ACTA NEUROBIOL. EXP. 1981, 41: 605-617

The Symposium "Brain and behavior" held in Jablonna near Warsaw Poster presentation

May 1981

CONDITIONED EMOTIONAL RESPONSE AFTER DORSOHIPPOCAMPAL, VENTROHIPPOCAMPAL OR ENTORHINAL CORTICAL LESIONS IN RATS

Natalia P. BALEZINA, Alicja MARKOWSKA, Tomasz WERKA and Kazimierz ZIELINSKI

Department of Neurophysiology, Nencki Institute of Experimental Biology Pasteura 3, 02-093 Warsaw, Poland

Key words: CER, hippocampus, entorhinal cortex, rat

Abstract. Acquisition and extinction of the conditioned emotional response (CER) was studied in 24 male hooded rats which, prior to training, received small electrolytical lesions in the dorsal hippocampus, the ventral hippocampus, the entorhinal cortex, or were given sham operations. The rate of the on-going bar-pressing behavior for food pellets was highest in rats with lesions in the ventral hippocampus and the lowest after lesions in the entorhinal cortex. CER acquisition was markedly retarded and suppression was the weakest only in rats with dorsal hippocampal lesions. When compared with the level of suppression established toward the end of training, the greatest resistance to extinct- ion of the CER was observed after entorhinal cortical lesions. The results of the experiment indicate functional heterogenity of the hippocampal formation.

INTRODUCTION

The hippocampus, has been viewed as a brain structure involved in different functions: recent memory (15, 19), or working memory (I%), internal inhibition (4, 12, 13), spatial location in terms of cognitive maps (17), registration of information (21) and suppression of interference

factors effecting retrieval of scored information (5). Recent discussions strongly suggest that no single unitary neuropsychological theory of hip- pocampal fucctions is valid (see commentaries to Olton et al. paper). Some experiments seem to indicate involvement of the hippocampus in motivational control of defensive behavior of animals. However, most of the experiments performed on hippocampally lesioned rodents involv- ed a strong spatial character of the task.

The aim of the present study was to retrace the effects of hippocam- pal lesions in rats on acquisition and extinction of classically conditioned defensive responses measured as suppression of on-going food motivated ~nstrumental behavior according to the Estes and Skinner (8) conditioned emotional response (CER) technique. Brady and Hunt (2) study, extended further by other authors (9, 14, 16) discovered that the CER deteriorated after bilateral injury of the hippocampus in rats. In the present experini- ent we took into account anatomical and functional distinctions betweell the anterodorsal and posteroventral hippocampus (16). A g r m p wi1.h lesions of the entorhinal cortex was also included in the experiment because of the strong phy~iological relations of this structure with the hippocampal formation.

MATERIAL AND METHODS

The subjects were 30 experimentally naive, male hooded rats, appro- ximately 3 mo old and weighing 280-350 g at the beginning of the ex- periment. Prior to any treatment 24 of the rats were assigned to one of four groups, 6 subjects in each: dorsohippocampal (DH) group, ventro- hippocampal (VH) group, entorhinal cortical (EC) group, and control (C) group. The operations were done under semiaseptic conditions. Follon- ing intramuscular administration of atropine sulfate (1 mgkg) rats were anesthetized with intraperitoneal injection of sodum pentobarbital (40 mglkg). All brain lesions were performed bilaterally by passing 2 mA of anodal current for 15 s. The electrode was 0.4 mm diam., tungsten wire insulated except for 0.5 mm at the tip. The stereotaxic coordinates established during a pilot experiment were for Group DH 2.3 mm and 3 mm behind bregma, 2 mm lateral to the midline and 4.3 mm below the top of the skull at bregma. For the Group VH the coordinates were 2.8 mm and 3.5 behind bregma, 4.8 mm lateral to the midline and 9.1 mm down from the top of the skull at bregma for the first point, but 8.7 mm below for the second point. The coordinates for the Group EC were 3.1 mm and 3.7 mm behind bregma, 5.5 mm lateral and 10.2 mm below the skull surface. Each rat of the control group was treated in different way. One subject of Group C received a skin incision and trephine holes were drilled, but no electrode was inserted. Three sham operated suh-

jects were treated exactly as respective lesioned rats, except that the current was not passed through the lowered electrode. One rat was anesthetized only and one was left intact. Five subjects from different groups were lost during surgical treatments or shortly afterwards, and one rat was discarded at the beginning of training due to middle-ear infection. All of these subjects were replaced by other rats, so that a total of 24 subjects were used.

Following surgery, the rats were given 4 days recovery. Then they were gradually reduced during 12-14 days to 75O/o of their ad lib. body weight and maintained a t that weight on a 24 h feeding rhythm during the entire experiment. Daily portions of food were given after each experimental session. Two times during the experiment, all rats were injected by C, B-2, K and PP vitamines.

The training was conducted in four identical operant chambers with electrifiable grid floor, a single bar on one of the wall and a fsod-tray under it. Each chamber was located in separate acoustically shielded enclosure. Preliminary training consisted of initial presentation of 43 "free" 45 mg food pellets on a 1-min variable interval (VI) schedule (magazine training), followed immediately by a period with a continuous reinforcement schedule until 120 food pellets were delivered in a single session. After this training, six daily 2-h sessions of bar-pressing under a 2.5 min VI food reinforcement schedule were given, which resulted in exquisition of stable on-going bar-pressing behavior for food. On the 6th day of bar-pressing training (labelled as Dummy day, D-day) the numbers of bar presses emitted by each rat in 3-min periods before, during, and after the CS presentations that were subsequently sche- duled during the following experimental sessions were collected. The CS was a 3-min period of 80 dB (0.0002 dyne/cm*) white noise delivered via a permanent magnet speaker placed below the floor of the experi- mental chamber. On the Pretest day (P-day) following the D-day, the CS was presented alone, while on the next seven CER training sessions the CS terminated with 0.5 s of scrambled unescapable shock of 2-mA intensity. The onsets of the CSi were a t 14, 48, 72, and 79 min after the beginning of the session. The final stage of the experiment was an acute extinction procedure, wherein the CS was given at 14 min of the session and remained on until the end of the 2-h session with no US presentation during this period (10). This procedure was given over three consecutive days.

The magnitude of the CER was measured by the "suppression ratio ', described by Annau and Kamin (I), of B/(A + B), where B represents the number of bar-presses emitted during the 3-min period of the CS and A represents the number of responses during the 3-min period immediately before the CS onset. For each subject and presentation of

the CS on the P-day or during the CER acquisition sessions, suppression ratios were computed independently. Additionally, daily suppression ra- tios were calculated by summing the numbers of responses emitted during all 3-min actions of the CS and in 3-min periods immediately prior to consecutive CS onsets of a given CER acquisition session. To evaluate the immediate effect of the CS offset and US presentation on the on-going behavior, the number of bar presses emitted during the first min after the CS and US termination was collected (the C1 score) and comparted with the rate of responding before the CS onset using the formula 3C1/(A + 3C1). During extinction sessions, the suppression ratios were computed for each consecutive 3-min period of the prolonged CS presentation and, in each case, the number of responses emitted ~mmediately before CS onset was used as the A score in the "suppres- sion ratio" formula.

At the completion of the study, the subjects were administered a lethal dose of sodium pentobarbital and intracardially perfused with a 10°/o formalin solution. The brains were removed from the cranium and stored in formalin solution for several days. Each brain was cut frozen at 50 p frontal sections and stained with the Nissl method.

RESULTS

CER acquisition. The groups differed i n the frequency of bar presses emitted in absence of the CS (Fig. 1). A mixed design analysis of va- riance based on daily A scores for D-day, P-day, and the 1-7 CEIt days

C E R t r a l n l n g

Fig. 1. Median numbers of bar-press responses per minute emitted during D-day, P-day and CER training in the control Group (filled circles), the dorsohippo- campal group (triangles), the ventrohippocampal group (squares), and the entor-

hinal cortical group (open circles).

revealed significant group effects (F3/,, = 3.43, P < 0.05). Further, Dun- can tests showed that Group VH and Group EC differed from each other ( P < 0.01), whereas the other lesioned groups did not differ statistically from either VH or EC Groups. The overall level of responding decreases with progressive CER training and the effect of daily sessions was highly significant (F,,,,, = 6.53, P < 0.001). Duncan tests showed diffe- rences between the D-day and the 2nd-7th days of CER acquisition, be- tween the P-day and the 4th-6th days and between the 1st day of CER and the 4th or 6th days ( P s < 0.01). Daily A scores for the 2nd or 3rd CER day differed each from those for the 6th day ( P < 0.05). No diffe- rences were found among 4th-7th CER days. The lowest A scores were observed on the 1st ,CER day for Group C, at the 4th CER day for Groups DH and EC, and at the 6th CER day for Group VH. However, the interaction between the two main effects was negligible (F < I), probably due to marked individual variability of the scores and clear daily fluctuations of the A scores in Groups DH and VH.

The first presentation of the CS during the P-day attenuated bar pressing, while the next presentations of the CS during this session rather accellerated the on-going responding. The analysis of variance revealed differences among suppression ratios in consecutive presen- tations of the CS during the P-day (F3/60 = 4.02, P < 0.01), and Duncan tests showed significant differences between the 1st and the 2nd CS presentations ( P < 0.005) and between the 1st and 3rd CS presentations ( P < 0.05). Neither the group effect nor the interaction reached signi- ficance.

During the first day of CER training the median daily suppression

ratios estimated for each group independently were close to the 0.50 vhlue, similar to the P-day (Fig. 2). On the next day of training, the median daily suppression ratios for each group were below the 0.50

Fig. 2. Median daily suppressi~on ratios during D-day, P-day and CER training. Group denotations as in Fig. 1.

level with the greatest suppression in Group C and weakest in Group DH. Smooth learning curves with low suppression ratios were obtained in Groups C and VH only. Training was more rapid in Group C, in which median daily suppression ratios reached asymptote on the 4th CER day, whereas for Group VH the asymptote was reached on the 6th CER day. Then, gradual recovery of bar-pressing during the CS actions was observed in both group. Group EC was only slightly worse than Group C in terms of suppression ratio scores, however marked day-to- day fluctuations in suppression ratios were observed in this group. Group DH showed very moderate suppression throughout training with substantial day-to-day fluctuations of the ratio scores. The analysis of variance revealed a highly significant effects of progressive daily sessions (F6II2, = 21.58, P < 0.001), a significant main effect of group difference (F3,,, = 2.59, P < 0.05) and a significant interaction (Fleilzo = 1.92, P < < 0.05). The Duncan tests showed that the daily suppression ratios for the 3rd-6th CER day differed each from the suppression ratios of the 1st and the 2nd CER day (Ps<O.Ol). Suppression ratios for the 7th CER day differed from those for the 1st and the 2nd CER day (Ps < < 0.05).

The Duncan tests based on the cell means used for the evalu i t ' lon of the interaction showed that in Group C suppression ratios for the 3rd-5th CER days differed from those estimated for the 1st CER day (Ps < 0.01). In Groups VH and EC such differences were observed for the 3rd-7th CER days, and in Group DH only the suppression ratios for the 6th CER day differed from those for the 1st CER day a t a weaker level of significance (P < 0.05). In Group VH the suppression ratio for the 5th CER day differed also from that estimated for the 2nd CER day (P < 0.01). Other within group differences between daily suppression ratios of the CER training were not significant. The results of this ana- lysis reflected between group differences in the rapidity of CER acquisi- tion. The day in which a given group reached asymptotic value of suppression may serve as an index of the rapidity of learning. These measures were: the 3rd CER day for Group C, the 4th for Group EC, the 5th for Group VH, and the 6th for Group DH.

It should be mentioned that the overall comparison of the curves presented in Figs. 1 and 2 indicated a lack cf correspondence between levels of the A scores and the suppression ratios.

Median daily ratios of 3C1/(A + 3C1) presented in Fig. 3 showed the immediate effect of the CS and US offsets on the on-going bar-prcssirg behavior. The curves presented in Fig. 3 indicate that during the P-day and first three CER days, just after the CS (or CS plus US) offsets, the rate of bar pressing was lower than before the CS onset, and on the

subsequent CER training sessions these differences were not stable. An analysis of variance of the daily ratios of 3C1/(A + 3C1), estimated for the 1st-7th CER days, revealed a significant effect of daily sessions (F6/120 = 3.38, P < 0.005), but the group effect and the interaction were not significant. The lowest level of scores was observed during the 2nd CER day and they differed from those for the 6th and 7th CER days (Ps <0.01) and from scores for the 4th and 5th CER days (Ps < 0.05). In spite of the fact that the interaction was not significant (FIUlz0 = 1.38, P < 0.1), some differences between groups and days appeared. I t was found that during the 2hd CER day for each rat from Group C and also from Group EC the scores were lower than the 0.50 value, so that the suppressing effects of the CS plus US offsets was significant for this day and these groups at the P < 0.05 level (comparisons between A and 3C1 values, Wilcoxon test). In no other group or day did these differen- ces reach an acceptable level of significance.

Fig. 3. Median daily ratios of 3C,/(A + 3C1) indicating the immediate effect of the CS or the CS plus US offsets on bar-pressing rates during D-day, P-day and

CER training. Grpup denotations as in Fig. 1.

Extinction of the CER. The effect of the extinction procedure may be analyzed in different ways. To begin with we compared suppression ratios during the first presentation of the CS on the 7th CER day with suppression ratios estimated for the first 3 min periods after the CS onset on each extinction session. An analysis of variance showed that the group effect fell short of significance (F3120 = 2.89, P < 0.1) with the most pronounced suppression for Group C and the weakest suppres- sion for Group DH. As expected, in each consecutive extinction session the CS onset exerted a weaker suppressive effect on the on-going bar- pressing behavior. This finding was evident in the significant effect of progressive days (F3/60 = 8.18, P < 0.001). The Duncan tests revealed diffe-

7 - Acta Neurobiol. Exp. 8/81

rences between the suppression ratios on the 1st CS presentation during the 7th CER day and those during the 2nd and 3rd extinction dayis, each significant at P < 0.001, and between the 1st extinction day and the 2nd extinction days, each significant at the P < 0.01 levels. Smooth extinction curves were observed for each group but the DH Group, in which the median suppression ratios estimated for the first 3 rnin period after the CS onset showed considerable day-to-day fluctuations. However, the group and day interaction was not significant.

The suppressive effect of the CS on the on-going behavior persisted longer than for the 3 rnin period after the CS onset. Fig. 4 shows sup-

I s t Ex t 2nd E x t 3 rd E x t

Fig. 4. The course of CER extinction in the ist-3rd extinction session. Suppression ratbos are presented for 10 ,consecutive 3-min periods of the p~olonged CS action.

G ~ o u p dendabions as in Fig. 1.

pression ratios estimated for the first ten 3 rnin periods of the CS action for each group and extinction session independently. As seen, during the first extinction session Group C was marked by strong sup- pression lasting longer than the 30 rnin of the CS action, whereas in the other groups the bar-pressing rate recovered to the pre-CS level after about 15 rnin of CS action. In the s e c o ~ d extinction session a mar- ked suppressive effect of the CS was observed in Groups C and EC, whereas in Groups DH and VH the suppression ratios fluctuated around the 0.50 value. Some residual suppressive effect of the CS was observed in all groups during the third extinction session. An analysis of variance revealed a group effect (F3Iz0 = 3.44, P < 0.05), an effect of consecutive 3 rnin periods of CS action (F91360 = 8.33, P < 0.001), and also the inter- action between extinction sessions and consecutive 3 rnin periods of CS action (F181360 = 4.39, P < 0.001). This interaction reflects significant dif- ferences between the slope of the extinction curves observed during the first extinction session and on the next sessions.

One of the effects of CER extinction procedures is the recovery of the rate of bar presses in periods when no CS is presented. The com- parison of the bar press rates in A periods before the first CS presen- tation of the 7th CER and the 1st-3rd extinction days is presented in Fig. 5. The analysis of variance showed group (F3,,, = 3.20, P < 0.05) and

Fig. 5. Median numbers of bar-press responses per minute emitted during 3 min periods before the CS onset on the 1st trial of the 7th CER training session and before CS onsets on the 1st-3rd extinction sessions. Group denotations as in

Fig. 1.

session (F,,,, = 4.06, P < 0.025) effects. The Duncan tests revealed that Group VH differed ( P < 0.05) from the Groups DH and EC. The lowest level of baseline responding was observed during the 7th CER day and it differed ( P (0.01) from that during the 3rd extinction day.

Histology. The results-of histological verification of the lesions are presented in Fig. 6. Histological cross sections for typical rats from each group are presented also in Fig. 7.

Examination of the slides for Group DH revealed that the damage comprised bilaterally a portion of the anterodorsal part of the hippo- campus and the dentate gyrus, with considerable sparing of t h most lateral and medial aspects of these structures. In one rat the dentate gyrus was intact unilaterally. In all animals the alveus was slightly damaged in the plane a t which the maximal lesion was inflicted. No damage to thalamic structures was noted in any cases.

The lesions in Group VH were restricted to the posteroventral part of the hippocampus including also the dentate gyrus. The upper portion

Rot 22

Rot 1L

Fig. 6. Reconstructions of the lesions for the DH (left), ,VH (middle) and EC (right collumn) groups.

of the 'hippocampus was left intact in all cases. The subiculum was partially invaded in all rats. In three animals some damage to the ante- roventral part of the hippocampus was observed.

The lesions in Group EC bilaterally damaged mainly the deep layers of the medial entorhinal cortex, although some destruction of the lateral entorhinal cortex was also found. The most medial and lateral parts of this cortex remained intact. The angular bundle, which cacries the projection from the entorhinal area to the hippocampal formation, as well as the subiculum, were damaged bilaterally to some extent in all six rats.

DISCUSSION

The variable investigated in the present experiment was the locali- zation of small electrolytical lesions within the hippocampal formation. These lesions resulted in between group differences of the following measures of behavior: (i) the rate of on-going bar-pr.?ss responding. (ii) the rapidity of the CER acquisition, and (iii) the persistence of the suppressing effect of prolonged CS action during CER extinction.

Fig. 7. Histological cross sections for typical rats from each lesioned group.

The highest level of on-going bar-press responding was observed after lesions in the ventral hippocampus (Group VH) and the lowest after lesions in the entorhinal cortex (Group EC). These groups differed significantly on this measure both during CER acquisition and CER extinction. Additionally, during the CER extinction sessions, Group VH had a higher bar press rate than Group DH.

Due to the very restricted lesions employed in the present study it is difficult to compare our results with those obtained by other authors with rather massive hippocampal ablations. Nevertheless it is worth mentioning that hippocampally ablated fats learned to press a lever for food or water reward more rapidly than normals (3, 20). Further, it has been shown that switching from a continuous to a va- riable interval reinforcement schedule resulted in a smaller reduction of the lever-pressing rate in hippocampally lesioned rats than in ;lor- mals (11). These data suggest greater strength of bar-pressing in ape- titively motivated responses in hippocampally lesioned rat? than in normals. Our data indicate that lesions in the ventral hippocampus are respon~ible for the elevated bar pressing rate. Such a n effect from ven- tral hippocampal lesions was expected by Smaltz and Isaacson (20) when they discussed reasons for discrepances of their results and those ob- tained by Ellen et al. (6, 7) on rats with lesions confined to the most dorsal aspect of the hippocampus.

The course of CER acquisition was different in each group, however, clear retardation was observed in Group DH only and the suppressing effect of the C S was the weakest in this same group. In other lesioned groups acquisition of the CER was slower than in the control rats, ne- vertheless the figures with daily suppression ratios for Groups C, EC and VH were intercrossed.

Marked attenuation of the CER after dorsal hippocampal lesions was not observed by other authors, who reported either no change (14) or even enhancement (16) of CER after similar selective hippocampal lesions. Significant differences in methods may be responsible for these discrepances. In other studies reporting the effects of selective dorsal hippocampal lesions on CER, the on-going behavior was a licking re- sponse for water (or sugar solution) reinforcement, the CS-shock pairings were given in a different experimental situation and then the effects of aversive conditioning were tested in the licking chamber under extin- ction conditions, using latencies of the licking response as the primary measure of CER magnitude. Moreover, it has been shown that the effects of hippocampal lesions on CER are dependent on the reinforcing value used. When the licking response was reinforced with strong incen- tive (32010 of sucrose), hippocampally lesioned rats showed a weaker

CER than in sham operated rats, whereas with a weak incentive (4O/o of sucrose) hippocampals showed a stronger CER than controls (9). Thew results indicate that comparisons between experiments ecploying diffe- rent reinforcements of the on-going behavior has to be done with a great caution.

The highest resistance of the CER to extinction was observed in the sham operated rats. Not only during the first prolonged CS action but also in the next extinction sessions, the suppressing effect of the CS lasted longer than 30 min in Group C. During the first extinction session no differences were observed among the lesioned groups. Ho- wever, on the next day the suppressing effect of the CS in Group EC was comparable with that in Group C, whereas in both hippocampal groups the CS did not change the bar pressing r a t s Thus, as compared with the level of suppression established toward the end of the training, the persistence of the CER was greater in Group EC. On the other hand, neither Group DH nor Group VH were deficient in extinction of the defensive response elicited by the CS onset.

In summary, the results of the present experiment indicate functio- nal differentiation of the hippocampal formation. Comparison of the results of the present experiment with those obtained by other authors suggest that methodical details may have important influences on the behavior of hippocampally lesioned animals.

We are greatly indebted to Mrs. G. Walasek and Mrs. M. Wesierska for in- valuable technical assistance.

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Natalia P . BALEZINA, Institute of Higher Nervous Activity and Neurophysiology, USSR Academy of Sciences, Butlerova 5a, 117485 Moscow, USSR.