Response of cochlear nucleus neurons in the unanesthetized cat to slowly repeated tones

EXPERIMENTAL

NEUROLOGY

66, 64-77 (1979)

Response of Cochlear Nucleus Neurons Unanesthetized Cat to Slowly Repeated

in the Tones

Department of Physiology and Mental Retardation Research Center, Brain Research Institute, University of California, Los Angeles, California 90024 Received March 30, 1979 Extracellular unit recordings were made in the cochlear nucleus of adult decerebrate cats. The responses of 43 units were studied during 206 repetitive tone sequences; each sequence consisted of 25 trials with tone durations and intertone intervals from 1 to 9 s. Control responses were obtained before and after the tone sequences. Many sequences produced response decrements of 25 to 35%; decrements of more than 40% developed during continuous tone stimulation. Decrements were most marked during the initial 5 to 10 trials and approached asymptote thereafter. Spontaneous recovery occurred within the first 10 s and was generally complete by 30 to 40 s. The rate of recovery was not influenced by stimulation beyond asymptote. Significant positive correlations existed between magnitude of decrement and response latency and interspike intervals of the initial four spikes of the response. A weak negative correlation existed between magnitude of decrement and spontaneous activity. Constant-latency units (0.2 ms standard deviation in 10 control trials) did not show onset response decrements but did show decrements in the remainder of their response. Upits with more variable latencies showed decrements in both early and late response components.

INTRODUCTION The following experiments were carried out to extend earlier observations on acoustic response modification as a function of stimulus 1 This work was supported by U.S. Public Health Service research grants NS-05437, MH-24344, and HD-05958. Dr Huang’s present address is Department of Physiology, College of Medicine, University of South Alabama, Mobile, AL 36688. The authors wish to express appreciation to Dr. Don Guthrie, Computer Resources Center, Mental Retardation Research Center, at UCLA for his assistance in the statistical analysis of the data. Support for this component of the MRRC is provided by USPHS grant HD-04612. Computations were carried out at the UCLA Health Sciences Computer Facility. 64 0014-4886/79/100064-14$02.00/O Copyright All rights

Q 1979 by Academic Press, Inc. of reproduction in any form reserved

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experience (6,33,38). Acoustic habituation sequences with relatively long tone-on, tone-off times, (i.e., on the order of seconds), in which behavioral response decrements developed (2, 11, 28), were previously utilized for studies of response plasticity in the cochlear nucleus (7, 17,20,23). Those experiments showed that progressive, reversible, multiple-unit response decrements developed in the cochlear nucleus of unanesthetized cats. However, the complex nature of the multiple-unit responses precluded any conclusions regarding single neurons. Although there have been studies of single auditory nerve fibers during repetitive acoustic stimulation (22, 3 1, 39), these experiments utilized tone-on, tone-off times on the order of milliseconds. Studies of single neurons in the cochlear nucleus and the superior olivary complex which utilized long (e.g. 10 s)-duration acoustic stimuli investigated adaptive changes during the stimulus period (15, 16) but did not investigate the effects of repeated presentations of the stimulus. The purpose of the present study, therefore, was to determine effects of repetitive stimulus trials on cochlear nucleus neurons with stimulus on and off durations on the order of seconds. An electrophysiologic profile of spontaneous activity, response latency, and response interspike interval, established for each cell, was used to determine whether any electrophysiologic parameters correlated with the effects of stimulus repetition. The term “habituation” is used only in relation to stimulation procedures which have been reported to produce behavioral responses decrements. METHODS Adult cats were anesthetized with a mixture of N20, 02, and methoxyflurane. Tracheal and venous cannulae were installed. The animal was placed in a stereotaxic frame with hollow ear bars. After bilateral exposure of the occipital cortex, decerebration was carried out by aspiration of the cortex and subsequent brain stem transection at the midcollicular level. The posterior fossa was opened, the cerebellum immediately overlying the cochlear nucleus was aspirated, and the cochlear nucleus was exposed with magnification provided through a Leitz surgical microscope. Anesthesia was terminated and the animal was paralyzed with Flaxedil(l0 mg/kg i.v. initial dose, 5 mg/kg/h thereafter) and artificially respired. These procedures have been described in detail elsewhere (7, 9). Glass pipets filled with 1 M potassium citrate with impedances of 30 to 60 Ma (re 1 kHz) were used for recording. Initial positioning of the electrode over the cochlear nucleus was made under magnified visual guidance; subsequently the electrode was advanced by a micromanipulator. Activity was amplified at 100 to 1000 x gain, filtered at 300 Hz to 3 kHz -e3 dB, and

66

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recorded on a Honeywell tape recorder (Model 5600) FM channel at 3.75 in. per second. Typical spike.amplitudes were between 2 and 10 mV. Both spontaneous firing rate and response to test tones were monitored by an on-line spike counter to rule out the possibility of cell injury; an isolated cell could usually be held for 30 min to 2 h without significant changes in its firing patterns. Recordings were carried out in an Industrial Acoustic chamber. The ambient noise level in the chamber was less than 40 dB (0 dB = 0.0002 dyn/cm*) as measured by a General Radio sound level meter (Model 1565A, B filter setting). Acoustic stimuli were generated by a Wavetek (Model 112) function generator. In all repetitive stimulation sequences, a single moderate intensity of 70 dB SPL was used. Monaural stimuli were delivered to the ipsilateral ear by a Bruel and Kjaer (Model 4144) condenser microphone biased at 200 V DC (26). The microphone was connected to the hollow ear bar inserted into the external acoustic meatus. The condenser microphone-hollow ear bar output was precalibrated for each frequency with a second condenser microphone attached to the central end of the ear bar through a 2 cc coupler. An electronic switch was not used to shape the stimulus envelope at tone onset (or offset) because the waveform of the speaker output did not contain a significant click component. The amount of voltage increase at onset was approximately 15% of the sustained voltage, calculated as 20 log (1.15) = 1.2 dB above the intensity of the sustained voltage (19). As the electrode was lowered, wide band clicks were delivered at a rate of 2/s as search stimuli. After a unit was isolated, the following protocol was carried out. (i) Best response frequency was determined. (ii) One thousand spontaneous action potentials were recorded in the absence of any acoustic stimuli. (iii) Several tone frequencies (always including the best frequency) which produced a response at least two times greater than the spontaneous firing rate were selected. (iv) Five control test tones, each with a duration of 1 s, were presented at 10-s intervals (previously determined to cause no response change), and the number of action potentials in each response was’ counted. (v) Twenty-five responses were recorded during repetitive stimulation with a preselected combination of tone-on and tone-off times (in the case of continuous tone stimulation, a l-s count of spike discharges was made every second for 25 s). (vi) At least five responses were recorded following repetitive stimulation to the control l-s tone presented at 10-s intervals. (vii) Procedures (iv) to (vi) were repeated with different combinations of tone duration and intertone interval for the repetitive stimulation sequence. The recording was terminated immediately if the neuron showed irreversible change in either the ongoing firing rate or in the response level to the test tones.

COCHLEAR

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67

UNITS

In addition to on-line monitoring of the spontaneous firing rate and control response rates, changes in firing patterns during the tone sequence were analyzed off-line by a DEC PDP 11/40 computer. Each stimulation sequence was analyzed on a trial-by-trial basis. The total number of spikes was counted in response to each tone. The single-unit discharges for the entire stimulation sequence including the control tones were analyzed by computing Kendall rank correlation coefficients to determine whether or not a significant response decrement had occurred. These data were also subjected to regression analyses, using linear, polynomial, and exponential curves to test for best fit. A five-term polynomial curve showed the best fit and was used for all the regression analyses to be discussed. The amount of change in unit responses was expressed as the percentage change in the fitted curve projected from a polynomial regression analysis of the 25 trials. Each unit was also characterized by an electrophysiologic profile which consisted of the following: spontaneous firing rate (f), response latency (to), interval between the first and second action potentials of the response (tJ, interval between the second and third action potentials ( tJ, and interval between the third and fourth action potentials (t3). For-f, 1000 spontaneous action potentials were recorded and averaged as spikes per second. To obtain the value to as well as t 1, tz, and f3, measurements were made on the TABLE

1

Significance of Response Decrements Habituation

Percentage of sequences showing response decrements”

procedure

2%Trial sequences (NJ

Tone-on (s)

Tone-off (s)

Duty cycle (%)

P < 0.05

P < 0.01

9 5 9 13 9 42 8 8 7 7 89

1.0 1.5 1.0 0.5 2.0 1.0 1.5 2.5 3.5 8.5 25.0

9.0 8.5 4.0 1.5 3.0 1.0 1.5 1.5 1.5 1.5 -

10 15 20 25 40 50 50 63 70 85 100

22 40 33 46 33 88 50 88 71 43 83

40 22 15 33 81 50 63 29 43 73

0

” Data based on Kendall rank correlation within each 25-trial sequence between trial number and spikes per trial. Only those habituation procedures with five or more 2%trial sequences are shown.

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unit’s 10 control responses. The latency and interval data were obtained from oscilloscope photographs of the unit firing pattern near the tone onset. These resultant latency and interval measurements were averaged and the mean and standard deviation computed. Possible relations between the effects of repetitive stimulation and a unit’s electrophysiologic profile were next examined. The data,f, to,tl, tz, fB, were used in a Pearson matrix to correlate with the magnitude of the response decrement during repetitive stimulation. Precise localization of units was not possible although visualization of the glass pipet as it entered the nucleus allowed a gross estimate as to whether it was anterior or posterior in the structure. In three animals the glass pipets were withdrawn, a stainless-steel electrode was stereotaxically lowered to the same target locus, and current passed to provide a blue dot (Gamori reaction) for localization of the subdivisions of the cochlear nucleus that the electrode track traversed. RESULTS Significance

of Response Decrements

Habituation Sequences. The responses of 43 cochlear nucleus units were studied during 206 habituation sequences; each sequence consisted of 25 trials of a particular tone-on, tone-off procedure. These data are presented in Table 1 with the habituation procedures ordered with respect to the “stimulus duty cycle,” defined as the ratio of (tone-on time): (tone-on time + tone-off time). To test for the effect of successive trials on the response of the unit, Kendall rank correlation coefficients were computed for trial number and spikes per response. Correlations which were negative indicated that the spikes per response decreased as a function of successive trials. In only 3 of the 206 cases was there a significant positive correlation between trial number and spikes per response, i.e., a significant response increment. Table 1 also shows that the percentage of sequences with response decrements at the P < 0.01 and co.05 levels of significance increased as the stimulus duty cycle increased. Thus the stimulus sequences with larger duty cycle values were more likely to produce significant response decrements. The most data were obtained with duty cycles of 50 and 100%; in no case was the tone-off time less than 1 s (except for the continuous tone). Thus, the significant response decrements which developed indicate that the effects of a prior acoustic stimulus can extend for one to several seconds of tone-off time. Control Runs. In 61 cases in which there were at least 10 test tones both before and after the tone sequences, responses to these test tones were

COCHLEAR

NUCLEUS TABLE

69

UNITS

2

Degree of Decrement in Response of Units in Various Habituation Habituation Cochlear nucleus units 0’)

Tone-on (s)

7 2 4 2 7

Procedures

procedure

Tone-off (s)

Duty cycle (%I

Percent decrement in response0

1.0 1.5 1.5 1.5 -

50 62.5 70 85 100

33.9 35 31 42 47.7

1.0 2.5 3.5 8.5 30.0

a Data are based on regression analysis of spikes per response during each 25-trial sequence. Only sequences showing decrements at the 0.05 to 0.01 significance level without comparable changes in the before- and after-control responses were averaged. Repeated control-habituation sequences for any unit at any duty cycle value are represented by a single average, i.e., no weighting is given to units with multiple runs.

analzyed in detail. The control responses after the habituation sequence were compared with those before the sequence by a one-sided t test to determine if the response level had significantly changed. Forty-two of sixty-one habituation sequences showed no significant change in control response. These results, summarized in Table 2, indicated that a significant TABLE

3

Amount of Response Decrement Correlated with Unit’s Electrophysiologic Response Latency Duty cycle

Interval

I

characteristtcs Interval

SD(b)

UJ

SD(b)

U*)

0.7475

0.7817



0.7457

0.7535

0.7576

0.7617





100%~ PGUSOll correlation coefficient Significance level (P)

10.0168

0.2717

0.2833 ~0.0125

0.2986 ~0.0098

Spontaneous firing mte

2

(to)

50%” PG3lXTl correlation coefficient Significance level (PI

Profile

SD(h)

U)

SW)

0.7075

0.3767

-0.4657

-0. II62

~0.0001

CO.0197

<0.0032

co.4872

-0.2980

-0.1391

<0.0076

<0.2216

0.2304

0.2%7

0.2969

0.2742

<0.0483

<0.0103

<0.0102

<0.0181

0.1242 co.2918

q Correlations made for all units run in a 50% duty cycle sequence of I s tone-on. I s tone-off. A total of 38 habituation sequences from I4 units is included m the correlation. o Correlations made for all units run in a 100% cuty cycle sequence of 30-s continuous tone with response measured at l-s mtervals for 25 s. A total of 77 habituation sequences from 24 umts IS included in the correlation.

70

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decrement in the response of a cochlear nucleus neuron as a function stimulus experience was reversible through spontaneous recovery. Amount

of

of Response Decrement

The method of least squares was used to fit the habituation data to linear, exponential, and other models. The best fits were obtained with a five-term polynomial. In the analysis, the initial and final levels of the curve best fitting the 25 successive responses were used as the “initial” and “final” responses. The amount of decrement was then expressed as 1 - (final/initial). A summary of the amount of response decrement produced by 22 units in several different habituation sequences is presented in Table 2 which includes only runs followed by complete recovery. As indicated in Table 2, decrements at the 30 to 40% level consistently occurred across tone-off times of 1.0 to 1.5 s. The responses during continuous tone stimulation, successively measured for 1 s periods for 25 s, showed decrements which were greater than any of those in the intermittent sequences. Correlation

between Response Decrement Electrophysiologic ProJite

and Unit

For the habituation procedure of 1 s tone-on, 1 s tone-off, positive correlation coefficients were found between the magnitude of response decrement and the response latency (to), as well as with the standard deviation of latency, SD (to), i.e., the more variable the latency the greater the decrement (Table 3). Positive correlations also existed between magnitude of decrement and the intervals between the first four spikes following the stimulus (ti, t2, t3). A weak negative correlation was indicated between spontaneous activity and amount of response decrement, i.e., large decrements were weakly correlated with low discharge rates. A comparable analysis for the continuous-tone data indicated little correlation between the electrophysiologic profile and the response decrement. The high correlation coefficients in the 50% duty cycle data may primarily reflect the unit’s capacity for rapid recovery, a process obscured in the continuous stimulation sequences. Onset vs. Sustained

Components

Response Decrement. To compare effects on onset versus sustained unit response components, spikes were counted for the entire period of each response, the initial 100 ms, the initial 50 ms, the initial 20 ms, and the initial IO ms. The unit in Fig. 1 showed clear decrement in total response and in the 0- to lOO-ms response component. Less marked were decrements in the

COCHLEAR

NUCLEUS

71

UNITS

1251

,

r-.

.

‘.

4’

ci

lo--__** ___.-*

.__

___-_--.

--/ ./’

0 ./

CN UNIT 27Y LATENCY 3.0 +_0.2msec ONGOING LEVEL 2/5.x -15 SC (lotolrssponse) ---, -_ mrec : I-a-, 04

15

10

TRIALS

15

(l/3

20

set)

25

1

2

RECOVERY

3

(l/l0

4

set)

FIG. 1. Responses of a constant-latency cochlear nucleus unit to 1.5 s tones repeated at 3 s intervals for 25 trials and to subsequent control tones repeated every 10 s. Response components are plotted for the initial 10,20,.50, and 100 ms of the response as well as for the total response period of 1.5 s. All values are presented in terms of percentage of mean control response level. Note that the total response showed a marked decrement even though the onset response component (0 to 10 ms) showed no change.

initial 50 ms, and the first 10 ms response component showed no change. At the end of the habituation sequence, all components recovered to control values. The absence of decrement in the first 10 ms was typical of units with constant response latencies, i.e., less than 0.2 ms standard deviation in 10 latency measurements. Figure 2 illustrates the discharge pattern of such a constant-latency unit with no change in onset response but marked decrements in the later part of the response. In Fig. 3, the same kind of data are graphed for another unit. The course and magnitude of decrement for the total response were similar to those illustrated in Fig. 1. However, in this case, the initial response component also decreased. Units showing this kind of onset response decrement were variable in latency, as illustrated in Fig.4 . The constant-latency cells showed features of primary, chopper, and pauser units which have been described for the cochlear nucleus (4). None showed an onset response alone, without a sustained response component.

72

HUANG

AND BUCHWALD

CN UNIT TRIAL

NO.

II

12

21

22

IOmV IO msec

FIG. 2. Traces of a constant-latency unit during trials of a 1.5 s tone-on, 1.5 s tone-off habituation sequence. Note that the later portion of the response changed markedly whereas the onset response remained constant.

The variable-latency units resembled build-up type cells. Thus, it is possible that all cell types in the cochlear nucleus may have shown response decrements during the kinds of sequences used in this study. Spontaneous Recovery. Spontaneous recovery was shown by most

COCHLEAR

NUCLEUS

73

UNITS

.

.

.

.

CN UNIT 14G LATENCY 3-12 msec ONGOING LEVEL I&c 0 -1 5 5ec (1OlOl reswnse) ---- O-50 msec -O-20msec * O-10 msec

.-*-,-* “f-

5

--(a10

15

TRIALS

cp-.~~-c.-.-(-.-.-.-.-20

60

, , 65

(l/3 set)

70

1

, , , , , , 10

RECOVERY (l/l0 set)

FIG. 3. Responses of a variable-latency unit to 1.5 s tones repeated at 3 s intervals. Responses were recorded beyond 25 trials to determine the asymptote. Response components plotted as in Fig. 1. Note that the initial 10 ms of the response, as well as all other response components, decreased markedly during the first 25 trials, with the steepest decrements within the initial 10 trials.

units. Rapid recovery occurred within the first 10 s after cessation of the habituation sequence and was usually complete by 30 to 40 s (Figs. 1, 3). The duration of the recovery process was related to the amount of response decrement and occurred more rapidly when the amount of decrement was small. When the stimulation sequence was extended to 70 trials, little additional decrement developed nor was the rate of recovery extended (Fig. 3). DISCUSSION These data indicate that responses of cochlear nucleus cells are modified as a function of repeated experience with a moderate-intensity tonal stimulus across tone-off periods extending to 8 s. In the unanesthetized, paralyzed preparation, such decrements are not simply reflections of habituated ear muscle reflexes or alterations in other motor systems (30). Possible influences of recurrent auditory projections from forebrain levels (33-35) were deleted by the midcollicular decerebration. Thus, indepen-

74

HUANG

AND

BUCHWALD

CN UNIT TRIAL

NO.

21

IOmV

20

mssc

FIG. 4. Traces of a variable-latency unit during trials of a 1.5 s tone-on, 1.5 s tone-off habituation sequence. Note that the initial as well as the late components of the response changed.

dent of muscle reflexes and descending forebrain projections, single cells in the cochlear nucleus show response decrements during relatively slow tone repetition sequences. In earlier studies of multiple-unit activity in the cochlear nucleus, similar reversible response decrements were shown to develop in the paralyzed

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75

decerebrate cat (7, 20). In those studies, decrements occurred: in the absence of change in the cochlear microphonic potentials, suggesting absence of hair cell adaptation (1, 10, 25, 36, 37); after injections of strychnine to block olivocochlear inhibition of hair cell activity (12); and in the cochlear nucleus that was surgically separated, i.e., isolated, from the medial brain stem (3). Thus, mechanisms intrinsic to the auditory nerve-cochlear nucleus complex were considered the most likely source of the decrements in the multiple-unit studies, an interpretation which also seems relevant to the present study on single units. Although there was no decrement in the “on” response of the constant-latency cells sampled, when the response during the entire stimulus period was analyzed across repetitive stimulus trials it is significant that most units in the present study showed a response decrement, a result which extends previous multiple-unit response decrement data (7,20). Other studies have indicated that evoked potentials in the cochlear nucleus and the acoustic nerve show no response decrement at stimulus rates comparable to or faster than those in our procedures (19, 27). If synchronous activation of constant-latency cells produces cochlear nucleus evoked potentials, as suggested by other studies (8, 13, 14, 18,21, 24, 29), the lack of “on” response decrement in the constant-latency units could explain the absence of decrement in the evoked potentials. Other data suggest that lower levels of the sensory systems may contribute significantly to the elaboration of a variety of adaptive behavior patterns (5, 32). Stimulation procedures similar to ours are effective for behavioral habituation (2, 11, 28). However, behavioral habituation also occurs over longer interstimulus intervals, and spontaneous recovery may require minutes or days (6). Thus, depending on parameters of stimulus duration and rate, neural changes at the level of the cochlear nucleus may relate to some forms of behavioral habituation but have no relation to other more prolonged forms. REFERENCES I. E., AND F. J. GITHLER. 1949. The effects of jet engine noise on the cochlear response of the guinea pig. J. Camp. Neurul. 42: 517-525. ASKEW, H. R. 1969. Effects of stimulus duration and repeated sessions on habituation of the head-shake response in the rat. J. Comp. Physiol. Psychol. 67: 497-503. BROWN, K. A., AND, J. S. BUCHWALD. 1976. Response decrements during repetitive tone stimulation in the surgically isolated cochlear nucleus. Exp. Neural. 53: 663-669. BRUGGE, J. F., AND C. D. GEISLER. 1978. Auditory mechanisms of the lower brainstem. Ann. Rev. Neurosci. 1: 363-394. BUCHWALD. J. S., AND K. A. BROWN. 1977. The role of acoustic inflow in the development of adaptive behavior. Ann. New York AC@. Sci. 290: 270-284. BUCHWALD, J. S., AND G. L. HUMPHREY. 1973. An analysis ofhabituation in the specific sensory systems. Prog. Phpsiol. Psychol. 5: l-75.

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2. 3.

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10. 11. 12.

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