prefrontal unit activity during associative learning in the monkey

Exp Brain Res (1990) 80:296-309

Experimental Brain Research �9 Springer-Verlag t990

Prefrontal unit activity during associative learning in the monkey

M. Watanabe

Department of Liberal Arts, Tokyo Engineering University, Katakura 1404, Hachioji, Tokyo 192, Japan

Summary. Single unit activity was recorded from the dorsolateral prefrontal cortex of two monkeys which were trained on a stimulus-reward association task. The monkeys were trained on a reaction time task overlapped with a classical conditioning paradigm. The sequential events of the task were as follows: (1) lever pressing to start the trial; (2) presentation of a visual cue for 1 s; (3) delay period of 1 s; (4) imperative stimulus presentation; and (5) release of the lever by the animal. The visual cue signaled whether or not a drop of fruit juice would be given (its associative significance) for the animal's release response instead of signaling what response the animal should perform (its behavioral significance). In this task, the animal had to release the lever even on the trial where no juice was given in order to advance to the next trial. A total of 423 units showed activity changes in relation to one or more of the task events, such as the cue presentation, delay, release response and reward delivery. Among 313 units which showed cue-related activity changes, 179 units showed differential activity in relation to the different cues. A majority of them (Type M; n = 120) showed activity changes in relation to whether the cue indicated juice delivery or not, independent of its physical properties. The activity of 13 units (Type P) was related to the physical properties of the stimulus, and the activity of the remaining 46 units (Type MP) appeared to be related to both aspects of the stimulus. Sustained activity changes during the delay period were observed in 68 Type M, in 3 Type P and in 24 Type MP units. The results suggest that the prefrontal cortex plays important roles in the stimulus-reward association and that prefrontal units are involved in higher order information processing, extracting and retaining the "associative significance" of the stimulus independent of its physical properties.

Key words: Associative significance - Prefrontal cortex - Single unit activity - Classical conditioning - Monkey

Introduction

Many studies have been done to investigate the neural mechanisms of object recognition. In the visual modality,

the flow of information has been traced from the retina to the temporal and posterior parietal association cortex via the lateral geniculate body, the striate cortex and the prestriate cortex (Cowey 1981; Gross 1973; Ungerleider and Mishkin 1982). In these studies, the receptive fields of the units become larger and their trigger features become more complex, the later the stage of information processing (Gross 1973). It has also been shown that there are units in the posterior association cortices which respond to complex stimuli (Gross 1973; Sakata et al. 1986; Bruce et al. 1981). However, whatever complex trigger features these units in the posterior association cortices have, they code only "what is" - the physical properties of the stimulus.

On the other hand, it has been shown that there are units in the dorsolateral prefrontal cortex which code the "meaning" of the stimulus independent of its physical properties (Watanabe 1981, 1986a). Such units show activity changes in relation to the "behavioral significance of the stimulus", i.e., in relation to what behavioral response it indicates to the animal. They respond similarly to different stimuli which have the same behavioral significance, and respond differentially to the physically identical stimulus when it has different behavioral significance depending on the situation. According to Thorpe et al (1983), a few orbitofrontal (OBF) units responded when the animal looked at an aversive saline-containing syringe, and their activity was altered by feeding glucose solution to the animal from the same syringe. These OBF units may code another aspect of the meaning of the stimulus, i.e., its "associative significance" in relation to whether it is associated with the aversive or appetitive event.

Prefrontal unit activity of the monkey has been investigated in several kinds of (operant) discrimination tasks such as the delayed response (Fuster 1973; Niki 1974b), delayed alternation (Kubota and Niki 1971 ; Niki 1974a), delayed matching to sample (Rosenkilde et al. 1981; Fuster et al. 1982), differential reinforcement of long latencies (Niki and Watanabe 1979) and Go/No-go discrimination (Komatsu 1982; Kubota and Komatsu 1985; Watanabe 1986a0 b) tasks. However, there is almost no study in which monkey prefrontal unit activity is investigated during the "associative learning" except for a preliminary report by Thorpe et al. (1983). This

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study was conducted to investigate neuronal correlates of associative learning, and to examine further the characteristics of those units which may reflect the "associative significance" of the stimulus, in the dorsolateral prefrontal cortex which is considered to be more related to the cognitive function than the OBF cortex (Fuster 1988).

The animal was trained on a newly devised "associative learning" which consisted of a simple reaction time task overlapped with a classical conditioning paradigm; the animal was required to make a behavioral response (lever-release) on all trials in order to obtain another trial, but juice reward was provided to the animal only on trials where certain discriminative stimulus had been presented. In this task situation the discriminative cue indicated whether it was associated with the juice reward or not (associative significance) instead of indicating what behavioral response the animal should perform (behavioral significance). A preliminary report has appeared elsewhere (Watanabe 1987).

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Material and methods

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Subjects

Two Japanese monkeys (Macacafuscata), one male weighing 11.2 kg and one female weighing 10.8 kg were used in the present experiment. They were cared for in the manner prescribed in Guiding Principles in the Care and Use of Animals of the American Physio- logical Society.

Apparatus

The monkey was seated on a primate chair and faced a panel (40 cm high and 50 cm wide) which contained a central window and a hold lever (HL). The window, which was transparent and rectangular (8 cm high and 6 cm wide), was located at eye level, 40 cm in front of the animal. The HL, which was 5 cm wide and protruded 5 cm, was situated 10 cm below the window. The window could be illuminated from behind by a rear projection unit (Industrial Electronics Engi- neering, Series 80). A microcomputer (NEC TK-85) and electrical circuits were used for controlling the task events.

Behavioral training

The animal was at first trained on a reaction time task (Fig. 1A). In this task the animal had to depress the hold lever (HL) to start the trial. After a variable intertrial interval (ITI; 4.5-6.5 s, Mean = 5.6 s), a pattern stimulus of either a circle or stripes was presented as a cue on the window for 1 s. This cue period was followed by a delay period of 1 s. If the animal continued to depress the HL, a red or green light was presented on the window as an imperative stimulus (IS). When the animal released the HL within 1 s after the IS presentation (adequate trial), the IS light was turned off with or without a drop of fruit juice (0.2 ml) depending on the previously presented cue.

If the animal released the HL before the IS presentation, the animal had to resume the trial from the beginning. If, on the other hand, the animal did not release the HL within 1 s after the IS presentation (no-release trial), the IS light was turned off without juice reward and the animal had to resume the trial where the same cue as in the preceding (no-release) trial was presented. When a red light was presented as an IS (original situation), a circle pattern indicated that a juice reward would be given to the animal after the adequate release

reversal [~ "I' [ ] NJ

J

Fig. 1. A Sequence and timing of events in the lever-release response task. Abbreviations; IS, Imperative Stimulus; HL, Hold Lever; J, Juice. B Cue and IS presented for both original and reversal situations on Tasks 1 and 2. "R" indicates red light and "G" indicates green light. " J" indicates juice delivery while " N J " indicates no juice delivery

response (juice trial), whereas a striped pattern indicated that no juice would be given even after an adequate release response (no juice trial). On the other hand, when the IS light was green (reversal situation), the striped pattern indicated that juice would be given (juice trial), whereas a circle pattern indicated that no juice would be given (no juice trial) (Task 1 in Fig. 1B).

The animal had to release the HL even on the no juice trial to advance to the next trial. The cue did not indicate what response the animal should perform (behavioral significance), but indicated whether or not juice would be given to the animal after the adequate release response. In other words, the lever-release response task was overlapped with a differential classical conditioning procedure where the cue was the CS and juice was the UCS.

In a conventional classical conditioning paradigm, it is not certain whether the animal attends to the cue every trial, since the cue is presented irrespective of the animal's situation. On the other hand, in the paradigm employed in the present experiment, the animal was thought to perform the task only when he was mo- tivated to do so. Thus, as long as the animal performed the task, it was thought that the animal attended to the cue. In behavioral reaction time (RT) experiments, it has previously been shown that the animal's RT is shorter when a preferable outcome is expected than when an unpreferable outcome is expected (e.g., Medin and Davis 1974). As will be shown later, the animal's RT after the IS presentation was significantly shorter on juice (J) trials than on no juice (N J) trials (See Results).

The animal was first trained in the original situation (red IS) and then in the reversal situation (green IS). Thereafter original and reversal situations were alternated with a block of 50 trials each in about 2500 trials of daily training. After the animal was well trained on this task (Task 1 in Fig. 1B) (both original and reversal), i.e., the RT was found to be well differentiated between J and NJ trials, the

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animal was then trained on an additional task (Task 2 in Fig. 1 B) where plus and square patterns were used as cues. A plus indicated juice delivery and a square indicated no juice delivery in the original (red IS) situation, whereas the reverse was true in the reversal (green IS) situation. It took 1 to 2 months for the animal to be well trained on Task 1 (both original and reversal), and another month was necessary for the training of Task 2 (both original and reversal).

The animal was also trained on an auditory task where auditory cues were used. Data obtained on the auditory task will be presented in a separate paper.

Surgery and unit recording

After the training was completed, the animal was anesthetized and a stainless steel cylinder (18 mm in diameter) as a microdrive receptacle and 4 bolts for head fixation were implanted at appro- priate locations on the skull. Details of this procedure are the same as in a previous study (Watanabe 1986a). After a recovery period of about 10 days, unit recording was started. A search for units was done in the dorsolateral prefrontal cortex, mainly in the principalis, arcuate and inferior convexity areas while the animal was perform- ing Task 1. A substantial number of premotor units were also recorded from one hemisphere of one monkey. The unit action potentials were processed through a window discriminator and converted into square-wave pulses. Throughout the recording ses- sion, both unit discharges and shaped pulses were monitored on an oscilloscope (Tektronix 5103N) to ensure reliability of the conver- sion. The shaped pulses and DC voltage changes for the task events were displayed on an inkwriter during the experiment. Only those units which showed clear changes in discharge rate in relation to one or more of the task events were selected by visual inspection of the inkwriter record. Concerning those units, the unit activity, shaped pulses, and DC-voltage changes for the task events were recorded on an FM tape recorder (TEAC, R-61) for later analysis.

The IS light was changed and the associative significance of the cue was reversed about every 50 trials during the unit recording. Only when a unit showing differential activity for the different cues was found, was the activity of that unit also examined on Task 2 in order to determine the aspect of the stimulus to which the unit was responsive. The principal objective of this study was to discover those units which would show differential activity to the different cues. Consequently, electrode penetration was done intensively in the vicinity of such units, when one such unit had been found. Thus, there is presumably a sampling bias.

Since unit recording was done after the animal was well trained on Tasks 1 and 2, it was not possible to examine the modification of the activity of the unit during the course of the learning of the two tasks. However, unit activity was examined in three cells during the course of new learning by introducing a new combination of c u e s .

Data analysis

The data were analyzed later using a signal processor (Nihon Koh- den, ATAC-450). ANOVA was used to analyze the RT data. For unit activity, data were collected for 5.12 s for each trial. Raster display and frequency histograms were used for graphic representa- tion and these data were also plotted on an X-Y plotter. Non- parametric statistics (U and H tests) were used for statistical analysis, as was done in a previous study (Watanabe, 1986a).

Histology

A direct anodal current (20 gA, 30 s) was passed through the recording electrode to mark the locations of selected units. At the end of the experiment, the monkeys were given an overdose of anesthet- ic (Nembutal) and perfused through the heart with normal saline

followed by 10% formalin. Then the dura was removed and the location of the cylinder on the cortical surface was determined. The brain was removed and fixed in 10 % formalin. The frozen brain was sectioned in the coronal plane at 50 gm, and then stained with thionin. Sections were microscopically observed to determine the areas of penetration.

Results

Behavioral data

The react ion t ime (RT) of the an imal after the IS p resen ta t ion differed depend ing on the an imal ' s mot iva- t ional state. Table 1 shows the R T da ta which were ob ta ined dur ing the early hal f of the daily un i t recording for one an ima l when it was well mot iva ted , and shows that the R T was shorter on J trials t h a n on NJ trials. Two-way A N O V A indicated a significant difference in the R T between J and NJ trials, a nd no significant difference between original and reversal s i tuat ions. The in te rac t ion was also no t significant. W h e n the s i tua t ion was changed between original and reversal dur ing the un i t recording, i.e., when the IS light was changed, RTs to bo th cues changed immedia te ly after only one or two trials of experience in a new si tuat ion.

Unit activity - general

A total o f 423 task-related uni ts were ob ta ined f rom four hemispheres of two monkeys . Since no clear difference

Table 1. Reaction times of an animal on Tasks 1 and 2 (in ms, 108 trials each). J indicates juice delivery and NJ indicates no juice delivery

Task 1 Original J 234.6 (SD = 85.6) NJ 405.1 (SD= 124.4)

Reversal J 223.8 (SD = 86.9) NJ 432.9 (SD = 130.6)

Task 2 Original J 230.4 (SD = 74.7) NJ 384.2 (SD = 141.5)

Reversal J 242.3 (SD = 81.2) NJ 394.5 (SD = 148.4)

Table 2. Classification of units which showed task-related activity changes (Numbers in parentheses indicate the number of units which showed differential activity in relation to the difference of the cue and/or the response)

Number

Cue-related only 57 (48) Response (R)-related only 67 (14) Post-trial (PT)-related only 31 (25) cue+ R related 214 (115) cue+ PT related 22 (19) R + PT related 12 (12) cue + R + PT related 20 (20)

Total 423 (253)

was observed in the characteristics of task-related activity changes between prefrontal and premotor units, units of both areas are treated together. These task-related units were classified depending on the events to which unit activity was related; i.e., (1) cue-related (anticipatory changes near to the cue presentation are also included), (2) response-related (anticipatory changes near to the release response are also included) and (3) post- trial-related (Table 2).

Cue~related activity

Out of 423 task-related units, 313 units showed cue- related activity changes (cue-related only, cue + R-relat-

299

ed, cue + PT-related, cue + R + PT-related, as in Table 2). Among them, 179 cue-related units showed differential activity in relation to the different cues, and 40 cue- related differential units were examined on both Tasks 1 and 2. These differential units were classified into 3 types depending on the characteristics of their activities (Types P, M and MP).

Type P (Property-related) units (n = 13) showed differential activity in relation to the different physical properties of the cue. The Type P unit pictured in Fig. 2, which was found in the inferior convexity, showed a higher rate of firing when stripes were presented as a cue than when a circle was presented in both original and reversal situations on Task 1 (A). On Task 2 (B) this unit showed a higher rate of firing to the square cue than to

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300

the plus cue. (This unit showed activity changes in relation to the release response as well.) Seven out of 13 Type P units showed a higher and 3 Type P units showed a lower rate of firing to the striped cue than to the circle cue. The remaining 3 units showed an activation only to the striped cue. Of 13 Type P units, 3 showed activity changes during both the cue and delay periods.

The activity of Type M (Meaning-related) units (n = 120) was different between J and NJ trials and was related to whether the cue indicated juice delivery or not. The principalis unit pictured in Fig. 3 showed a higher rate of firing to the J cue than to the NJ cue in both original and reversal situations on both Task 1 (A) and Task 2 (B).

Figure 4 shows another example of this type of unit. Unlike the Type M unit which showed a higher rate of firing to the J cue (Fig. 3), this arcuate unit showed activation to the NJ cue on both Tasks 1 (A) and 2 (B) while a suppression of firing was observed to the J cue especially on Task 1. The activity changes were observed during both the cue and delay periods. Among the 120 Type M units, 61 showed a higher, and 26 showed a lower rate of firing to the J cue than to the NJ cue. Seventeen units showed activation only to the J cue while 8 units showed activation only to the NJ cue. Three units showed suppression of firing to the J cue. Five Type M units responded reciprocally and showed an increase to one cue and a decrease to the other cue. Among the 120

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Type M units, 68 showed activity changes during both the cue and delay periods, as was found for the unit shown in Fig. 4.

Units were also found whose activity had complex characteristics (Type MP; n=46). Figure 5 shows an example. This unit found in the inferior convexity, showed activation only to the striped cue in the reversal situation on Task 1 (A). Similarly it showed activation only to the square cue in the reversal situation on Task 2 (B). The activity of this type of units could not be described solely in terms of the physical properties of the stimulus nor in terms of whether the cue indicated juice delivery or not, but in terms of both. Among 46 Type MP units, 24 units showed activity changes during both the cue and delay periods, as was the case for the unit shown in Fig. 5.

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M units and the animal's RT when correlation coefficient was calculated for all the J trials or for all the NJ trials.

The animal sometimes released the HL too early (before the IS presentation) or did not release the HL within 1 s after the IS presentation. It is interesting to know whether the activity of Type M units on "early- release" or "no-release" trials is different from that on adequate trials. At least one "early-release" response was observed in 23 of 120 Type M units for J and/or NJ trials. "No-release" response was observed predominantly on NJ trials in 62 of 120 Type M units. Examples are shown in Fig. 6. Results indicate that the activity of Type M units was not different among "early-release", "no- release" and "adequate" trials. Of special interest was the activity observed on those trials in which the animal released the HL too early on NJ trials (e.g., Figs. 6A and

B - 4). The activity changes observed on those "early- release" NJ trials were not different from those observed on adequate NJ trials, even though the RT on any early- release NJ trial was shorter than that on any adequate J trial (Adequate release responses occurred always after the IS whereas early-release responses occurred before the IS). Thus, the magnitude of activity changes of Type M units is not directly related to the animal's RT, and the adequate release response is not prerequisite for the activity changes of Type M units.

Activity changes during the course of learning

How the activity of the unit was modified during the course of learning with the new combination of cues was

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the adequate J trial and (2) shows the activity when the animal committed an "early-release" response on the J trial. (3) Shows the activity on the adequate NJ trials. (4) Shows the activity when the animal committed the "early-release" response on the NJ trial, and (5) shows the activity when the animal did not release the HL within 1 s after the IS presentation on the NJ trial. Other conventions are the same as in Fig. 2

also examined in three Type M units. An example is shown in Fig. 7. This unit observed in the inferior convexity, showed activation to the J cue on the original Tasks 1 and 2. When the animal was faced with a new task where the IS was red, and a circle remained a J cue, whereas a plus (which had also been a J cue in the original situation) became a NJ cue, this unit showed activation to both cues at first, but the activation to the (now N J) plus cue declined after about 20 to 25 NJ trials (Fig. 7A). The same tendency was also observed when the IS was green and a square became a NJ cue, whereas stripes remained a J cue (Fig. 7B), al though differential unit activity to these two cues appeared much earlier (after about 15 to 20 NJ trials). I t is interesting to note that, in all 3 units examined, the differentiation in unit activity between J and NJ trials appeared much earlier than the differentiation in RT, after a new combinat ion of cues was introduced.

Response-related activity

Response-related activity changes were observed in 313 units. Among them, seventy five units showed differential activity at and/or near to the time of the release-response between J and NJ trials. Figure 8 shows an example. This arcuate unit showed a noticeable activation only on J trials al though the behavioral requirement for the animal was the same for both J and NJ trials. The activity of 72 units, which were classified into this type for the sake of convenience, was more time-locked to the IS presenta-

tion than to the release-response, and thus was considered to be more related to the recognition of the IS light than to the release-response itself.

Response-related activity changes were observed in 77 of 120 Type M units, 30 of them showing response- related differential activity between J and NJ trials. Thir- teen of the 30 units showed gradual activity changes toward the time of the response f rom the cue period.

Post-trial activity

Eighty five units showed activity changes after the release-response. Twelve of them showed activity changes after the response irrespective of whether juice was given or not. The remaining 73 units responded differentially after J and NJ trials. Among them, 40 units showed an activation whenever juice was delivered. Ten units showed higher and 18 units showed lower firing rates after J trials than after NJ trials. Five units responded only to the juice, which was delivered to the animal 's release- response, and did not respond to free juice delivery.

Post-trial activity changes were observed in 18 of 120 Type M units. Among them, 2 showed non-differential activity changes after the response between J and NJ trials. Nine units showed a higher (or lower) rate of firing on J trials than on NJ trials, both at the time of the cue presentation and after the response, whereas the remaining 7 units with a higher (or lower) rate of firing at the cue presentation showed a lower (or higher) rate of firing after the response on J trials than on NJ trials.

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Premotor unit activity

S e v e n t y o n e o f 313 c u e - r e l a t e d un i t s w e r e f o u n d in t he p r e m o t o r a rea , 34 o f t h e m s h o w i n g c u e - r e l a t e d dif ferem tial ac t i v i t y ( T y p e M : n = 29 ; T y p e M P : n = 5 : T y p e P :

n = 0). S ix ty th ree o f 313 r e s p o n s e - r e l a t e d un i t s a n d 27 85 p o s t - t r i a l - r e l a t e d un i t s w e r e o b t a i n e d in t he p r e m o t o r a r e a as well . T w e n t y e igh t o f t he 63 r e s p o n s e - r e l a t e d p r e m o t o r un i t s s h o w e d differential ac t iv i ty b e t w e e n J a n d N J tr ials . Al l t he 27 p o s t - t r i a l - r e l a t e d p r e m o t o r un i t s

showed differential activity after J and NJ trials, 3 of them responded only after the animal's response and did not respond to the free juice delivery. Among 29 premotor Type M units, only 4 showed post-trial activity changes whereas t8 showed response-related activity changes, 10 of them showing differential activity between

Table 3. Distribution of stimulus-related differential units in the prefrontal and premotor cortex. The number in each cell indicates the number of units. PS, IC, AS and PM indicates principalis, inferior convexity, arcuate and premotor area

PS IC AS PM Total

Type P 3 6 4 0 13 Type M 27 31 33 29 120 Type MP 10 17 14 5 46

Total 40 54 51 34 179

305

J and NJ trials and 5 of the 10 units showed sustained activity changes from the cue period toward the time of the response.

Location of units

Units which showed stimulus-related differential activity were observed in the principalis, arcuate and inferior convexity areas of the prefrontal cortex (Table 3 and Fig. 9). Premotor units were recorded from one hemisphere of one monkey (where the largest number of units was recorded) because a cylinder was situated more pos- teriorly than had been intended. Since the cylinder did not cover the upper part of the post-arcuate area, most premotor units were obtained from the lower part of the post-arcuate area. No clear localization of specific types of stimulus-related differential units was observed in the prefrontal cortex.

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Fig. 9A-C. Locations of penetrations for each type of cue-related differential unit. A Type P units; B type M units; C type MP units. Different symbol in each figure indicates the number of units recorded from each explored site. Dotted line in A indicates ap- proximate boundary of the principalis, arcuate and inferior convexity areas, following the study by Rosenkilde (1979). Scale bar in C indicates 5 mm. Abbreviations: PS, principal sulcus; AS, arcuate sulcus

Discussion

Stimulus-related activity

Three types of stimulus-related differential units (Type P, M, and MP) were found in the present experiment. The activity of Type P units was related to whether the cue was a circle or stripes (plus or square) and was not related to whether the cue indicated juice delivery or not. In my previous experiments, similar prefrontal units were observed which coded the difference of the color or pattern of the cue (Watanabe 1981, 1986a). Those units and Type P units in the present experiment are considered to code the physical properties of the cue.

The majority of stimulus-related differential units showed Type M activity. The activity was related neither to the physical properties of the cue, nor to what behavioral response the cue indicated, but was related to whether the cue indicated juice delivery or not. Thus, it is considered that Type M units code the "associative significance" of the cue.

On the other hand, there is a possibility that the activity of Type M units may be related to the mouth movement or may reflect the animal's orofacial preparation for the juice delivery, instead of reflecting the associative significance of the stimulus, since a substantial number of premotor Type M units were obtained from the inferior part of the post arcuate area where units related to the mouth stimulation and mouth movements are reported (Rizzolatti et al. 1981a-c). Furthermore, this area is anatomically connected with the prefrontal area (Matelli et al. 1986) in which many Type M units were obtained.

However, Type M units did not usually show such activity changes as were observed at the time of the cue presentation, during the ITI when the animal moved the mouth from time to time (A few non-Type M premotor units were observed whose activity changes coincided with the mouth movements themselves). Although it is supposed that there might be differences in post-trial mouth movements between J and NJ trials, only a small

306

number of Type M units (n= 16) showed differential post-trial activity changes. Furthermore, seven of them showed a higher (or lower) rate of firing at the time of the cue presentation while showing a lower (or higher) rate of firing after the response on J trials than on NJ trials.

In relation to the unit activity before and at the time of the response where there might be differences in mouth movements, only 30 of 120 Type M units showed differential activity between J and NJ trials. Furthermore, 5 of the 30 units showed a higher (or lower) rate of firing at the time of the cue presentation while showing a lower (or higher) rate of firing at the time of the response on J trials than on NJ trials.

"Set-related" units have been reported in the premotor cortex which show sustained activity changes toward the time of the response when there is a delay between the cue presentation and the response (Weinrich and Wise 1982; Weinrich et al. 1984). Such sustained activity changes were observed in 13 of the 30 Type M response-related differential units in the present experiment. Since response-related differential units are considered to be related to preparing for the J delivery (See Response-related activity), it could not be denied that the activity of some of such set-related Type M units might reflect the preparation for the juice delivery, whereas most Type M units are not considered to be directly related to the mouth movements nor to the preparation for them, since there was no systematic relation- ship between their cue-related activity and the activity changes observed around the time of the response.

There is another possibility that the differential activity of Type M units may reflect the implicit process in the animal to prepare to release the lever in different RT; i.e., may reflect the difference of "preparing to respond quick- ly" and "preparing to respond slowly". However, it was not always possible to predict the RT from the magnitude of activity changes of Type M units (See Fig. 6), whereas it was almost always possible to predict the difference of the response from the activity of those units which were related to the behavioral significance of the stimulus (Watanabe, 1986a).

The activity of Type M units on "early-release" and "no-release" trials was not different from that on adequate trials (Fig. 6). This characteristic is different from that of "signal-related" premotor units (Weinrich et al. 1984) showing cue-related differential activity in relation to the difference of the response indicated by the cue, since the magnitude of activity changes of those premotor units decreases when the animal is not required to perform behavioral responses. Furthermore, when the modification of unit activity during the course of the learning was examined (Fig. 7), differential unit activity to the J and NJ cue appeared before the RT was differentiated. Thus, the activity of Type M units may be in- directly related to the animal's RT and it is more plaus- ible to consider that the activity of Type M units reflects the "associative significance" of the stimulus as those OBF units described in the Introduction do, except that certain set-related Type M units might participate in preparing for the orofacial movements.

The characteristics of activity changes of Type MP units were intermediate of those of Type P and Type M units. If Type M units are related to the associative significance of the cue, Type MP units are considered to reflect both the physical properties and the associative significance of the stimulus. Similar units which have intermediate characteristics reflecting physical properties and the behavioral significance of the stimulus have been observed in my previous experiments (Watanabe 1981, 1986a).

Sustained activity during the delay period

Three Type P, 68 Type M and 24 Type MP units showed sustained differential activity changes during both the cue and delay periods. Units which show such sustained activity changes have been reported in the inferotemporal cortex (Fuster and Jervey 1982; Miyashita and Chang 1988), in the hippocampus (Watanabe and Niki 1985), and in the prefrontal cortex (Niki and Watanabe 1976; Rosenkilde et al. 1981; Watanabe 1981, 1986a) of the monkey. These units are thought to participate in retaining the information coded at the time of the cue presentation, as a short-term memory during the delay period. Some units retain the difference of the color cue (Rosenkilde et al. 1981 ; Fuster and Jervey 1982) or pictorial design (Miyashita and Chang 1988). Some retain the locus of the cue in the delayed response (Niki and Watanabe 1976; Watanabe and Niki 1985). And some prefrontal units are shown to retain the "behavioral significance" of the stimulus (Watanabe 1981 ; 1986a). The present experiment suggests that prefrontal units are also involved in retaining the "associative significance" of the stimulus, as a short-term memory.

Response~related activity

Units have been reported in the prefrontal cortex of the monkey which show activity changes at the time of the key-release response (Kojima 1980; Ito 1982; Komatsu 1982). Such units are said to be involved in the initiation and execution of the response. Of great interest in the present experiment was the finding of units which showed differential activity in relation to the key-release response between J and NJ trials (Fig. 8). Such unit activity is not simply related to the initiation and execution of the response, but is thought to reflect also the preparation for receiving the reward.

Post-trial activity

Twelve units in the present experiment showed post-trial activity changes irrespective of whether juice was given or not. Similar units have been reported in the different task situations (Rosenkilde et al. 1981; Kubota and Komatsu 1985). Such units are considered to code the "end of the trial". In the present experiment, five units responded only to the juice given to the animal's ade-

quate response and did not respond to the free juice delivery. Similar units have also been reported (Niki and Watanabe 1979). They may be "reinforcement-register units". Twenty eight units (which showed higher or lower rates of firing after J trials than after NJ trials) may differentially code the existence and non-existence of the juice reward. The results obtained in the present experiment indicate that post-trial unit activity is commonly found in the prefrontal cortex irrespective of differences in the task situation.

Premotor unit activity

Substantial number of task-related premotor units were obtained in the present experiment. No clear difference was observed in the characteristics of activity changes of each type of task-related units between the prefrontal and premotor areas. However, among cue-related differential units, the proportion of Type MP units was smaller, and no Type P units was found in the premotor area. The proportion of response-related differential units was larger in the premotor area than in the prefrontal area. Although five prefrontal Type M units showed a higher (or lower) rate of firing at the time of the cue presentation while showing a lower (or higher) rate of firing at the time of the response on J trials than on NJ trials, no such Type M unit was observed in the premotor area. These results suggest that the premotor area is more related to the motor aspect of the behavior than the prefrontal cortex.

Prefrontal cortex and the associative learnin 9

The modification of neuronal activity in the prefrontal cortex during the course of learning with a new combination of cues was examined in the present experiment (Fig. 7A, B). In all 3 units examined, the differentiation in cue-related unit activity between J and NJ trials appeared much earlier than the differentiation in RT. The results are in accordance with those observed in the rabbit (Thompson et al. 1980) or rat (Hirano and Yamaguchi 1985) hippocampus during conventional classical conditioning where differentiation in unit activity preceded the appearance of the conditioned response.

Ablation of the medial prefrontal cortex of the rabbit (which is thought to be functionally homologous to the lateral prefrontal cortex of the monkey) has been reported to induce deficits in classical conditioning of the heart rate (Buchanan and Powell 1982). Also, the training- induced changes in rabbit prefrontal multiple unit activity appeared to parallel the development of the heart rate conditioned response (Gibbs and Powell 1988). Thus, the prefrontal cortex is considered to play important roles in establishing stimulus-stimulus associations.

In ablation studies, the monkey amygdala, which sends outputs to both the prefrontal cortex (Amaral and Price 1984) and the hypothalamus (Amaral et al. 1982), has been proposed as a center for playing critical roles in stimulus-reward association (Jones and Mishkin 1972;

307

Spiegler and Mishkin 1981). In this connection it is interesting to note that unit activity of the monkey amygdala is reported to reflect an early stage of filtering of stimuli on the basis of significance (Sanghera et al. 1979). The amygdala receives visual information from the inferotemporal cortex (Turner et al. 1980) and is considered to add motivational or associative content to it (Rolls 1981). The prefrontal cortex may also play important roles in the stimulus-reward association in the associative learning as was employed in the present experiment, receiving input from both the inferotemporal cortex (Chavis and Pandya 1970) and the amygdala (Amaral and Price 1984).

Associative and Behavioral significance of the stimulus

The prefrontal cortex is involved in higher order information processing and the extraction of the meaning of the stimulus may be one of the most significant functional roles of the prefrontal cortex. It is clear that the prefrontal cortex is involved in coding the "behavioral significance" of the stimulus (Watanabe 1981; 1986a). However, it has not been clear enough which brain areas are involved in coding the "associative significance" of the stimulus. Although unit activity of several brain areas has been examined during "classical conditioning", it is not clear whether learned CS-evoked unit activity changes reflect the "associative significance" of the stimulus. For example, CS-evoked unit activity in the hippocampus (Berger et al. 1980) and cerebellum (McCormick et al. 1982) during classical nictating membrane (NM) response conditioning in the rabbit is considered to be related to the "motor programming" or "motor plan" for the NM response.

Units in the lateral hypothalamus and substantia innominata (Mora et al. 1976; Rolls et al. 1979) of the monkey respond when the animal looks at objects which are associated with foods or juice reward. Since the animal is required to perform a certain behavioral response to obtain the reward, it is not clear again whether these units are related to the "associative" or "behavioral" significance of the stimulus. On the other hand, most Type M units in the present experiment and a few OBF units reported by Thorpe et al. (1983) are considered to reflect the associative, but not the behavioral significance of the stimulus.

In the present experiment, an attempt was made to separate two aspects of the meaning of the stimulus by devising a new task situation. However, complete separa- tion was not successful since there was a difference in RT and the animal might have made preparatory orofacial movements in different ways between J and NJ trials, although the activity of most Type M units could not be described in terms of the behavioral significance of the stimulus. To separate the two aspects of the meaning, it would be necessary to try to record single unit activity during the conventional classical conditioning paradigm where there is no difference in behavior between different discriminative-cue trials. Another approach may be to

308

del iver di f ferent a m o u n t o f ju ice r e w a r d to different cues where s imi lar o ro fac ia l m o v e m e n t s a re expec ted to occur . Or i t m a y be useful to r eco rd the ac t iv i ty f rom the same single p r e f ron t a l un i t in an an ima l t r a ined on b o t h classical a n d o p e r a n t cond i t ion ings . I t w o u l d also be necessary to c lar i fy whe the r m e a n i n g re la ted ac t iv i ty changes observed in the h y p o t h a l a m u s a n d subs t an t i a i n o m i n a t a a re re la ted to the associa t ive o r b e h a v i o r a l s ignif icance o f the s t imulus .

Acknowledgements. The author expresses his gratitude to Dr. H. Niki of the University of Tokyo for his helpful advice during the experimental work. He is also indebted to Mrs. A. Hashimoto for her histological work. This study was supported by a grant from the Ministry of Education, Science and Culture of Japan (no. 60510047), while the author was in the Department of Psychol- ogy, University of Tokyo.

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Received October 17, 1988; received in final form August / Accepted November 16, 1989

prefrontal unit activity during associative learning in the monkey

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