, death), so that 100 points would be given for a seizure that terminated in death. In half of the animals that were primed at ages up to 30 days, seizure testing occurred 5 days after priming. The remainder of these mice were tested for AP and/or AP thresholds at 4.5 days after priming,
1076 KENNETH R. HENRY
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Figure 1. Mean (- SE) cochlear microphonic (CM) and auditory nerve component of the brain stem evoked response (BSER) thresholds from 23-day-old C57BL/6 (top) and CBA (bottom) mice. (Subjects were 18 days old when acoustically pnmed [p] or sham primed [c] with 2 min of a 123-dB, 8-16-kHz octave band noise.)
and for seizures 5.5 days after priming. There was no difference in audiogenic seizures of these two groups, so their results were pooled Because an increase of age at priming results in a longer period for develop- ment of susceptibility in C57BL/6 mice (Henry, 1967), it was necessary to run pilot studies in order to deter- mine the proper prime-test interval for the CBA mice older than 30 days of age. This interval ranged from approximately 6 days for 30-day-old primed CBA mice to 20 days for mice primed at 54 days of age. The data presented represent seizure severity at the optimal prime-test interval. It was not necessary to make this adjustment on threshold measurements, because threshold shifts were stable from 4 to 20 days after priming in the CBA/J mice.
Results
Audiogenic Seizures
Priming induced a susceptibility to au- diogenic seizures in mice of both genotypes, and there were pronounced strain differ- ences in both the optimal age and the de- gree to which priming was effective (Table 1). None of the unprimed littermates dis- played audiogenic seizures.
The C57BL/6 were not susceptible to priming at 12 days of age; they were maxi-
NOISE, GENOTYPE, AND THE SENSITIVE PERIOD 1077
Table 1 Effects of Acoustic Priming at Various Ages on Susceptibility to Audiogenic Seizures in C57BL/ 6 and CBA Mice
Age at
priming (in days)
12 18 24 36 42
12 18 24 30 36 42 48 54
n
% of mice
WR C
C57BL/6 mice
8 16 7 6 0
0 69 86
0 0
CBA mice
6 11 7
14 9
12 16 10
0 27
100 93 89 67 31 40
0 31 14 0 0
0 27 86 93 89 67 25 30
responding
T
0 31 0 0 0
0 18 71 93 89 67 25 20
D
0 31 0 0 0
0 0
71 86 89 67 13 20
Note. No nonprimed mice exhibited audiogenic sei- zures. WR, C, T, and D represent wild running, clonic seizure, tonic seizure, and death, respectively.
mally sensitive at 18 days, and less so at 24 days. By 36 days, priming did not induce susceptibility to audiogenic seizures in any of the C57BL/6 mice.
The CBA mice were also insensitive to priming at 12 days but were only moder- ately so at 18 days. They were very sensitive by 24 days of age and remained at a high level for the next 18 days. The 48- and 54- day-old CBA mice had a considerably lower degree of sensitivity to acoustic priming.
Cochlear Action Potentials
The 124-dB acoustic priming stimulus also had a pronounced influence on the threshold of the cochlear action potential (AP). As was seen with audiogenic seizures, there was a strain difference, with the CBA being most severely affected. But the influ- ence of age, though not identical, was mote similar in the AP changes of the two strains than was the case with audiogenic seizures (Table 2).
Priming had no significant effect on the C57BL/6 AP threshold at 12 days of age. By 18 days, AP thresholds were elevated at all frequencies. An increase was seen at both 24 and 36 days, with the magnitude of AP threshold shift declining slightly in the C57BL/6 mice exposed at 54 days of age. At 18-54 days of age, the highest (16-64 kHz) frequencies were most severely af-
Table 2 Mean (± SEJ Noise-Induced Threshold Shift (in dB) of the Cochlear Nerve Action Potential in C57BL/6 and CBA Mice
Age at
priming (in days)
12 18 24 36 54
12 18 24 30 36 42 48 54
n (pairs)
5 10 9
12 8
8 11 9 9 9 7 9 8
2
1 2 ± 1.0 6.5 ± 1.0 7.4 ± 1.9
10.9 ± 2.1 45 ± 1.7
- 0 3 ± 2.3 5.1 ± 2 1
24.5 ± 2.4 31.4 ± 1.8 33.0 ± 2.9 30.2 ± 1.2 16.1 ± 2.6 16.9 ± 2 6
4
- 1 5 ± 2.7 4.8 ± 0.9 7.3 + 1.1
11.2 ±1.9 5.3 + 28
-3.4 ± 1.8 1.9 ±3.1
26.3 ± 2.1 33.9 ± 2.0 33.4 ± 3.4 27.8 ± 4.4 15.6 ± 2.5 14.7 ± 2.7
Frequency
8
(in kHz)
16
C57BL/6 mice
1.0+ 1.7 8.4 + 1.1
10.4 + 2.2 16.7 + 2.6 16.5 + 4.7
CBA mice
-3.6 + 1.6 2 5 + 4.0
44.1 + 4.2 57.0+1.8 50.9 + 5.2 48.8 ± 2.7 23.8 + 4.1 23.6 + 3.1
-2 4 ± 1.6 22.4 ± 3.7 42.1 ± 3.0 43.0 ± 3.6 38.8 ± 3.8
-2.0 ± 2.4 25.0 + 5.1 48.9 ± 2.9 59.2 + 1.1 56.1 ± 2.1 57 4 + 2.2 34.0 ± 4.8 36.1 ± 4.4
32
0.3 ± 5.6 36.4 + 3.1 43.4 + 3.1 38.1 + 4.6 33.7 + 7.0
- 3 3 + 3.8 18.8 + 6.4 49.2 + 1.6 55.3 + 2.2 60.3 + 1.0 58.5 + 2.5 32.3 + 6.3 43.2 + 5.6
64
-0.2 ± 4.3 19.5 ± 2.3 15.0 + 2.5 18.6 ± 2.9 10.6 + 2.5
-3.6 ± 2.9 6.8 ± 4.5
28.7 ± 3.8 47.6 ± 3.4 48.6 ± 3.1 38.2 + 3.1 31.9 ± 2.9 29.8 ± 5.5
Note. These values represent the difference between the thresholds of the primed mice and those of their nonprimed littermate controls
1078 KENNETH R. HENRY
fected. The noise-induced threshold in- creases correlated poorly over this age span with susceptibility to audiogenic seizures (r = .21).
The AP thresholds of the 12-day-old CBA mice were also unaffected by the priming stimulus. By 18 days, the 16- and 32-kHz thresholds were elevated. By 24 days, priming had elevated all AP thresh- olds, from 2 to 64 kHz. The AP of the CBA remained susceptible to noise-induced threshold increase throughout the remain- der of the study, with 30-42 days being the most sensitive. The frequencies from 8 to 64 kHz were those most adversely affected by the priming stimulus. The noise-induced threshold increases correlated highly over this age span with susceptibility to audio- genic seizures (r = .946).
Cochlear Microphonics
The cochlear microphonic (CM) also showed an age-related susceptibility to the acoustic priming noise exposure. The pat- tern was similar to that of the AP, but some interesting differences were seen (Table 3).
The 12-day-old C57BL/6 showed no ef- fect of priming on the CM thresholds, but, as was seen with the AP, at 18 days the 16- and 32-kHZ CM thresholds were elevated (this procedure did not allow reliable meas- urement of the CM at 64 kHz). By 36 days, CM thresholds were elevated at all frequen-
cies, with 8-32 kHz most severely affected. (No responses could be recorded in any of the primed mice at 32 kHz, so they were assigned the highest threshold value ob- tainable with this procedure. Therefore, the 32-kHz CM mean threshold elevation value is an underestimate of the actual shift.) In 54-day-old mice, the priming had no ob- servable effect on the CM threshold at any frequency. (By this time, age-related CM threshold elevation had progressed to a point at which it was no longer possible to measure 32-kHz CM thresholds in 6 of the 8 control C57BL/6 mice.)
The CBA mice had no CM elevations when priming occurred at 12 days. At 18 days, a small threshold increase was seen at 2-8 kHz, and a moderate increase at 16 and 32 kHz. By 36 days, maximum CM threshold elevation was observed at all fre- quencies, with 16 and 32 kHz still being most severely affected. This effect was still present at 32 days, although it was atten- uated. The overall CM threshold increase was greater for the CBA than for the C57BL/6 strain.
The interrelations of these three mea- sures are summarized in Figures 2 and 3.
Discussion
Genetically determined differences in the auditory systems of the CBA and C57BL/ 6 mice strongly influence the manner in
Table 3 Mean (± SE; Noise-Induced Threshold Shift (in dB) of the Cochlear Microphonic in C57BL/6 and CBA Mice
Age at priming (in days)
12 18 36 54
12 18 36 54
n (pairs)
6 9 7 8
8 7 7 9
2
-1.5 + 2.7 1.4 ± 2.4 7.5 ± 3.5 3.7 ± 4.0
-5.6 ± 1.5 5.0 ± 3.1
20.3 ± 3.2 11.1 ± 1.3
Frequency (in
4 8
C57BL/6 mice
-5.5 ± 2.0 -3.7 ± 1.8 2.9 ± 2.9 2.0 ± 2.5 8.1 ± 3.0 23.9 ± 2 7
-3.4 ± 4.4 1.1 ± 4.0
CBA mice
-1.0 ± 1.9 -3.3 ± 2.3 6.2 ± 2.9 8.9 ± 2.3
21.6 ± 1.9 22.4 ± 2.6 9.1 ± 2.9 8.1 ± 2.3
kHz)
16
2.5 ± 1.5 22.3 ± 3.0 20.8 ± 4 5 -4.1 ± 6.5
-0.7 ± 2.1 17.7 ± 4.5 35.4 ± 3.1 18.6 ± 4.3
32
-2.7 ± 3.8 19.8 ± 3.2
>22.7 ± 1.7
2.5 ± 2.7 16.4 ± 3.4
>38.9 ± 2.5 >26.8 ± 2.7
Note. These values represent the difference between the thresholds of the primed mice and those of their nonprimed littermate controls
NOISE, GENOTYPE, AND THE SENSITIVE PERIOD 1079
C_5 7_BL_/6
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CBA ,0 „
10CC
80 ^ • 20
.60
120
18
A G E
30
d a y s
36
W H E N
42 48
P R I M E D
Figure 2 Effects of noise exposure (acoustic prim- ing) on thresholds to the cochlear microphonic (CM) and action potential (AP) and audiogemc seizures as a function of age in C57BL/6 (top) and CBA (bottom) inbred mice. (This figure is a condensation of the data of Tables 1-3.)
which acoustic priming affects their physi- ology and behavior. The method of assess- ing changes of the cochlear microphonic (CM) appears to be equally important in interpreting how it is influenced by acoustic priming.
The age-related influence of noise on both strains of mice in the present study is similar to that reported for the hamster. Bock and Saunders (1977) noted that 27- 55-day-old hamsters had the greatest noise- induced threshold elevation of the cochlear microphonic. A similar effect was observed in thresholds of the auditory evoked poten- tial, as measured from the inferior collicu- lus; elevation was greatest in 40-day-old hamsters (Bock & Seifter, 1978). Lenoir, Bock, and Pujol (1979) reported an earlier sensitive period for acoustic trauma on the cochlear action potential (AP) threshold of the rat, beginning before 16 days and end- ing before 60 days of age.
Of all the published studies in which the influence of early noise exposure was sys- tematically examined, only Saunders and Hirsch (1976) reported a sharply defined period for CM threshold increase; noise had no effect at 14 days and elevated thresholds
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-18 d
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F I U Q I J C N C I I S A f F E C T E D BY N O I S E
Figure 3. Effects of noise on specific frequency ranges as a function of age in prepubertal C57BL/6 (left) and CBA (right) mice. (Low frequencies are those [2 and 4 kHz] below the range of the 8-16-kHz octave band exposure noise, middle frequencies are 8- and 16-kHz responses; high frequencies are 32-kHz for CM and 32- and 64-kHz responses for AP.)
by 30 dB at 20 days, but only by 10 dB at 28 days of age. These results are in sharp contrast to the present findings as well as to those in the hamster and rat studies discussed earlier. The reason for this dis- crepancy is unclear, but it may be at least partly related to the relative insensitivity of their recordings to high-frequency threshold shifts. This could have resulted from the opened bulla in their preparation which could have caused a localized cooling of the inner ear. This would have caused a loss of sensitivity which is greatest at high frequencies (Brown, Smith, & Nuttall, 1983).
Saunders and Hirsch (1976) found the C57BL/6 CM thresholds lowest at 5 kHz, contrary to other reports of thresholds of CM (Henry, in press), AP (Henry & Chole, 1980), evoked potentials from the inferior colliculus (Bock & Saunders, 1976; Henry
1080 KENNETH R. HENRY
& Saleh, 1973), and behavioral responses (Henry & Chole, 1980). In all of these stud- ies, the young C57BL/6 mouse was found to be most sensitive at or around 16 kHz. Saunders and Hirsch also reported that noise caused a threshold shift that was greatest at a frequency (5 kHz), more than an octave lower than the center frequency of their noise exposure (12 kHz). The lit- erature is clear that the threshold shift is greatest at or above the center frequency of the noise exposure (Cody & Johnstone, 1981; Davis, Morgan, Hawkins, Galambos, & Smith, 1950; Hawkins, Johnsson, Steb- bins, Moody, & Combs, 1976; Henry, 1982; Salvi, Henderson, & Hamernik, 1979).
The age-related influence of early noise exposure on audiogenic seizures, as de- scribed for the mice of the present study, confirms and expands previous findings. In the C57BL/6 mouse, a sharply defined sen- sitive or critical period, peaking at 16-20 days of age, exists for acoustic priming for audiogenic seizures (Boggan, Freedman, Lovell, & Schlesinger, 1971; Henry, 1967; Henry & Bowman, 1970a, 1970b; Saunders & Hirsch, 1976; Schreiber & Graham, 1976). The BALB/c mouse also appears to have a similar, sharply defined early sensi- tive or critical period for acoustic priming for audiogenic seizures (Chen, 1973). The C57BL/6 and BALB/c share another char- acteristic: progressive hearing loss which begins before adulthood (Henry & Chole, 1980; Rails, 1967).
In the CBA, the sensitive period for acoustic priming for audiogenic seizures be- gins later, lasts longer and results in more severe audiogenic seizures. Priming is rel- atively ineffective at 18 days, and most effective from 24 to 42 days of age. The end of this period is not yet known, but the results of pilot studies suggest it is weak, at best, by 120 days of age. The primed CBA mouse also maintains its sensitivity to au- diogenic seizures for a much longer time than the C57BL/6 or BALB/c strains. Pilot studies showed that CBA mice primed at 42 days of age still had maximally severe seizures (short latency to onset, terminat- ing in death) when testing occurred 40 days later. Fuller and Collins (1970) observed similar effects in the SJL mouse: The sen- sitive period began at about 18 days and
declined after 35 days of age, with no sharp cut-off of this period; priming of the SJL also remained effective, although the sever- ity was attenuated, when audiogenic seizure testing occurred 175 days after priming. Both CBA and SJL mouse genotypes main- tain normal hearing over this span of time (Henry, 1982).
It now seems possible to develop a more coherent description of the peripheral (and ultimately, central nervous system [CNS]) effects of priming. It is ineffective prior to the onset of cochlear function (Alford & Ruben, 1963). Cochlear maturation pro- gresses more rapidly in the C57BL/6 than in either the CBA or the SJL (Henry, 1982; Henry, in press), and the C57BL/6, corre- spondingly, is sensitive to priming at an earlier age than the other two genotypes (Fuller & Collins, 1970; Henry, 1967, pres- ent study). The most acute peripheral (CM and AP thresholds) sensitivity of the C57BL/6 occurs from 17 to 23 days of age (Henry, in press), corresponding with its most acute sensitivity to priming. In the CBA, the AP thresholds are lowest at ap- proximately 30-42 days (Henry, 1984, and unpublished observations, 1984), corre- sponding with its maximal sensitivity to acoustic priming (its CM thresholds, like those of the C57BL/6, are most sensitive at weaning, approximately 3 weeks of age).
The critical period for priming ends rap- idly in the C57BL/6 mouse, sooner than peripheral threshold changes might sug- gest. But in this genotype, behavioral au- ditory thresholds are much higher than AP measures (Henry & Chole, 1980). This sug- gests that early age-related CNS changes, of the type previously reported (Henry & Lepkowski, 1978), bring the critical period of C57BL/6 to a rapid end. The sensitive period of the CBA extends over a wider span (and primed mice remain susceptible to audiogenic seizures for a longer time), which may be related to their normal be- havioral and physiological auditory thresh- olds over this span.
In the CBA, there is a close correspond- ence between the effectiveness of priming on induction of susceptibility to audiogenic seizures and its ability to elevate both AP and CM thresholds. Fragmentary evidence suggests that the SJL strain is similar to
NOISE, GENOTYPE, AND THE SENSITIVE PERIOD 1081
the CBA strain in the timing and expres- sion of its physiological and behavioral re- sponses to priming (Fuller & Collins, 1970; Henry, 1982 and unpublished data, 1984). In the C57BL/6, this correspondence breaks down, possibly because of rapidly developing auditory CNS dysfunctions.
These findings suggest that it might be advantageous for future experiments on the physiological effects of priming to utilize the CBA or SJL mouse. This would allow one to observe CNS changes that are not confounded with early onset presbycusis.
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Received December 5, 1983 Revision received April 3, 1984 •