Department of Physiology, Monash University, Monash, VIC 3800, Australia
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ABSTRACT |
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Rajan, R.. Noise Priming and the Effects of Different Cochlear Centrifugal Pathways on Loud-Sound-Induced Hearing Loss. J. Neurophysiol. 86: 1277-1288, 2001. Priming/conditioning the cochlea with moderately loud sound can reduce damage caused by subsequent loud sound. This study examined immediate effects of short-term priming with monaural broadband noise on temporary threshold shifts (TTSs) in hearing caused by a subsequent loud high-frequency tone and the role of centrifugal olivocochlear pathways. Priming caused delay-dependent changes in tone-induced TTSs, particularly or only at frequencies higher than the peak tone-affected frequency, through two general effects: a short-lasting increase in cochlear susceptibility to loud sound and longer-lasting complex end effects of centrifugal pathways. The results indicated the following points. Priming noise had "pure" cochlear effects, outlasting its presentation and declining with delay, that exacerbated tone-induced TTSs at frequencies higher than the peak tone-affected frequency. The centrifugal uncrossed medial olivocochlear system (UMOCS) could prevent this noise exacerbation and as this noise effect declined, could even reduce tone-induced TTSs below those to the unprimed tone. For longer delays, when priming noise no longer had any exacerbative "pure" cochlear effects on TTSs, UMOCS exacerbated TTSs above those to the unprimed tone. The crossed medial olivocochlear system (CMOCS) appeared to show a gradual "build-up" of effects postpriming. A parallel study showed it exercised no end effect on TTSs when noise and tone were concurrent. With priming, CMOCS effects were observed. For the shortest priming delay, the CMOCS blocked a UMOCS effect preventing noise exacerbation of tone-induced TTSs. For longer delays, CMOCS end effects, when present, reduced tone-induced TTSs below those to the unprimed tone. The CMOCS may oscillate between producing these effects and exerting no end-effect. With increasing delay CMOCS protection occurred in a greater proportion of animals. Finally, with a delay of 600 s between primer and loud tone, all these systems appeared to have reset to normal so that TTSs were similar to those in the unprimed condition. Thus the effects of short-term priming are not simple and do not suggest that centrifugal pathways act automatically as a protective system during such priming.
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INTRODUCTION |
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Two protocols termed
"conditioning" or "toughening" reduce loud-sound-induced
cochlear damage. In the protocol of relevance here, an initial
moderately loud sound can reduce the damage caused by later loud sounds
(e.g., Campo et al. 1991; Canlon et al.
1988
; Fiorino et al. 1989
; Kujawa
and Liberman 1997
; Miyakita et al. 1992
;
Rajan 1996a
; Rajan and Johnstone 1983
;
Ryan et al. 1994
; Zheng et al. 1997b
).
Here a moderate-level "conditioning" sound, causing little or no
damage, is presented followed by a short rest period and then exposure
to short-duration trauma. In an early study (Rajan
1996b
; Rajan and Johnstone 1983
), the
conditioner was a short-duration tone causing some temporary loss in
cochlear threshold sensitivity (temporary threshold shifts, TTSs).
After complete recovery over 30 min, a higher-level same-tone exposure, also causing TTSs, was the terminal trauma. Subsequent studies (summarized by Canlon 1996
; Subramaniam et al.
1996
) examined conditioning effects on permanent threshold
shifts (PTSs) and/or morphological damage to cochlear structures caused
by short-duration high-intensity sound, generally with the same
spectrum as conditioner, given after the rest period. In both variants
of this protocol, conditioned animals show less damage (TTSs, PTSs, or
morphological damage) to terminal trauma compared with unconditioned animals.
Conditioning effects may (Fiorino et al. 1989;
Kujawa and Liberman 1997
; Zheng et al.
1997a
,b
) involve centrifugal olivocochlear pathways that, in
other conditions, reduce loud-sound-induced TTSs (Cody and
Johnstone 1982
; Rajan 1992
, 1995a
,b
, 1996a
,
2000
; Rajan and Johnstone 1983
, 1988
;
Reiter and Liberman 1995
) or PTSs (Handrock and
Zeisberg 1982
; Liberman and Gao 1995
;
Zheng et al. 1997a
). A recent study (Rajan
2000
) showed that the crossed medial olivocochlear system
(CMOCS) acted only when a loud tone was presented binaurally (as shown
previously for this pathway) and uncrossed pathways [likely uncrossed
MOCS (UMOCS), not lateral olivocochlear system (LOCS)] (see
Rajan 2000
) acted when a loud tone was presented either
monaurally or binaurally with concurrent noise. The nontraumatic noise
itself (in the absence of UMOCS) exacerbated the tone-induced TTSs. The
present study was designed to examine the time course of this effect
and the role of centrifugal pathways in a protocol with relevance to
conditioning/toughening. The term "priming" is used to describe the
protocol because here effects of the preceding nontraumatic stimulus on
cochlear damage to subsequent terminal trauma were remarkably different
to studies where conditioning stereotypically reduces damage induced by
terminal trauma.
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METHODS |
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Animal treatment and measurement of hearing sensitivity
Procedures for animal treatment and measuring cochlear
sensitivity have been detailed before (Rajan 1995a;
Rajan et al. 1991
). In brief, adult cats weighing
between 3 and 6 kg were tested under procedures approved by the Monash
University Standing Committee on Ethics in Animal Experimentation and
conforming to guidelines of the National Health and Medical Research
Council of Australia. Cats were anesthetized (60 mg/kg) and maintained
with continuous intravenous infusion of pentobarbital sodium (Nembutal)
at 2-3 mg · kg
1 · h
1. Depth of anesthesia was monitored through
continuous recording of rectal temperature, electrocardiograms (ECG),
electromyographic (EMG) activity from forearm muscles, and regular
hourly checks of response to strong noxious pinching of the forepaw,
the presence of pupillary dilatation, and absence of corneal reflexes.
Output from ECG/EMG electrodes was displayed on an oscilloscope and fed into a speaker for continuous monitoring of the cat's condition and
depth of anesthesia. Body temperature was maintained at 37.5 ± 0.5°C (range) by a thermostatically controlled warming blanket, regulated by feedback from a rectal probe. Cats were tracheostomized and artificially ventilated on room air. Tidal volume was determined from normogram data and rate set between 20 and 25 breaths/min depending on the cat's weight.
Stainless steel electrodes were implanted against the round window
membrane of both cochleas to measure cochlear hearing sensitivity (Rajan et al. 1991). Hearing sensitivity was assessed by
measuring thresholds for the compound action potential (CAP) of the
auditory nerve at frequencies from 1 to 40 kHz that were then compared with normative data (Rajan 1995a
; Rajan et al.
1991
), and only animals with normal hearing sensitivity
bilaterally from 1 to 40 kHz were used.
Tones and noise stimuli to each ear were generated independently by one
of four channels of a digital synthesis system, gated under computer
control, and passed through separate computer-controlled attenuators
before feeding into one of four channels of an electronic mixer box.
The mixer was used to manually switch delivery of stimuli to each ear
as desired. Cross talk between different channels of the mixer was more
than 100 dB up to 10 kHz,
100 dB from 10 to 20 kHz, declining to
95 dB at 40 kHz. Two output channels from the mixer box separately
fed sound to one of two Sennheiser HD 535 speakers, each in housing
leading to a sound delivery tube in one external auditory meatus
(Rajan et al. 1991
).
Surgical inactivation of efferent pathways
Inactivation of components of cochlear efferent pathways was
made using surgical lesions at the floor of the fourth ventricle after
removing overlying cerebellum (Rajan 1995a). Lesions
were made after measuring the CAP audiogram and prior to any priming or
trauma (see following text) and were made to totally de-efferent the
test cochlea or lesion only crossed efferent pathways (bilaterally), leaving uncrossed pathways intact (see Rajan 1995a
for
locations of cuts). To totally de-efferent a cochlea, a lesion was made 1.5-2 mm lateral of the midline and on the side ipsilateral to the
test cochlea. To cut only crossed pathways (bilaterally), the lesion
was made exactly at the midline. Lesions were 6-8 mm long, extending
about the facial colliculi, identifiable on the ventricular floor.
Postmortem histology, occasionally combined with staining for
acetylcholine esterase (which stains efferent pathways), was used to
confirm the location of cuts (Rajan 1995a
; Warren
and Liberman 1989
).
In all animals with brain-stem lesions, the CAP audiogram was measured prior to and after placing any lesions. Heart rate, ECG waveform, and body temperature were also noted prior to lesion and re-checked immediately postlesion.
Traumatic loud-sound exposures and measurement of cochlear desensitization
In all experiments, testing (both priming and loud sound
exposure) was monaural to the one ear. The primer was broadband noise (0.5-40 kHz), presented at 80 dB SPL continuously for 15 min, monaurally to the test ear that would subsequently be exposed to the
standard traumatic tone. Delays between the end of noise primer and
traumatic tone were 5, 80, 200, 300, 400, or 600 s. In animals
with delay 200 s, CAP thresholds from 9 to 28 kHz (see following
text) were often re-measured in the interval between primer and loud
tone, generally starting 10 s postprimer.
The traumatic tone to cause TTSs was at 13 kHz and was presented at 100 dB SPL continuously for 15 min. This was the same trauma used in a
concurrent study (Rajan 2000) of effects of concurrent noise on TTSs to the traumatic tone, and the role of cochlear efferents
in such a context. As noted there, this frequency is from within the
most sensitive part of the cat CAP audiogram (Rajan et al.
1991
); frequencies from this region cause TTSs more easily than
do other frequencies and more readily activate protective effects of
the crossed efferent pathway (Rajan 1995b
). For any delay, ears from different animals were grouped according to the status
of the efferent pathways to that ear: all efferent pathways intact
(OC+), all pathways cut (OC
), or only crossed pathways cut (COC
).
After loud-tone exposure, CAP thresholds were measured 5 min after the end of the loud tone at frequencies from 7 to 30 kHz, in constant (but not linear) order. It took ~2.5 min to measure thresholds from 9 to 28 kHz bilaterally. Frequency-specific TTSs were calculated as the difference between pre- and postloud tone thresholds. Comparisons between groups were comparisons between TTSs at corresponding frequencies. Two-way repeated-measures ANOVAs were used to compare effects between different experimental conditions. If the ANOVA revealed a significant difference between conditions, generally with a significant interaction term between experimental condition and frequency, unpaired Student's t-tests were used to compare threshold losses at corresponding frequencies in the two conditions.
Finally, under the anesthetic conditions of this study, middle ear
muscles are not active to loud sound, as demonstrated in Rajan
(1995a) using identical anesthetic conditions and similar loud
sounds, and would not be involved in effects described here.
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RESULTS |
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Basic effects of olivocochlear pathways on TTSs induced by a loud tone in a background of silence or of concurrent noise
The effect of noise primer on TTSs caused by the subsequent loud
tone will be contrasted against TTSs caused by the unprimed tone alone
and TTSs when noise and tone were concurrent. The latter two effects
were examined in a parallel study (Rajan 2000), but as
they are germane here, are briefly summarized here and in Fig. 1.
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In totally de-efferented (OC) ears (group Noise 7 OC
ears of
Rajan 2000
) monaural 80 dB SPL noise concurrent with the
loud tone resulted in larger TTSs at all frequencies (Fig.
1A) than in OC+ tone-alone ears (group Silence 1 of
Rajan 2000
). When cochlear efferents were intact
(Rajan 2000
: group Noise 6 OC+ ears) (Fig. 1A), this noise effect was absent and TTSs were similar
(Fig. 1A) to TTSs in tone-alone OC+ ears of group Silence 1. (The previous report also showed noise itself did not cause TTSs but
exacerbated tone-induced TTSs in OC
ears.) This monaural protection,
from exacerbative effects of concurrent noise, was due to uncrossed OC
(UOC) pathways. When only the COC pathway was lesioned (group Noise 7 COC
, Rajan 2000
), TTSs to tone in noise were still similar to TTSs to
tone in noise in OC+ ears of Noise 6 (and tone-alone ears of Silence
1). Thus under monaural conditions, UOC pathways act alone to
prevent noise exacerbating tone-induced damage.
Binaural loud sound activated the COC pathway to reduce
loud-tone-induced TTSs. In OC+ animals, binaural exposure to the
standard loud tone in a background of silence (group Silence 2 of
Rajan 2000) (Fig. 1B) resulted in
significantly smaller TTS from 11 to 28 kHz than did monaural exposure
in silence (group Silence 1). Total de-efferentation of only one
cochlea (OC
ears in group Silence 3, Rajan 2000
)
followed by binaural tone exposure resulted in TTSs similar to those
after monaural exposure with intact OC (Silence 1) (Fig.
1B), whereas OC+ ears in group Silence 3 suffered low TTSs
similar to those in OC+ binaurally exposed group Silence 2 (Fig.
1B). Thus in silence, binaural loud sound activates OC pathways to protect and monaural loud sound does not. The binaural protection was due to only the COC pathway. When only the COC pathway
was lesioned (COC
) prior to binaural exposure (group Silence 4 of
Rajan 2000
), TTSs in COC
ears were similar (Fig. 1B) to those in OC
ears of Silence 3 but significantly
larger than in OC+ ears in Silence 3. So although UOC pathways were
intact in Silence 4, they did not reduce TTS.
In summary, the results of relevance from that parallel study are that
the noise does not itself cause TTSs but can, in OC ears, exacerbate
TTSs to concurrent loud tone; UOC pathways prevent concurrent noise
exacerbating tone-induced TTSs (but do not modulate the
"pure" tone-induced TTSs) and can do so to monaural (ipsilateral) tone and noise; and the COC pathway reduces tone-induced TTSs but only
to binaural, not monaural, loud tone. It does not modulate noise
exacerbation of loud-tone-induced TTSs.
With this background, the effects of this study, in which the noise was presented prior to loud tone, are described.
Priming with nondamaging noise results in complex effects on TTSs to a subsequent loud sound
The effects of noise primer on TTSs to a subsequent loud tone in all-efferent-intact (OC+) ears are shown in Fig. 2 and compared with TTSs in OC+ unprimed ears exposed only to the monaural loud tone ("tone-only" group). Comparisons were made using two-way repeated-measures ANOVAs, with post hoc unpaired Student's t-tests on TTSs at corresponding frequencies between a primed group versus (unprimed) tone-only group when the ANOVA revealed a significant condition difference, or a significant condition × frequency interaction. [In all groups, TTSs varied with frequency in the manner shown in Fig. 1 and ANOVA F for Frequency was always significant (P < 0.001) and is not reported. For t-tests, because of the number of groups and frequencies, P values for significant differences are not detailed. Significance was taken as P < 0.05.]
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In essence, compared with unprimed "tone-only" ears, priming in OC+
ears increased or reduced TTSs to the subsequent loud tone as a complex
function of delay between primer and tone. Generally, TTS exacerbation
(by >4 dB) was at >15 kHz, with peak exacerbation just >10 dB from
17-22 kHz. TTSs reductions (by >4 dB) tended to extend across the
affected range, generally peaking at 15 kHz.
For priming delays 200 s (Fig. 2, A-C), TTSs in primed
OC+ groups "switched" at different delays between reductions or
exacerbations in TTSs compared with the unprimed tone-alone group. With
5-s delay (n = 5), TTSs at 12-22 kHz (i.e., at most
tone-affected frequencies) were significantly greater than
in the tone-only OC+ group (ANOVA: P = 0.014 for
condition F, P = 0.001 for interaction F), with peak
difference of ~10 dB in the range from 16 to 22 kHz (Fig.
2A2). This reversed with 80-s delay (n = 5;
Fig. 2B) when TTSs at most tone-affected frequencies (13-28
kHz) were lower than in the tone-only group
(P < 0.005 for condition and interaction factors; Fig.
2B2). These lower TTSs were comparable (P > 0.35 for condition and interaction factors) to TTSs in OC+ ears with binaural unprimed tone-alone exposure (see Fig. 1B). As
noted in the preceding text, in the latter condition, the COC pathway acts (alone) to protect the cochlea (Rajan 2000
). With
200-s priming delay (n = 5; Fig. 2C), TTSs
from 15 to 24 kHz (i.e., from the peak tone-affected frequency to
higher frequencies) were now again greater than in the
unprimed (monaural) tone-only group (condition P = 0.022, interaction P < 0.001) with peak exacerbation
of ~12 dB at 20 kHz (Fig. 2C2). These "oscillations"
in TTS in primed OC+ ears compared with unprimed tone-only ears are
seen clearly in difference curves (Fig. 2, A2-C2).
For longer delays of 300 and 400 s (Fig. 2, D and E), a dichotomy of effects occurred: some animals showed increased TTS and others decreased TTSs compared with the unprimed tone-only group. With 300-s delay (Fig. 2D) in most animals (5/6), TTSs at 16-24 kHz (high-frequency slope of affected range) were significantly greater (condition and interaction factors, P < 0.005) with peak exacerbation of ~12 dB at ~18-20 kHz (Fig. 2D2). In one animal, TTSs at almost all frequencies were markedly lower (Fig. 2D2) than in the monaural tone-only group and comparable to low TTSs with unprimed binaural tone exposure (cf. Fig. 1B). This dichotomy was more pronounced with 400-s delay (n = 7; Fig. 2E). In four animals TTSs at 16-24 kHz (same frequencies as at 300-s delay) were increased compared with the tone-only group (condition P = 0.052, interaction P < 0.001), with peak exacerbation of ~12 dB at 18-22 kHz (Fig. 2E2). In the other three animals, TTSs at most frequencies (13-28 kHz) were markedly lower than in the unprimed tone-only group (P < 0.001 for condition and interaction factors; Fig. 2E2) and similar to low TTSs with binaural unprimed tone-only exposure.
Finally, with 600-s delay between primer and tone (n = 6; Fig. 2F), TTSs were similar to the tone-only group (P > 0.05 for condition and interaction factors) with differences generally <3 dB (Fig. 2F2). Thus 10 min after the 15-min-long primer, the primer did not modulate TTSs to the tone.
These complex sequelae of priming consisted of two effects. First, the noise primer had "pure" cochlear-only effects that exacerbated tone-induced TTSs well post primer, with this effect decaying rapidly postprimer. Second, COC and UOC end effects were complex such that TTSs to the tone could be reduced (protected) or increased (exacerbated) from TTSs caused by an unprimed tone-alone exposure. These two general effects are distinguished and treated separately in the following text.
Nondamaging priming noise has lasting effects that exacerbate TTSs to subsequent loud sound
Noise itself could exacerbate TTSs, as established in ears where
the cochlea was totally de-efferented (OC) prior to testing to remove
any OC effects. "Raw" TTSs from OC
groups at different delays are
shown in Fig. 3, A-D, and
E shows differences in TTSs in each group and the unprimed
tone-only group. The latter panel also shows the exacerbative effect of
this noise on the same loud tone when both were concurrent (Noise 7 OC
of Rajan 2000
). Compared to the tone-only group, in
the concurrent-noise group TTSs were increased mainly >15 kHz, the
peak tone-affected frequency, but small increases also occurred <15
kHz. With 5-s priming delay (n = 5), only TTSs from 15 to 24 kHz were significantly exacerbated compared with the tone-only
group (P < 0.001 for condition and interaction
factors). The effects diminished markedly with 80-s delay
(n = 5) and only 15-17 kHz suffered significantly
higher TTSs compared with the tone-only group (condition
P = 0.12, interaction P = 0.018).
Finally, with delay
200 s, noise did not exacerbate tone-induced TTSs
(200 s, n = 5; 400 s, n = 4;
600 s, n = 5) which, in all three groups, were
similar to the tone-only group.
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Pair-wise comparison between groups where noise was coupled with loud
tone showed the progressive decrease with delay in noise exacerbation
of TTSs. Thus 5-s priming delay resulted in TTSs at 11-13 and 19-28
kHz being significantly lower (P < 0.005 for condition
and interaction factors) than in the concurrent noise group and only
14- to 18-kHz TTSs were similar. With 80-s delay, 18-24 kHz suffered
significantly lower TTSs (condition P = 0.14, but
interaction P = 0.001) than with 5-s delay. Since noise
exacerbated TTSs from 15 to 24 kHz in the latter group compared with
the tone-only group, then by 80 s all these frequencies, other
than 15-17 kHz, had recovered from noise exacerbation. By 200-s delay,
there was no noise exacerbation: comparison against the primed 80-s
delay group showed significantly lower TTSs from 11 to 19 kHz with the longer delay (condition P = 0.027, interaction
P = 0.024). Finally, pair-wise comparison of OC
groups primed with delays of 200, 400, or 600 s showed no
significant differences (see Fig. 3, C-E).
Noise priming results in complex TTS end-effects of uncrossed and crossed efferent pathways
Comparison of OC+ and OC primed ears suggested priming also
resulted in complex end effects of OC pathways on tone-induced TTSs.
For example, with 80-s priming delay, cochlear efferents appear to
mitigate noise exacerbative effects and further protect the cochlea:
TTSs in OC
primed ears were generally similar to unprimed tone-only
(OC+) ears (except at 15-17 kHz), but TTSs from 13 to 28 kHz in OC+
primed ears were lower than in the unprimed tone-only group.
In contrast, with 200-s delay, cochlear efferents exacerbated TTSs:
TTSs at 15-24 kHz in OC+ primed ears were greater than in the unprimed
tone-only group but in OC
primed ears, were similar to TTSs in the
unprimed tone-only group. Most dramatically, with 400-s delay, TTSs in
OC
primed ears were similar to the unprimed tone-only group, but TTSs
in OC+ primed ears could be exacerbated or reduced from the control group.
To examine these effects, selective lesions of the COC pathway while
leaving intact UOC pathways were used (noting the converse is not
possible). Comparison of such COC ears against the unprimed tone-only
group and against OC+ and OC
groups at the same delay allowed
inferences about the role of COC and UOC pathways. Effects varied with
delay and appeared, at the first level, to correlate with the presence
of noise exacerbation of tone-induced TTSs.
SHORT DELAYS WITH NOISE-INDUCED TTS EXACERBATION: UOC ACTION CAN
PREVENT THE NOISE EFFECT.
As shown previously, with 5-s priming delay noise exacerbated
tone-induced TTSs in OC ears (Fig. 3E) and OC+ ears (Fig.
2A) to similar levels above the unprimed tone-only group
(OC+ vs. OC
groups: condition P = 0.93, interaction
P = 0.38), suggesting OC pathways would not modulate
noise exacerbation of TTSs. Selective COC pathway de-efferentation
(n = 5) showed a surprising result. TTSs in COC
ears
were similar (Fig. 4A1) to the
unprimed tone-only group (condition P = 0.096, interaction P = 0.65) but significantly lower across
most of the range than in primed de-efferented (OC
; Fig.
4A2; condition and interaction P < 0.001;
significant at 14-26 kHz) or efferent-intact (OC+; Fig.
4A3; condition P = 0.007, interaction
P = 0.024; significant at 12-22 kHz) ears. Thus UOC pathways could prevent noise exacerbation of TTSs but only in the
absence of the COC pathway.
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LONGER DELAYS WITH NO NOISE-ALONE EFFECT: UOC ACTION EXACERBATES TTSS AND COC ACTION CAN REDUCE TTSS. Selective de-efferentation showed that for longer priming delays of 200 and 400 s, when noise exacerbation of tone-induced TTSs was absent, UOC pathways exacerbate tone-induced TTSs and COC pathways can reduce TTSs.
With 200-s delay, OC pathways significantly exacerbate TTSs at frequencies from the peak-affected frequency to most high frequencies: in OC+ primed ears TTSs from 15 to 24 kHz were higher than in the tone-only group (Fig. 2C) and the OCSIX-HUNDRED SECOND DELAY RESETS ALL OC ACTIONS.
Priming with 600-s delay did not cause noise exacerbation or OC
modulation of TTSs. which were similar in OC primed ears (Fig.
3E), OC+ primed ears (Fig. 2F), and in the
tone-only group. Lesioning the COC pathway also did not show any
"hidden" OC effect (viz., 5-s delay). TTSs in COC
primed ears
(Fig. 4E; n = 5) were similar to those in
the tone-only (condition P = 0.37, interaction P = 0.07), OC
primed (Fig. 4E2; condition
P = 0.41, interaction P = 0.79), and
OC+ primed (Fig. 4E3; condition P = 0.57, interaction P = 0.99) groups.
Comparison of efferent effects across priming delay
A final comparison of primed OC+ ears was made, across delays from 80 to 400 s, of TTSs reduced (protected) or exacerbated compared with the tone-only group. With respect to protected TTSs, data at 80-s delay was compared with data from the single animal (1/6 animals) at 300-s delay that showed protected TTSs and to data from the protected subgroup (3/7 animals) with 400-s delay. Statistical comparisons made between the 80- and 400-s groups found no difference (P > 0.25 for condition and interaction factors). Data from the protected animal at 300 s were in the range for the other two groups. For cases with exacerbated TTSs, pair-wise comparisons between the group with 200-s delay, exacerbated subgroup (5/6 animals) at 300-s delay, and exacerbated subgroup (4/7) at 400-s delay found no differences (P always more than 0.4 for condition and interaction factors for all comparisons). Thus for priming delays from 80-400 s, when TTSs were reduced from the tone-only group, they remained at the same low level across delay, and when increased above the tone-only group, they remained at the same high level across delay. The significance of these data are discussed later.
Effects of noise priming on CAP thresholds
In 40 animals with priming delay 200 s, CAP thresholds from 9 to
28 kHz were re-measured between primer and loud tone, generally starting 5-8 s postprimer. CAP thresholds were unaltered except in six
animals in which there was a small transient 5-6 dB elevation of
thresholds at the first test frequency postprimer but not at any other
frequency or even at the first-tested frequency when re-tested (within
30 s of the 1st measurement). In the six animals, this frequency,
in the range 12-18 kHz, was measured within 5 s postprimer. In
other animals in which such early measurement was made, no such effect
was seen even at the first frequency re-measured postprimer. Thus
generally, the noise primer appeared to have no effect on CAP
thresholds; these results are therefore not illustrated.
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DISCUSSION |
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Since lesions were always made prior to priming, this study did not determine whether priming directly activated OC pathways or whether it "primed" these pathways for activation by the subsequent loud tone. This could be addressed by varying the timing of lesions, and will be examined in later studies.
As noted in RESULTS, noise priming caused two general effects. First, the primer had "pure" cochlear-only effects that exacerbated tone-induced TTSs. Second, after priming, COC and UOC pathways could reduce (protect) or increase (exacerbate) tone-induced TTSs compared with TTSs caused by an unprimed tone-only exposure. These two general effects are distinguished in this discussion.
Noise priming and exacerbation of loud-tone-induced TTSs
This study and the parallel one (Rajan 2000) show
(from effects seen in OC
ears) that noise can exert a cochlear effect
that exacerbates loud tone-induced TTSs. This was greatest (Fig.
3E) when noise was concurrent with loud tone (Rajan
2000
), and then tone-induced TTSs were exacerbated at
frequencies on either side of the peak tone-affected frequency, by
greater amounts on the high-frequency side than at lower frequencies.
With delays between noise and tone (this study), this effect only
occurred at frequencies higher than the peak tone-affected frequency
and declined rapidly with delay, being absent for delay
200 s. Noise
itself did not cause TTSs in this or the parallel study (except
inconsistently, here, at one variable frequency in 6 of 40 ears).
Using free-field conditions, Kujawa and Liberman (1997)
found, in OC
ears, long-term conditioning over many days with
low-level narrowband noise elevated PTSs to subsequent trauma of the
same noise at a high-level, compared with PTSs in unconditioned
trauma-alone ears. This occurred at frequencies higher than the
exposure band (cf. Fig. 6A in Kujawa and Liberman 1997
)
and is equivalent to the effect here despite different exposure
laterality conditions (free-field/binaural vs. the present monaural
condition). Kujawa and Liberman report their exacerbative effects in
OC
ears (ears effectively monaural with respect to centrifugal
influences). For the unprimed monaural tone-only exposure here
(Rajan 2000
), OC
ears are equivalent to OC+ ears and
TTSs are similar. Hence comparison of primed OC
ears here to either
OC+ or OC
unprimed monaural-exposure ears would show priming has
"pure cochlear" deleterious effects on TTSs. Thus this exacerbative
effect appears to occur whether traumata cause TTSs (present study) or
PTSs (Kujawa and Liberman 1997
) and despite differences
in spectra of conditioner/primer and later loud sound and time course
of conditioning. Exacerbative effects of conditioning on PTSs and
morphological damage caused by terminal trauma were also reported
(Subramaniam et al. 1993
) with long-term free-field
low-frequency conditioning followed by higher-frequency terminal trauma
but not (Campo et al. 1991
) when conditioner and
terminal trauma had the same frequency content. The former study has
some analogy here in that different sounds were used for conditioning
and terminal trauma. However, given the broadband primer here included
the terminal trauma frequency and that Kujawa and Liberman
(1997)
found exacerbative effects when conditioner and primer
were identical, a difference in exact frequency content of primer and
terminal loud tone is unlikely to be relevant in exacerbative primer
effects here. The mechanism of such prolonged exacerbative effects of a
nontraumatic primer remains to be elucidated (Rajan
2000
).
Efferent components involved in priming effects on TTSs
Priming elicited complex OC end effects on TTSs, and both UOC and
COC pathways could modulate TTSs for priming delays <600 s. These
effects will be treated as a continuum from effects seen when monaural
noise was concurrent with monaural loud tone (Rajan 2000). It is likely that OC effects here are due to only to MOC efferents. The COC pathway consists almost exclusively of the CMOCS,
and therefore this system must mediate COC pathway effects here. UOC
pathways consist of the UMOCS terminating on OHCs, and the LOCS
terminating on dendrites of afferent neurons. TTSs measured 5 min
postexposure (as here) appear due to only OHC effects (Patuzzi et al. 1989
). UOC effects on TTSs here must therefore be
exercised at OHCs, implying they are exercised specifically through the UMOCS component. It is also difficult to see how LOCS actions at
afferent dendrites could reduce TTSs (this study) or prevent noise from
exacerbating loud-tone-induced TTSs (Rajan 2000
).
Support for attributing TTS-modulating effects of UOC pathways to the UMOCS comes from the observation (with 5-s priming delay) that the
CMOCS blocked a protective effect of UOC pathways. The selective lesion
that revealed this effect interrupted only CMOCS fibers along their
course at some distance from the cell bodies and therefore would not
prevent interactions between UOC and COC systems at the cell bodies. A
blocking effect at the latter level should still have been present when
only the COC pathway was lesioned. Since this was not the case, the
CMOCS must block protective UOC effects at the cochlea, suggesting that
these CMOCS and UOC effects are exercised at the same site, namely
OHCs. For these reasons, UOC effects seen here will be attributed to
the UMOCS.
Priming and UMOCS modulation of TTSs
When monaural noise and tone were concurrent (Rajan
2000), only UOC pathways exercised effects and prevented noise
exacerbation of TTSs but did not reduce TTSs below those to tone alone.
It was concluded (Rajan 2000
) that UMOCS acts on the
mechanism whereby noise exacerbates tone-induced TTSs rather than the
mechanism(s) whereby sound causes TTSs. With priming, UOC pathways can
act on the TTS mechanism(s) and reduce or exacerbate TTSs compared with
tone-alone TTSs.
For short priming delays when noise had a persistent, decreasing,
exacerbative effect on tone-induced TTSs, the UMOCS could prevent this
noise effect. However, with a very short priming delay of 5 s,
this UMOCS effect was blocked by the CMOCS and was observed only after
COC pathway lesion. With a longer delay of 80 s, this UMOCS effect
was present; further the UMOCS worked with the CMOCS to reduce TTSs to
below those to a monaural unprimed loud tone. For longer priming
delays, at which the noise exacerbative effect was absent, the UMOCS
only increased tone-induced TTSs with the proportion of
animals so affected decreasing with delay (200 s: 5/5; 300 s: 5/6;
400 s: 4/7). (Although 300-s delay was not tested with selective
de-efferentation, testing with 200- and 400-s delays suggested that for
delays >80 s, TTS exacerbation was likely due to UOC pathways alone.)
This difference is unlikely to be due to two different UMOCS actions on
OHCs. OHCs possess nicotinic- and muscarinic-type ACh receptors (e.g.,
reviews by Guth and Norris 1996; Puel
1995
), but both cause OHC hyperpolarization (albeit on
different time scales) and MOCS effects at the cochlea are relatively
stereotyped (reviews by Guinan 1988
; Weiderhold 1986
). The most likely hypothesis is that with respect to TTSs, the UMOCS exerted only one action "designed" to work against the mechanism whereby noise exacerbates tone-induced TTSs. For the 15-min-long noise and loud tones of the parallel (Rajan
2000
) and present studies, this noise exacerbation is present
only for delays
80 s. For delays <80 s, UMOCS effects only prevent
the noise exacerbative effect rather than modulate tone-induced TTSs. The 80-s priming delay represents a "cross-over" point where noise exacerbation of TTSs is present but weak, and UMOCS actually reduces tone-induced TTSs. [Note that with concurrent noise + loud tone (Rajan 2000
), the UMOCS effect is strong and prevents
noise exacerbation of TTSs by
25 dB (at 20-22 kHz). As noise
exacerbation waned, the same strong UMOCS action may reduce pure
tone-induced TTSs. This would account for the fact that with 80-s
priming delay, where noise exacerbation of TTSs was small the UMOCS
contributed with the CMOCS to significant reduction in TTSs in OC+
ears.]
To account for effects at priming delay 200 s, it is postulated that
when the same UMOCS action occurs in the total absence of
the mechanism whereby noise exacerbates tone-induced TTSs, it
exacerbates TTSs and is the sole UMOCS effect at priming delay
200 s.
This persists to
400-s delay, and even in the protected OC+ subgroup
at this delay, the UMOCS may have been exacerbating TTSs (Fig.
5D2). TTS exacerbation by UOC pathways has been reported to
tone-alone exposure (Rajan 2001
) in animals with a
chronic partial hearing loss in one ear. There, as here, when there is no noise effect on tone-induced TTSs, UOC pathways when activated can
exacerbate TTSs (Rajan 2001
). As in that study, however,
the mechanism of such action is unknown.
Priming and CMOCS effects at the cochlea
CMOCS effects on TTSs occurred with delays between monaural noise
primer and loud tone (this study) but not when monaural noise and tone
were concurrent (Rajan 2000), suggesting the primer may
cause a slow "build-up" effect (likely facilitatory) in CMOCS cell
bodies, allowing a later loud tone to activate them. Alternatively, when UMOCS end effects are dominant (as with concurrent noise and
tone), they may block potential CMOCS end effects. A blocking interaction was seen between end effects of the MOC systems with 5-s
delay (though then it was the CMOCS blocking UMOCS end effects on
TTSs). Further, with 400-s delay, in the protected OC+ subgroup, it
appeared possible that CMOCS action blocked a UMOCS exacerbative effect
and, further, reduced TTSs. Such interaction may be produced through
presynaptically located (on MOCS efferents) muscarinic-type receptors
(Bartolami et al. 1993
) suggested to function as
autoreceptors that may decrease ACh release from presynaptic elements.
These receptors may also be used by one MOCS component to modulate the other component. It is not yet possible to directly confirm such interactions between the two MOCS systems because it is not possible yet to selectively block (either surgically with lesions, or
pharmacologically at the cochlea) the UMOCS without affecting the CMOCS.
These putative blocking interactions may account for "oscillations" in occurrence of CMOCS protection. With a very short delay of 5 s, the COC pathway blocked, either by effects exercised on to UOC efferents or through an end-effect that directly exacerbated TTSs, a UMOCS effect that would have prevented noise exacerbation of tone-induced TTSs. Thereafter any CMOCS effects were protective and appeared exerted directly on the mechanism whereby sound causes TTSs, reducing TTSs below those to monaural unprimed loud tone. This effect appeared to oscillate, being relatively small with 80-s delay, absent for 200-s delay, and present thereafter in increasing proportion of animals (likely 1/6 for 300 s and 3/7 for 400 s). These oscillations may not have been due to waning of a dominant UMOCS end effect on TTSs. For the protected OC+ subgroup at 400-s delay, CMOCS protection may have occurred in the presence of a strong UMOCS exacerbative end effect on TTSs, equal to that with 200-s delay when only UMOCS effects occurred without any CMOCS protection. One explanation is that the UMOCS exercised an end effect on TTSs and a separate blocking effect on the CMOCS. For 200-s delay, both effects were present, and therefore the only OC effects on TTSs were UMOCS effects. Thereafter the UMOCS blocking effect on CMOCS may have waned (without any change in UMOCS exacerbative end effect on TTSs). Thus as the CMOCS was released from UMOCS block, it exerted protective effects in 1/6 cases with 300-s delay and 3/7 cases with 400-s delay. I will present evidence in a report in preparation that the UMOCS can block a CMOCS effect.
Finally, as noted in the preceding text, in the protected OC+ subgroup
at 400-s delay the UMOCS may have been exercising an exacerbative
effect as in the exacerbated subgroup. Then in the protected OC+
subgroup, CMOCS protection may not have been just the protection
(maximally 18 dB) due to all-OC effects (Fig. 5D2)
because the CMOCS would have to also negate the UMOCS exacerbative effect. When CMOCS protection was calculated, as in all other cases,
from differences between COC
and OC+ data (Fig. 5D2), it
did appear to exert a much larger protection of almost 25 dB, as large
as the largest protection seen with CMOCS action to binaural (unprimed)
tone (Rajan 1995b
, 1996b
, 2000
).
Mechanism of action of OC pathways to modulate TTSs
With respect to protection, the UMOCS and CMOCS may act on one
(the same) locus/process contributing to the overall TTS after loud
sound. This is suggested by the fact that for delays from 80 to
400 s, all protected OC+ cases showed similar TTSs even though
protection at 80-s delay was due to both UMOCS and CMOCS, whereas at
400 s was due to only the CMOCS. These protected TTSs were similar
to TTSs (Rajan 2000) to binaural (unprimed) tone-alone exposure, when only CMOCS protects. Recent studies (Dallos et al. 1997
; Ota and Dolan 2000
; Reiter and
Liberman 1995
; Sridhar et al. 1995
) show that,
additional to well-described fast cochlear effects of (M)OC pathway
stimulation, a slow effect is exercised through
Ca2+-dependent mechanisms in OHCs. The latter has
been suggested (Reiter and Liberman 1995
; Sridhar
et al. 1995
) to be causally related to CMOCS protection from
TTSs, but this is inconsistent with two observations. First, although
such slow effects occur in vitro in OHCs from different cochlear
regions (Dallos et al. 1997
), in vivo they are
negligible or absent at frequencies
10 kHz (Ota and Dolan
2000
; Reiter and Liberman 1995
; Sridhar
et al. 1995
). CMOCS protection from TTSs occurs for all tone
exposures from 3 to 20 kHz (in a complex manner detailed in
Rajan 1995b
). Second, the slow effect declines with
maintained MOC electrical stimulation (Sridhar et al.
1995
) and is almost totally absent by the end of 5 min
stimulation (Reiter and Liberman 1995
). This differs from sound-evoked CMOCS protection both in regard to absolute duration
required for protection to occur and trend of protection with
increasing duration. For pure tone-induced TTSs, CMOCS protection was
present for 3-, 7-, or 20-kHz-loud exposures for 10-40 min (depending
on frequency) but not shorter duration (Rajan 1995b
). For 11-, 15-, and 20-kHz exposures (Rajan 1995b
), CMOCS
protection increased with exposure duration from 7 to 10 min (11 and 15 kHz) or 10 to 15 min (20 kHz). These data make it questionable whether the slow MOCS effect is involved in TTS-reducing CMOCS effects. No
other plausible explanation is evident for this CMOCS action, or
TTS-reducing UMOCS effects (present study), or TTS-exacerbating UMOCS
effects (Rajan 2001
; present study). However, the
present results add weight to the hypothesis (Rajan
2001
) that UMOCS and CMOCS can exert different effects at the
one cochlear locus, the OHCs, because the former could exert
exacerbative effects not seen with the latter.
Priming and activation of UMOCS fibers
This study and the parallel one (Rajan 2000) show
that UOC pathways (presumed UMOCS) can modulate TTSs when noise and
loud tone (concurrent or consecutive) are in their projection ear
alone. This challenges the view that UOC neurons (most likely UMOCS
neurons) are driven by the ear other than that to which they project
(Liberman and Brown 1986
) and facilitated by noise in
the projection ear (Brown et al. 1998
; Liberman
1988
). Liberman (1988)
has described prolonged
facilitatory aftereffects, outlasting the stimulation period, of noise
on single efferent neural responses to tones. Such effects have
correspondence to the present effects, but linkages have to be made
cautiously. In Liberman's study, aftereffects (as opposed to
within-stimulation period effects) were reported to occur only when
noise was at high levels, particularly levels causing TTSs, whereas I
report OC effects with priming noise that did not cause TTSs. Second,
aftereffects in Liberman's study may not have occurred at frequency
ranges under study here. Liberman did not report on a relationship
between prolonged aftereffects and characteristic frequency (CF) of
efferent neurons. However, for within-stimulation period effects,
Liberman (1988)
reported that only very high CF efferent
neurons were facilitated by noise in the same ear as tones to which the
neuron responded, and Fig. 9 of Liberman (1988)
suggests
this occurs for neurons with CF >20 kHz. In the present study,
efferent aftereffects with the primer noise + later tone condition in
the same ear were seen at lower (CAP) frequencies. Nevertheless effects
such as those described by Liberman must play a role in effects in this study.
Comparison to other studies of conditioning
Previous studies of conditioning stereotypically found protection
from damage caused by a terminal trauma (e.g., Campo et al.
1991; Canlon 1996
; Canlon et al.
1988
; Kujawa and Liberman 1997
; Miyakita
et al. 1992
; Ryan et al. 1994
;
Subramaniam et al. 1996
; Zheng et al.
1997b
). Methodological differences between the present study
and these studies [using free-field (binaural) sounds, long-term
(i.e., many repeated) conditioning sessions] qualify direct
comparisons. Furthermore this study used terminal trauma causing TTSs,
whereas previous studies used trauma causing PTSs and/or morphological
damage, and PTSs have been suggested (Liberman et al.
1986
) to be due to different mechanisms than TTSs
(Patuzzi 1992
; Patuzzi et al. 1989
).
Finally the present study was carried out with priming under deep
anesthesia unlike long-term conditioning studies, and this may also
have implications for expression of conditioning-related protection.
Nevertheless, some effects in this study (the first to systematically
examine effects of a wide range of delays between conditioner/primer and trauma) also appear to occur for PTSs with conditioning. TTSs could
be exacerbated by priming, as also appears to occur for PTSs with
conditioning (Kujawa and Liberman 1997). Furthermore there are suggestions, for some sounds, that protective or exacerbative effects may occur at different delays after long-term conditioning. Long-term free-field conditioning with octave-band noise at 4 kHz
reduced PTSs and morphological damage when the terminal same-frequency trauma was 18 h after the last conditioner but exacerbated PTSs and morphological damage when the trauma was 5 days postconditioning (Subramaniam et al. 1996
). Given these points of
concurrence, the present study makes it imperative for a detailed time
course study to be carried out with long-term conditioning before it can be stated definitively that conditioning provides a valuable tool
for ameliorating hearing damage. Because long-term conditioning studies
have used repeated conditioning sessions over days/weeks, this
time-scale postconditioner may be needed for equivalence to the present
study using a single 15-min-long primer and delays
10 min postprimer.
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ACKNOWLEDGMENTS |
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This work was supported by National Health and Medical Research Council of Australia Grant 970505.
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FOOTNOTES |
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Author E-mail: ramesh.rajan{at}med.monash.edu.au
Received 27 March 2001; accepted in final form 22 May 2001.
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REFERENCES |
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