ACTA NEUROBIOL. EXP. 1974, 34: 339-352

Lecture delivered at Symposium "Brain and behavior" held in Jablonna near Warszawa

July 1972

CONDITIONED BLINK REFLE'X AND NEURONAL ACTIVITY IN THE AUDITORY CORTEX OF THE CAT

G. L. VANETSIAN

Institute of Higher Nervous Activity and Neurophysiology Academy of Sciences of the USSR, Moscow, USSR

Abstract. The present study is concerned with conditioned reflex changes in background and evoked activity of the neuranal population of the auditory cortex (AI) in three waking cats. For the elaboration of a conditioned blink reflex, a xr ies of eight clicla was used as the signal. The unconditional stimulus was rhythmic blowing of air at the eye. During the elaboration of a positive conditioned reflex there was a significant increase in the level of background activity. During condi- tioned reflex extinction, background activity showed a further increase. When ex- tinguishing inhibition became profound, it was equivalent to sleep, and there was a strong fall in the level of background activity. During the restoration of an ex- tinguished conditioned reflex, background activity fell to the level observed during conditioned reflex extinction, at the stage of consolidation. Application of an acous- tic stimulus elicited a general, sometimes a slight increase in the number of spike discharges. Within the range of 300-350 msec - the time of appearance of the evoked response - neuronal activity underwent a reorganization, sometimes with a tendency to phasic variations. Phasic variations of the given population in re- sponse to sound were observed at all stages of the study.

INTRODUCTION

An interesting aspect of higher nervous activity is the correlative excitability of cortical s tmctu~es wmbined during the elaboration of a conditioned reflex (CR), in particular the functional state (FS) of the cortical points of the signal stimulus. As known, this question attracted the attention of Pavlov and has been studied by many of his followers, including Asratyan and his co-workers (2, 3, 31). While the data on

changes in FS of the sites of representation of the unconditional stimulus are more or less consistent one with another, the studies of FS of sites of the conditional stimulus have produced ambiguous results. Some believe that the excitability of these sites increases while others think that it decreases. Still others have reported biphasic changes in FS.

The studies concerned with conditioned reflexes a t the cellular level are limited, in must cases, to descriptions of various reorganizations in neu~olnal activity (e.g., 19, 20, 28, 33, 41). Attempts to elucidate the functional significance of these reorganizations involve considerable difficulty. However, there are cogent reasons to believe that the impulse activity of neurons is a more delicate and specific indicator of FS of the central neural structures than other electrophysiologica1 indices (e.g., 5, 17, 20, 33, 40).

The present study is concerned with conditioned reflex changes in background and evoked activity of the neuronal population of the auditory cortex in cats when the acoustic stimulus was assigned a po- sitive or an inhibitory significance. This investigation proceeded from the generally recognized view that the level of background activity (BA) reflects the excitation state of neural structures (e.g., 11, 22, 23, 32-34, 38) as well as from the data on changes in BA and, consequently, in FS of the cortical sites of conditional and unconditional stimuli during the formation of a temporary connection (e.g., 5, 25, 33, 39, 40).

METHODS

Three waking cats were used. The background impulse activity of the cortical neuronal population was studied via chnonically implanted electrcdes, based cn the procedure described by O'Keefe and Bouma (27). Under anesthesia, a bundle of five 50 pm nichrome electrodes was inserted into the auditory cortex. The occurrence of evoked potentials indicated that the electrodes had reached the desired site. The electrodes were rigidly fixed to bone with protacryl. Observations of neurcmal activity were begun on the following day on the alert animal. The observation period varied from several days to several weeks. After the experiment, a morphological control was done which showed that the electrode tips were located in layers 111-IV of the auditory cortex, in its primary projection zone (Fig. 1). The method of preparation and implantation of electrodes for the chronic study of neuronal activity of the cortex and subcortex has been described elsewhere (8).

For the elaboration of a blink CR, a series of eight clicks was used as the conditional stimulus (CS) Clicks, 60 db in intensity, were pre- sented over the threshold of appearance of the primary response at

Fig. 1. Frontal section of the cat's brain a t A-14. Note track of chronically implanted electrodes in the inner

wall of ectosylvian gyrus.

CONDITIONED BLINK REFLEX AND NEURONAL ACTIVITY 341

a frequency of one click per 1.6 sec. The unconditional stimulus (US) was rhythmic blowing of air at the eye, also at the frequency of one puff per 1.6 sec. Blinking was registered electromyographically via steel electrodes implanted subcutaneously in the region of the orbicular muscle of the stimulated eye. At the beginning d CR development puffs were combined with each of the eight clicks, and as the reflex developed the US was separated from the CS by ever longer intervals. When the CR had been elaborated, five clicks were presented alone while the re- maining three clicks of the series coincided with the puffs. The interval between presentations of the combined stimuli varied from 1.5 to 3 min. A total of 10 to 20 combinations were presented per session. In all, two or three sessions were run per day at intervals of 2-3 hr.

The neuronal autivity of a particular population located under a gi- ven electrode, the electromyogram, and the presentation of the acoustic stimulus, were all recmded by means of a universal apparatus UEFI-3 designed at the Central Designing Bureau of the Academy of Sciences of the USSR.

Neuronal activity was recorded simultaneously on film and magnetic tape 2.0-1.5 min prior to presentation of the conditional stimulus and also during the isolated presentation of the latter, i.e., during the blink CR.

The results were processed on ART-100 and SA-40 computers using two programs to calculate the frequency of spikes at consecutive record- ing intervals of 1.6 sec and to obtain the post-stimulation histogram. The threshold of spikes fed to the computer from magnetic tape was con- trolled by means of a discriminator, and the discharges of great and medium magnitude exceeding the noise by 113 or more were registered by counters (Fig. 2).

1 SOJIV lOOm sec

Fig, 2 . Background activity of the neuronal population of cat's auditory cortex for a period of 1 min.

A series of control tests was also run in which a series of clicks (the future CS) was presented without reinforcement for 10-12 times per session at intervals of 1.5-3 min. BA was recorded prior to (for 2-3 min) and after 10-12 series of clicks (for 5-10 min).

2 - A c t a Neurobio logiae E x p e r i m e n t a l i s

33-2 G . L. VANETSIAN

RESULTS AND DISCUSSION

It is convenient first to describe the changes in background neuronal activity which characterize the conditioned state.

Analysis of the results obtained has revealed an increase of spon- taneous activity during the elaboration of the positive CR. Figure 3 shows an instance of compu,ter processing of background activity of a single neuronal populaticn recorded for a period of 80 sec prior to

Fig. 3. Impulse background activity of neuronal population of cat's auditory cortex for 80 sec during elaboration of blink CR (data of multi-channel analyzer). Ordinate, number of spike discharges for 1.6 sec. Abscissa, number of bins. A, background activity; B, C , D, and E. after 10, 20, 30 and 40 combinations, respectively. The

percentage refers to occurrence of CR.

the presentation of the next series of clicks a t different stages of the experiment: A, prior to training, when the stimulus was still "neutral", i.e., 80 sec before presentation of the first click series with reinforcement; and (B, C) during the consecutive stages of establishment of the CR: after every 10 combinations of clicks with unconditional reinforcement (80 sec prior to presentation of the 11th combination; and after 20, 30 and 40 combinations, i.e. before presentation of the 21st, 31st and 41st

CONDITIONED BLINK REFLEX A N D NEURONAL ACTIVITY 343

combinations, respectively). It can be clearly seen that the level of BA progressively increased in the course of formation of the blink CR.

Mter 40 c~mbinatio~ns, when the reflex occurred to 70°/a of the pre- sentations, the level of BA inc~eased nearly threefold compared with the baseline level observed prior to the combinations. In another cat (Fig. 4)

Fig. 4. Impulse background activity of neuronal population of cat's auditory cortex for a period of 80 sec of consolidation of blink CR (data of multi-chalnnel analyzer). Ordinate, number of spike discharges for 1.6 sec; abscissa, number of bins. A, back- ground activity; B, C, D, E and F, after 50, 60, 70, 80, and 140 combinations, res-

pectively. The percentage refers to occurrence of CR.

BA was studied after 50 combinations, and it can be seen that the level of BA after 50 combinations (Fig. 4B) exceeded the initial value also by almost threefold, and continued to increase after 60 and 70 combinations, the reflex occurring 60°/o of the time (Fig. 4CJl). Analysis of the histo- grams shows that the level of BA stabilized in the interval between 80 and 140 combinations, the BA before the 141st cornbinaticm being the same as that before the 81st combination (Fig. 4EF). It should be noted that during that stage of reflex consolidation the percentage of CRs was high - up to 90°/o. The data from oscillograms and computer counters obtained for the three cats indicate a threefold increase of activity following stabilization of the CR compared with the initial value.

344 G . L. VANETSIAN

Following stabilization of the blink CR, an acute intermittent ex- tination was performed in all three cats. Extinction of the effector r e - ponse (absence on five consecutive presentations of the CS) occurred in two cats after 60-70 non-reinforcements of the click series, and in one cat after 50 ncm-reinforcements. As the extinguishing inhibition de- veloped, the spike activity increased further by 40-50°/o over the BA level before extinction. The increase of BA; occurred in two phases: a phase of increased activation accompanied by partial effector res- ponses, followed by a phase d certain reduction of BA, the latter phase occurring when the CR had been completely extinguished. It is note- worthy that the level of BA remained significantly higher than when the CR had been stabilized.

Fig. 5. Impulse background activity of neuronal population of cat's auditory cortex for a period of 96 sec during extinction and restoration of blink CR (data of multi- channel analyzer). Ordinate, number of spike discharges for 1.6 sec; abscissa, number of bins. A, background neuronal activity of the population after 140 combinations a t the stage of consolidated reflex, with 100°/o occurrence of blinking response; B, C, D, E and F, extinction, after 10, 20, 30, 40 and 50 non-reinforcements, respectively: G, H, restoration, after 10 and 30 reinforcements. The percentage refers to occur-

rence of CR.

CONDITIONED BLINK REFLEX AND NEURONAL ACTIVITY 345

Figure 5 shows one example of computer processing of BA during extinction. The BA observed at the stage of consolidated reflex after 140 combinations with khe 100°/o occurrence d the CR (A) (96 sec before presentation of the 141st combination), appreciably increased already after 10 non-reinforcements (B), although the percentage of reflex occurrence remained high. The BA also increased after 20 non-rein- forcements of clicks, when the CR was pantly extinguished (C), blinking in response to clicks occurring only in 5O0/o of the cases. A further in- crease of BA occurred after 30 non-reinforcements, the CR occurring in 30°/o of the cases (D). In the interval between 30-40 non-reinforce- ments, BA remained unchanged, at a high level. After 50 non-rein- forcements (F), when the CR had been completely extinguished, BA de- creased but its level was significantly higher than that at the consoli- dated reflex stage.

In some cases, when extinguishing inhibition was strongly developed and the interval inhibition became equivalent to sleep the level of BA strongly decreased.

The next stage of work consisted in the restoration of an extinguished CR and the recording of BA of the nezlronal population after each 10 series of clicks with reinforcement. The reflex was restored relatively quickly. As soon as after 10 reinforcements, the effector response ocur- red in 50°/u of the cases (Fig. 5G), while after 30 reinforcements i t occurred up to 80°/o of the time (H). During CR restoration, the BA changed in two phases. A phase of increased activation (relative to the level of BA at the extinguished reflex phase) which was observed after the first 10 reinforcements of the CS by the US, was succeeded by a phase of reduced BA. But the level of BA did not differ significantly from that prior to extinction, at the reflex consolidation stage (Fig. 5A).

Analysis of CR changes in evoked activity shows the following. A time interval of 500 msec (with 50 samples) was analyzed in studying evoked neuronal activity and in comparing it with BA preceding the stimulus. Figure 6 will serve as an example; i t shows that neuronal BA under- went the changes refered to above. Presentation of a click caused a ge- neral, sometimes slight increase in the number of spike discharges. In the range of 300-350 rnsec, i.e., the time of occurrence of the evoked response, neuronal activity altered, sometimes showing an obvious ten- dency to phasic variations (Fig. 6 I I A ) . The phase of a short-term in- hibition of neuronal activity was followed by a period of enhanced activity which gradually (by 45-50 msec after stimulus application) attained its maximum. After that, by 100 rnsec, there occurred a second fall of BA which in turn was succeeded by a new more prolonged activation. Phasic variations of this population in response to clicks

346 G . L. VANETSIAN

were observed at all stage of the study: when the clicks were "neutral" (Fig. GIIA), when they became positive (Fig. 61IB) signals, and also during extinction and restoration of the conditioned reflex (Fig. 61ICD). Com-

Fig. 6. Time-course of background (I) and evoked (11) spike activity of neuronal population of cat's auditory cortex during CR activity (data of multi-channel analyzer, post-stimulation histogram). Ordinate, total number of spikes per 5 msec (with 50 repetitions); abscissa, number of bins. A, prior to conditioning; B, CR cmsolidated; C, CR extinguished; D, CR restored. Arrow indicates application of acoustic stimuius. In brackets, number of combinations reinforced or non-reinforced.

Percentage refers to occurrence of CR.

parison of the time parameters of the evoked responses and of phasic variations in evokd neuronal activity of individual populations of the cortical "center" of the CS did not allow any definite conclusions as to their correlation. To resolve this question, it is necessary to have more data and to undertake a correlation analysis of indices of neuronal and total activity which can be acoomplished only on general-purpose com- puters. It should be noted that at the stage of restoration of an ex- tinguished CR, the level of evoked neuronal activity remained high compared with the initial level observed prior to CR elaboration, but there was the following difference: the level of BA decreased while the evoked activity remained high. This difference is difficult to account for as yet, and it may be only assumed that if the restoration of the extinguished CR were prolonged, the level of evoked neuronal activity would possibly decrease as well.

CONDITIONED BLINK REFLEX AND NEURONAL ACTIVITY 347

Before proceeding to the evidence obtained, it is appropriate to dis- cuss the results of ciontrol tests. Prior to CR elaboration, the cats were presented, in one-two tests, series of clicks at the same rate, i.e., with the interstimulus interval of 2-3 min. Analysis d BA recorded during 5 min after 10 presentations of click series suggests that by the 2nd min after presentation of the 10th click series the level of BA returned to normal, i.e., to the initial level cbserved prim to click presentation (Fig. 7 F ) . In poststimulus histograms with an epoch of 1,000 msec it is seen that the trace events associated with acoustic stimulation are ,( 2 min (Fig. 7). It should also be noted that the post-effect of clicks

Fig. 7. Background and evoked neuronal activity of cat's auditory cortex prior to conditioning during presentation of an indifferent stimulus (click) (data of multi- channel analyzer, post-stimulation histogram). Ordinate, total number of spike for 10 msec (with 50 repetitions); abscissa, number of bins. A, background activity prior to presentation of click series; B, evoked activity upon presentation of 1-5 click series a t a frequency of l> click/sec and an interval between series of 2-3 min: C,, same but upon presentation of 6-10 series; D, background activity during the first 50-sec period after presentation of 10 click series; E, F, G, H and I, same

during the second, third, fourth, fifth and sixth 50-sec period, respectively.

was less marked when the above procedure' was repeated, because the time of occurrence of trace processes decreased as the indifferent sti- mulus was presented.

Turning now to the results it is necessary in the first place to solve the question of whether the shifts in BA of the neuronal population re- flect the process of closure of the temporary omec t ion or whether they arose as a result of generalized non-specific increase of excitation under the effect of application of each of the stimuli used. It is known that the

- -

excitability of receiving neural elements may increase when two in-

348 G. L. VANETSIAN

different stimuli are combined (4, 18), or when indifferent and uncondi- tional stimuli are presented in a random manner (9), etc. Long-term activation of cortical neurons after peripheral stimulation (20, 22, 28-30, 32, 36, 37, etc.), is also regarded as a manifestation of enhanced exci- tability. There are reasons to believe, however, that the changes noted in BA, were of CR origin. This is favored first by the character of the time-course of BA at the different stages of CR functilming. The US was presented in combination with a click at two stages: during the elaboration of a positive CR and during its restoration after an acute intermittent extinction. The changes in BA were different in these cases. During CR elaboration, BA rose significantly, while during CR restora- tion it decreased. If the changes in BA observed during CR elaboration were result of a gene~al increase of excitability, then disccmtinuation of reinforcing stimulation would have led to a fall of the general level of activation, to reduced tonus and to decreased BA. This was not the case, however.

That the changes of BA were of a conditioned nature is also sug- gested by the phasic character of the time-course of background im- pulses during extinction, when at the beginning of extinction the activa- tion was greater then during other periods, a fact known both from work using the classical and electrophysiological procedures (e.g., 10, 12, 17, 21). The observed changes in background activity in the form of activation cannot be regarded as a manifestation of the summation re- flex, expressed in the form of "wmking-out" of neurons (28), since the interval between presentations of combinations was much longer than the duration of trace processes observed upon application, at the same rate, of future CS (contrlol tests). Moreover, the respmse of "working- out" neurons differed from conditioned discharges by instability and a slight increase of activation (e g., 19, 25, 26, 28, 36, 37). Finally, the observed changes of BA cannot be considered as a manifestation of the reflex to time, since the interval between combinations was varied randomly from 1.5 to 3 min. Thus, there are sufficient reasons to con- sider the described increase in spontaneous BA activity of the neuronal population under study as a reflection of CR processes in the functional system of neurons. Further analysis raises another question as to which particular phenomena in cortical activity are reflected in the observed changes. There are reasons to believe that the observed changes of BA are partly a reflection of the formation of a situational reflex due to enhanced situational afferentation of projection elements on the part of non-specific structures. This involves, as i t were, an expansion of the receptive field of neurons of the population (33), because impulse activity begins to be effectively modulated by those situational stimuli

CONDITIONED BLINK REFLEX AND NEURONAL ACTIVITY 3-19

to which no response occurred before the temporary connection had been elaborated.

Enhancement of background activation in these experiments sug- gests enhanced excitability of the neuronal system under study, an in- creased level of BA being observed during the elaboration and mani- festation not only of a positive but also of negative CR. It should he emphasized that the development of extinguishing inhibition led to a further increase of excitability of the structures under study. It may be thought that the complex integrative processes unfolding during internal inhibition, were carried out when there was an optimal degree of excitation of the analyzer system. This agrees with the results of a number of studies in which, using various procedures, it was shown that the excitability of structures of the signal analyzer increased during the formation of positive and inhibitory CRs. In these experiments, when the extinguishing inhibition increased and the animals developed a dor- mant state. BA decreased in the structures under study. The time-course of BA, during extinction may be underStood if one proceeds from the concept of Asratyan (1) that initially inhibition is localized in elements of the conditioned connection itself, when the cortical foci of the combined stilnuli are not only free of ccnditioned inhibition but may become more excited. According to this concept, as conditioned inhibition increases, the process spreads both to the focus of the CS and that of the US, i.e., to all central components of the conditioned reflex arc.

In studies on neuronal mechanisms of learning, facts are accomulat- ing which suggest that internal inhibitilon is a process not associated with global inhibition or cessation of activity of the involved cortical cells (e.g., 7, 13, 16, 20, 28, 33, 39).

For an understanding of the neuronal mechanisms of learning it is important that miclloelectrode studies can analyse only a small number of neurons responding by decreasing activity when the stimulus is non- reinforced (6, 14, 15, 35). Some studies describe cases of increases of both evoked and background activity of projection neurons of the zones of conditional (33) and unconditional (39) stimuli when reinforcement is dscontinued.

There are reasons to believe that activity is redistributed between different functional elements of the system under analysis a redistribu- tion which leads to optimal activation marked by blocking of the effec- tor. The genesis of enhanced activation may be associated with known thalamo-cortical reverberation cycles (24), and neurlonal chains (29) con- sisting of cortical cells only. A tonic activation of reticular origin also cannot be excluded.

G . L. VANETSIAN

CONCLUSIONS

During the elaboration of a positive conditicmed blink reflex there was a significant increalse in the level of background activity of the n e u m a l population of the auditory cortex of waking cats, recorded via an implanted microelectrode (50 pm).

During conditioned reflex extinction, background activity showed a further increase. When extinguishing inhibition became profound, it was equivalent to sleep, and there was a strong fall in the level of back- ground activity.

During the restoration of an extinguished conditioned reflex, back- grlound activity fell to the level observed during conditioned reflex ex- tinction, at the stage of consolidation.

Application of an acoustic stimulus elicited a general, sometimes a slight increase in the number of spike discharges. Within the range of 300-350 msec - the time of appearance of the evoked response - neuronal activity undelrwent a reorganization, sometimes with a ten- dency to phasic variations. Phasic variations of the given population in response to sound were observed at all stages of the study.

Comparison of the temporal parameters of the evoked response and of phasic variations in evoked neuronal activity of individual populat- ions of the cortical point of the conditional stimulus does not allow any conclusions as to their correlation.

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Received 3 July 1972

G. L. VANETSIAN, Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Pyatniskaya 48, Moscow, USSR.