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ACTA NEUROBIOL. EXP. 1977, 37: 151-177

DIFFERENTIAL EFFECTS OF DORSOMEDIAL PREFRONTAL LESIONS ON ACTIVE AND PASSIVE AVOIDANCE IN YOUNG

AND ADULT RATS

James F. BRENNAN, Evelyn A. POWELL and John P . VICEDOMINI

State University of New York, College a t Buffalo Buffalo, New York, USA

Abstract. In Experiment I, four weanling and four adult rats had dorsomedial prefrontal lesions administered prior to initial 2-way avoidance acquisition, while in Experiment I1 surgical procedures for eight subjects were interpolated between acquisition and a first generalization test along CS tonal frequency. Results indicated impairment of initial avoidance acquisition following lesions, which recovered after a 30-day interval, permitting generalization testing in extinction. When DM lesions were interpolated between acquisition and testing, the effects on avoidance responding were comparatively minimal, but after 30 days lesioned subjects could not reacquire criterion avoidance levels. In all generalization tests there was little evidence of frequency control in lesioned subjects compared to eiiht sham operated controls of each age. Age effects in both experiments were confined to somewhat greater deficits and less recovery of responding in the pups. Two additional experiments examined passive avoidance acquisition and retention in 144 rats of 18-20, 30-32 and 1004- days of age after dorsomedial prefrontal lesions administered either prior to (Experiment 111) or following (Ex- periment IV) initial training and testing. These data suggested rather minimal lesion effects since variability in retention was readily attributed to age differences. Data were related to prefrontal deficits that are specific to age and task requirements.

INTRODUCTION

Ontogenic relationships in aversively motivated behavior have 'typically indicated age-related differences in the acquisition and retention of behavior classes that involve response inhibition. For example, Schu-

lenburg, Riccio and Stikes (39) reported improved acquisition of passive avoidance that increased among rats ranging in age from 15 to 100 days. Further, an age-dependency was found in retention of passive avoidance, even when initial acquisition was equated across ages by prolonged training for younger subjects. Age-related influences on active avoidance behavior are not as clear. Several studies (e.g., 15, 19, 35) reported acquisition of one-way active avoidance to be relatively invariant across ages, while Egger and Livesey (14) found acquisition deficits in immature subjects when the performance criterion was made more stringent (see also 20). Age differences in extinction of active avoidance have emerged with response produced punishment (36), after CS habituation (42) or with a complexity of CS cues (2). Conversely, assessments of stimulus control between ages revealed highly comparable generalization gradients in the context of two-way active avoidance learning (see 4, 37). Distortions of CS generalization gradients relative to age have been found, however, when Pavlovian discrimination training is interpolated between avoidance training and generalization testing (5) and seem to involve age deficits in inhibitory control generated from CS-(1). Accordingly, the empirical evidence suggests that performance deficits in younger rats are apparent when a response inhibitory component is emphasized in the task requirements. Campbell and Spear (8) have examined behavioral findings with respect to neurological and metabolic changes during development in the rat. They concluded that response inhibitory behavior deficits are related to parallel neurobiological changes that are most dramatic in the develop- ing rat to approximately 35 days of age.

The major purpose of this study focused on differences in cortical maturation as measured by lesion deficits in young and adult rats. Alt- hough there is little precedence concerning selective cortical effects on aversively motivated behavior in rats, studies of prefrontal injury on discriminative alimentary behavior have been reported. Eukaszewska (28) found response perseveration after frontopolar (FP) ablations in adult rats related to the difficulty of discriminating alternatives, and attributed such deficits to decreased utilization of proprioceptive cues (29, 30). If the delay between stimulus and response is omitted (16) or if the response to be alternated is made visually discriminable (10, 27), FP lesions do not necessarily lead to perseveration. Eukaszewska (29) has suggested that FP rats compensate for deficits associated with spatial or positional discriminative requirements through alternative cue utilization.

Extending her data to other prefrontal sites, Eukaszewska (31) found that frontomedial lesions resulted in impairment of delayed response mediation. Other investigators have assessed functionally dissociable effects of selective ventrolateral (VL) and dorsomedial (DM) lesions to

prefrontal cortex (e.g., 24). Anatomically, both prefrontal subregions represent dissociated projection sites of thalamocortical fibers, Efferents to the VL and DM subregions arise from the anterior and posterior portions of the nucleus medialis dorsalis respectively (12, 25, 26). Functional dissociations between VL and DM subregions in rats have been reported for a variety of responses: activity (21, 33), emotionality (34), social behavior in open field situations (22), activation of consumma tory regulation (23), and spatial reversal, delayed reinforcement, DRL schedules and bar press extinction (24). Comparison of DM and VL lesion effects revealed that in tasks involving postoperative retention and performance of delayed alternation or spatial reversal, DM lesions produced greater deficits than VL lesions (11, 41). Behaviorally, the DM/VL ditinction is maintained in a strikingly similar fashion to that of dissociated orbital and dorsolateral prefrontal areas in primates (e.g., 32, 38).

This study reports four experiments that examined DM lesion effects on discriminative performance in rats under conditions of aversive mo- tivation. Further, the experiments attempted to delineate prefrontal effects on aversively motivated tasks that have demonstrated behavioral sensitivity to maturational differences (passive avoidance) and that have been shown to be relatively comparable across ages (control of active avoidance).

EXPERIMENT I: EFFECTS OF DORSOMEDIAL LESIONS ON ACQUISITION AND GENERALIZATION OF 2-WAY ACTIVE AVOIDANCE IN YOUNG ADULT

RATS

Subjects. Sixteen naive male Sprague-Dawley albino rats of the Wistar strain bred in the animal colony of State University College served as subjects. Half of the subjects were pups weaned a t 20 days of age and housed in pairs, while the remaining eight subjects were adults housed singly. Food and water were available ad lib. in the home cages for both age groups. Half the subjects at each age level were assigned to the lesion condition and the remaining subjects served as sham operated controls. Surgery was administered a t 20 days of age for the pups and a t 60 days of age for adults. Avoidance training in both age groups began after a 4-day recovery period.

Apparatus. Acquisition training and generalization testing were con- ducted in a clear acrylic double compartment shuttle box measuring 74 cm long X 22 cm wide X 30 cm high. Subjects could move between compartments through a 9 X 9 cm opening in the center partition. For the young subjects acrylic inserts in each compartment reduced the space of mobility to 25 cm long X 14 cm wide. Shock from a matched

2 - Acta Neurobiologiae Experimentalis

impedance source (9) was delivered to the steel grid floor through a Foringer Shock Scrambler. Campbell (7) has reported shock-induced activity data indicating that matched impedance shock is perceived as equally aversive across ages in rats a t moderate intensities. Photocells were mounted 14 cm from the center partition in each compartment; the distance between photocells was constant for both age levels. Tonal stimuli were presented through two 10 cm speakers mounted on the acrylic lid covering each compartment. Tonal frequencies of 1,000-, 2,000-, 3,000-, 4,000-, 5,000-Hz were delivered from a Heathkit Audio Generator (Model IGW-18) and the intensity of the 3,000 Hz tone was measured a t 74 dB (0.0002 dynelcmz) a t the center of the chamber by a sound level meter (General Radio Corp. Model 551-C). Variations of tonal intensity at the five frequency values did not exceed 5 2 dB (SPL). A Standard Electric Timer activated with CS onset and terminated by interruption of a photocell beam permitted measurement of response latencies to 1/100th s. A 15 W bulb suspended over the center of the apparatus provided the only room illumination.

Subjects in the surgical and sham-operative groups were mounted in a stereotaxic frame manufactured by David Knopf Instruments. Skull holes were made using an Emesco Dental drill. In surgical subjects a radio frequency lesion generator (model FRG-4) manufactured by Radionics, Inc. activated an insulated electrode tip of 1 mm exposure.

Procedure

1. Surgery. All subjects were anesthetized with an IP injection of sodium pentobarbital (Nembutal 50 mglkg). Each subject was placed in the stereotaxic, a midsagittal incision was made and periosteal tissue was deflected. For each subject the angle of head placement in the stereotaxic was determined. Briefly, the distance between Bregma and Lambda skull references along the 0 sagittal plane as well as the displacement between both points were calculated. These measurements defined two arms of a right-angle triangle having a hypotenuse that indicated the skull orientation relative to a horizontal 0 plane from the point of inter- aural intersection. The ratio of Bregma-Lambda sagittal distance to the dorsoventral distance yielded the tangent of the appropriate skull re- ference angle. Accordingly, with the upper incision bar of the stereotaxic kept constant the specific angle of placement was determined for each subject, which could then be used to lower the lesioning electrode. In addition, the individual angles could be replicated when the brains were blocked prior to sectioning. Two trephin holes were drilled 2 mm bila- terally from the midline suture a t Bregma and 4.0 mm anterior to Bregma in the adults, and 2.3 mm anterior in the pups. The electrode

tip was lowered to a depth of 1.5 mm from the dura a t the appropriate orientation angle of each subject. After grounding of each surgical subject, a tip temperature of 70 " C was maintained for 1 min for the surgical subjects while the electrode tip was not activated for the sham- operated subjects. Subjects were returned to the home cage for 4 days recovery.

2. Avoidance training. At ages 24-25 days in pups and 64-65 days in adults avoidance training began. Subjects received 100 trials per day on 3 consecutive days. On a given training trial, onset of a 3,000 Hz tone was followed 5 s later by foot shock of 175 V. Shuttle escape responses elicited after shock onset coterminated both the shock and tone, while shuttle responses emitted within the 5 s interstimulus interval terminated the tone and precluded shock occurrence. Training trials in which subjects did not escape within 30 s after shock onset were automatically terminated. Trials were separated by a varying interval aver- aging 30 s. Intertrial crossings did not affect the avoidance contingency since interruption of a photocell beam opened the circuit until the beam in the opposite compartment was broken.

3. Generalization testing. The original experimental sequence planned a frequency generalization test immediately after initial avoidance training and then repeated 30 days after surgery. However, a stable avoidance criterion was not obtained after 3 days of training so that subjects were returned to their home cages and 26 days later were again retrained for 3 consecutive days. On the fourth day, after subjects attained a criterion of five consecutive avoidance responses, the shock was disconnected and a frequency generalization test proceeded during avoidance extinction. Tones of 1,000-, 2,000-, 3,000-, 4,000-, 5000-Hz were presented on successive trials with the order randomized within blocks of five testing trials. Response latencies to each test value were recorded, and if a subject did not respond within 12 s of tonal onset, the trial was automatically terminated. The testing session ended if a subject failed to respond on five consecutive trials, or if 100 test trials elapsed, which- ever occurred first. For data analysis and presentation, trial latencies were converted to speed scores by calculating the reciprocal of latency for each test trial.

4. Histology. Following the 30-day generalization test, subjects were administered a lethal dose of sodium pentobarbital, and intracardially perfused with 100la formalin. The brains were then removed from the cranium and stored in 30°/o formalin for 4-6 days. Each brain was blocked a t the angle of lesioning, frozen and serially sectioned at 100 :Lm throughout the extent of the lesion. Mounted sections were stained with cresyl violet.

Results and discussion

Histology. Figure 1 shows representative series of coronal sections for the smallest, median and largest lesions in both young and adult subjects. Reconstructions of lesion sites revealed that the damage was largely confined to the neocortei and a small portion of the genu corpus collosum.

Fig. 1. Reconstructions of the lesion sites as coronal section representations in the young (Y) and adult (A) subjects of Experiments I and 11. The first panel (1) indicates lesion extent from a site approximately 4,170 pm anterior to Bregma, the second panel (2) contains reconstructions of lesions approximately 4,000 lim from Bregma and the third panel (3) shows reconstructed lesions a t 3,840 pm anterior to Bregma. Shaded areas indicate the smallest lesion damage, hatched marks show median lesion size and the open areas indicate the extent of the largest lesions. Note that the young subjects were 60 days of age when sacrificed. Cag, agranular cortex; Cg, granular cortex; FMI, forceps minor; GCC, genu corporis callosi; TCC, truncus corporis callosi; RCC, radiatio corporis callosi; cp, n.

caudatus putamen; VL, ventriculus lateralis.

Behavioral data. Four days after surgery, subjects began avoidance training, and none of the lesioned pups or adults attained acquisition criteria during the 3 days of testing, while all sham subjects acquired consistent avoidance behavior. Examination of the number of avoidance responses indicated that the overall effect of Age was nonsignificant (F < I), while the Surgery variable produced a significant effect between lesioned and sham subjects (F(1112) = 48.10, P < 0.001, w" 0.54) 1. Since the number of avoidance responses increased with successive training, a significant effect from repeated measures over the 3 days of training emerged (F(2124) = 31.53, P < 0.001, co2 = 0.20) as well as a significant Days X Surgery interaction (F(2/24) = 3.42, P < 0.05, w2 = 0.02). Another dependent variable examined during avoidance training involved a measure of activity, assessed by intertrial crossings. This index revealed only that the number of intertrial crossings increased during the 3 days of training (F(2124) = 21.85, P < 0.001, o2 = 0.22). The main effects of Age (F < 1) and Surgery were insignificant, as were all interactions.

Subjects rested in their home cages for 30 days after surgery, a t which time avoidance reacquisition training began. The number of avoidance responses during reacquisition indicated a significant increase over the 3 Days of Training (F(2/24) = 67.22, P < 0.001, w2 = 0.52), and there was also a significant Days of Training X Surgery interaction (F(2124) = 6.37, P < 0.01, w2 = 0.04). On closer scrutiny the latter finding indicated that operated pups and adults tended to have less avoidance responses than the shams on Day 1 of training, but revealed little difference in number of avoidances on Days 2 and 3. The main effects of Age, Surgery, their interaction, as well as interactions with Age and Days were insignificant (every F < 1) suggesting relatively comparable avoidance performance among groups after 30 days rest. The number of intertrial crossings indicated significant effects of Age (F(1111) = 6.42, P < 0.05, w" 0.12), with the pups having greater intertrial crossings than adults. A decrease in crossings for all ages across the Days of Training (F(2124) = 5.56, P < 0.05, w2 = 0.12) was noted as well. The main effect of Surgery (F < 1) and all interactions were insignificant.

On the fourth day of retraining, subjects were exposed to the avoidance contingency until a criterion of five consecutive avoidance resp-

Analyses of the data often revealed highly significant effects in terms of probability levels of Type I errors. To better differentiate among significant effects, tests of the strength of the relationship between independent and dependent variables are reported for each significant effect. The statistic we accounts for the proportion of total variability by the relationship, and the rationale for such a test is described by Hays (17), while Dodd and Schultz (13) offer applications to commonly used analysis of variance designs. w

onses was obtained. Analysis of the number of trials to criterion revealed significant effects from the Surgery variable (F(1112) = 7.21, P < 0.05, mz = 0.22) and the interaction of Age X Surgery (F(1112) = 7.97, P < 0.05, cur = 0.24). The lesioned adult group (X = 63.75) was largely responsible

PUPS

FREQUENCY IN HZ

Fig. 2. Individual gradients of generalization for lesioned (L) and sham operated control (C) pups and adults to varying tone frequency values 30 days after sur-

gery in Experiment I. Original CS = 3,000 Hz.

for the disparite trials to criterion; the mean numbers of trials to criterion were 24, 39, and 40 for the sham adults, lesioned pups and sham pups respectively.

Following avoidance criterion on Day 4 of retraining, a test for frequency generalization under extinction conditions followed. Figure 2 shows mean individual gradients for the subjects in this experiment. As the data indicate, fairly symmetrical gradients were obtained from sham subjects of both ages, while little evidence of systematic control is suggested by the gradients of the lesioned subjects, with the exceptions of P28 and A23. Analysis of these data confirms the impression from Fig. 2. That is, significant effects Stimuli (F(4148) = 13.28, P < 0.001, (19 = 0.23) and the Surgery X Stimuli interaction (F(4148) = 10.03, P < 0.01, w2 = 0.17) were found, while the main effects of Age, Surgery and all remaining interactions were nonsignificant (F < 1). The number of trials during the generalization test did not differ according to age or surgical conditions.

The results of this experiment suggest that the effects of dorsomedial prefrontal destruction were nondifferential a t both ages. Specifically, a pronounced disruption in avoidance acquisition resulted immediately after surgery in all lesioned subjects. Although the 30-day rest produced recovery of avoidance behavior, discriminative stimulus control was not spared in six of the lesioned subjects. Further, the age difference a t the time of surgery did not emerge as a critical variable.

EXPERIMENT 11: EFFECTS O F DORSOMEDIAL LESIONS ON RETENTION AND GENERALIZATION OF %-WAY ACTIVE AVOIDANCE IN YOUNG AND

ADULT RATS

Method

Sixteen experimentally naive, male albino rats of the Wistar strain, bred in our animal colony served as subjects. Half of the subjects were pups weaned a t 20 days, and avoidance training began at 24 days of age, so that the age a t initial conditioning was constant between Experiments I and 11. The young subjects were administered the surgical treatments after 3 days of avoidance training when they were 27 days of age. The remaining eight subjects were adults of 60+ days of age. The apparatus was identical to that described for Experiment I.

The design of this experiment was similar to that of Experiment I, with the single major exception that surgical treatments were interpolated between initial avoidance acquisition and generalization testing. More specifically, subjects received 3 days of avoidance training in the manner described for Experiment I. Subjects that made fewer than 25 avoidance responses on Day 2 of training were discarded from the experiment and

replaced with naive animals. Under this criterion, one young subject was eliminated from the experiment. After the third avoidance training session, half of the subjects a t each age level received bilateral lesions of the DM prefrontal cortex using the previously described technique. The remaining eight pups and adults served as sham-operated control subjects. Four days following the surgical treatments, all subjects were trained for reacquisition of shuttle avoidance until the criterion of five consecutive avoidance responses was met. The shock source was then disconnected, and a frequency generalization test proceeded immediately. Procedures were identical to those outlined for Experiment I. When the extinction criterion of either five consecutive failures to respond or the elapse of 100 test trials was met, subjects were returned to their home cage. At 30 days post-operative recovery, subjects were retrained in shuttle avoidance for the purpose of administering a second generalization test.


Histology. Examination for the extent of lesion damage in the surgical subjects indicated highly comparable destruction to the areas re- presented in Fig. 1.

Behavioral 'data. Initial presurgical acquisition training resulted in greater vigor in the avoidance level of the adults, although both adults and pups successfully met the minimal number of avoidance responses on Day 2 of training. The number of avoidance responses over the 3 days of presurgical training indicated significant effects of Age (F(1112) = = 41.54, P < 0.001, 0 2 = 0.28) and successive Days of Training (F(2124) = = 28.06, P < 0.001, 0 2 = 0.38), while none of the interactions were significant sources of variation. Further, during acquisition training, the adults showed more intertrial activity than the young subjects (F(1112) =

= 10.31, P < 0.01, w* = 0.20). Postsurgically, there was no reliable difference due to age in the

number of trials required to obtain five consecutive avoidance responses. However, the lesioned subjects a t both age levels had more difficulty reaching avoidance criterion than the sham control subjects (F(1112) =

= 15.93, P < 0.005, o2 = 0.25). Individual mean gradients of running speeds to the five test frequency values are shown in Fig. 3. Fairly symmetrical gradients around the original avoidance CS value of 3,000 Hz were obtained from sham controls of both ages, while all lesioned animals yielded gradients that were unsystematically related, to frequency values. Analysis of the speed scores to each test stimuli indicated the main effects of Age (F < I), Surgical treatment and their interaction

(F < 1) were nonsignificant. The effect of testing frequency collapsed across age and surgical conditions revealed significance (F(4/48) = 3.67, P < 0.05, w2 = 0.10) as did the interaction of Surgical Treatment X Test Stimuli (F(4148) = 3.60, P < 0.05, w2 = 0.10). That stimulus control was differently affected by age and surgical treatment was supported by the lack of significant differences in the number of test trials as a function

FREQUENCV IN HZ

Fig. 3. Gradients of mean speed to the test frequency values 4 days after surgery in Experiment I1 for lesion (L) and control (C) pups and adults.

of these variables. Accordingly, the data from immediate postsurgical generalization testing suggest that avoidance responding was spaied after dorsomedial lesions, but frequency control was severely disrupted a t both age levels.

A very dramatic regression in avoidance response levels of the lesioned animals was apparent when the subjects were retrained to the reacquisition criterion of five consecutive avoidance responses 30 days after surgery. Specifically, three of the lesioned pups failed to attain criterion within 150 trials, while the remaining young subject (PI) re-

FR'EQUENCV I N nz Fig. 4. Generalization gradients obtained 30 days after surgery in Experiment 11 from those lesioned subjects (L) that attained acquisition criterion (top panel) and

all sham operated controls (C).

quired 75 trials to meet criterion avoidance. Within the lesioned adult groups, one subject (A4) failed to reacquire the appropriate level, two subjects (A5 and A9) needed 100 training trials and the fourth animal (A2) took 21 trials to meet criterion. Among the sham groups, means of 83 and 65.65 trials to criterion were obtained from the pups and adults, respectively; the difference,between groups was not statistically significant. Figure 4 shows the mean gradients obtained from subjects that did meet avoidance criterion. Among the three adult and one young subjects (top panel) the response speeds were unrelated to test frequencies as was typically found during immediate postsurgical testing. However, the comparative elevated levels of response speeds, especially in subjects A2 and A9, are striking. In the sham control groups, reliably symmetrical gradients around the 3,000 Hz values were again obtained, and analysis of the control data revealed significant effects from Test Stimuli (F(4124) =

= 62.89, P < 0.001, (u2 = 0.80), while both the effects of Age and Stim- uli X Age interaction were nonsignificant. Comparison of gradients from initial (Fig. 3) to second (Fig. 4) generalization tests in the control sub- jests suggests comparable control. This impression is supported by the analysis of generalization in both tests, which revealed no differences due to Age (F < 1) and TestjRetest (F < 1) performance, while the effect of varying stimuli in both tests was significant (F(4124) = 11.62, P < 0.001, to2 = 0.37).

The data from this experiment indicate minimal interference from lesion damage on already-established avoidance behavior when subjects were retrained immediately after surgery. However, rather clear re- gressive effects in avoidance levels emerged from same subjects when examined 30 days postsurgically. Further, the disruptive effect noted 30 days after surgery was more pronounced in those subjects that incurred' lesion damage earlier ontogeny. With respect to generalization, there was little evidence of control by frequency in either age group immediately after surgery or in those subjects that reacquired the avoidance response 30 days later. In addition, more rapid latencies were found in the four lesioned subjects tested 30 days after surgery when compared to their overall response levels during the initial generalization test.

EXPERIMENT 111: EFFECTS OF DORSOMEDIAL LESIONS ON POST-OPERATIVE ACQUISITION OF PASSIVE AVOIDANCE AND ITS

STABILITY IN YOUNG AND ADULT RATS

Method

Subjects. A total of 72 male albino Sprague-Dawley rats were se- lected from each of the following age levels: 18-20, 30-32, and 100+ days of age. The younger subjects were weaned at 21 days of age and

housed in groups of four animals while the adults were housed singly. Food and water were available ad lib. in the home cages.

Apparatus. All subjects received avoidance training in a two-compartment chamber measuring 74 cm long X 22 cm wide X 30 cm high, and the compartments were separated by a wall containing a 9 X 9 cm opening with a guillotine door. For the pups, acrylic inserts were used that reduced the space of mobility in each compartment to 25 cm long X 14 cm wide. The floor of both compartments consisted of steel grids spaced 1.5 cm apart. The walls and lid of the start or "safety" compartment were white, with a continuously activated white jewel light mounted on the wall opposite that of the door opening separating compartments. The "fear" compartment had black walls and lid, and the grid floor was connected to a matched impedance shock source through a Foringer Shock Scrambler. During a given shock series, five inescapable 175 V shocks of 0.5 s duration were delivered to the floor grids of the black side of the chamber, and the shock presentations were separated by intervals of 1 min. Cross-through latencies were recorded from a stop- watch. The apparatus used for surgery and lesion administration were the same as described in Experiment I.

Procedure. Three groups of eight subjects a t each age level were assigned to either a lesion treatment, sham control condition or nonoperated control treatment. Subjects in the lesion and sham treatments were anesthetized with sodium pentobarbital (Nembutal 50 mglkg) and placed in the stereotaxic apparatus. Administration of the DM lesions and treatment of sham control subjects were similar to that described in Experiment I. Coordinates were 2.0 mm bilateral to the midline suture, and points anterior to Bregma were 2.3 rnrn for the 18-20 day-old pups and 4.0 mm for the 30-32 day-old and adult subjects. The nonoperated control subjects were simply handled briefly in their home cages.

Four days after the surgical treatments or handling, all subjects received passive avoidance training by initial placement in the white compartment of the avoidance chamber with the guillotine door raised. When the subject passed into the black compartment the guillotine door was lowered and a series of five inescapable shocks lasting 0.5 s was administered with intershock intervals of 1 min. The subject was then lifted out of the black compartment and immediately placed into the white compartment with the guillotine door raised for the first retention test. The cross-through latency was then recorded. Subjects that returned to the black side (four paw criterion) within 180 s received a second series of five shocks, while subjects that met the 180 s limit were simply left out of the white side briefly and returned for the second retention test.

Those subjects given the second shock series were retested for retention by immediate placement on the white side with the door raised. We re- asoned on the basis of prior studies (see above) that age differences in immediate retention would emerge, and we did not want to exaggerate age-related deficits in retention by an inordinate disparity in shock exposure between ages. Accordingly, subjects that failed to remain on the white side for at least 120 s during the retest were discarded from the experiment and replaced so that all subjects could receive a maximum of only two series of five shocks.

One week after the initial training and testing session each subject was again placed in the white compartment and the cross-through latency was recorded. For subjects that passed into the black compartment within 180 s, the guillotine door was lowered and a shock series was administered. Subjects were then placed back into the white compartment for a final retention test. Those subjects attaining the 180 s criterion were removed momentarily from the white compartment and replaced again for the final retention test.

All subjects were adults when they were intracardially perfused with saline and 10010 formalin. The brains were removed from the skull encasement and stored in 30010 formalin prior to blocking a t the appropriate angle of skull orientation during surgery for each subject. Serial tissue sections of 100 ym were stained with cresyl violet.


Histology. Figure 5 contains series of saggital sections representative of the lesion damage. It should be recalled that all subjects were not perfused until they were adults and the destruction did not appear different due to age a t the time of lesioning. The extent of damage was confined to the neocortex, with some damage to the genu of the corpus collosum as well.

Behavioral data. Panel A of Fig. 6 shows mean latencies on the first retention test after the initial shock series 4 days following surgery for each age group and surgical condition. More specific examination of the data revealed that none of the pups under any of the surgical treatments attained a latency score of 180 s to preclude the second shock series. Among the 30-32 day-old subjects, only one subject in the sham group reached the maximum latency criterion, but half of the surgical subjects had scores of 180 s. Three of the control adults, two of the shams and two of the lesioned adults met criterion. Comparison of the latencies for the initial retention test over all age levels revealed the presence of a signi-

ficant effect from Age (F(2J63) = 11.21, P < 0.001, co* = 0.24), while neither the effect of surgical treatment nor the interaction of Age X Sur- gery were significant (F < 1). Panel B of Fig. 6 depicts the mean retention latencies obtained after the second shock series, wherein subjects had to attain retention latencies of at least 120 s. The highly comparable performance, reflected for this test in Fig. 6, was confirmed by the

Fig. 5. Reconstructions of sagital sections for left (L) and right (R) hemispheres for subjects in Experiments I11 and IV taken a t 1,550-, 2,000- and 2,400-pm from the midline. Shaded areas indicate the smallest lesion, hatched marks represent the area of median lesions and open areas show the largest lesions. Note that the youngest groups in these experiments were a t least 75 days of age when sacrificed. GCC, genu corporis callosi; HIA, hippocampus, pars anterior; HI, hippocampus; cp, n. caudatus putamen; sf, n. septalis fimbrialis; F, columna fornicis; ca, n.

commissurae anterioris.

statistical analysis that revealed insignificant effects from age, surgical treatment or their interaction.

Retention of passive avoidance after the elapse of 1 wk is summar- ized in Panel C. Across ages, the differences were significant (F (2163) = 35.64, P < 0.001, to* = 0.50), but the effect of surgery was not reliable nor was the Age X Surgery interaction (F < 1). Retention deficits from

l o 16-20 3 0 - 3 2 4 ADULT

Fig. 6. Mean group latencies for control (C), sham operated (Sh) and lesioned (Su) subjects a t each age level during the four successive retention tests (see text) in

SURGICAL TREATMENT Experiment 111.

the second test immediately after surgery to the test 1 wk later (i.e., Panel B vs. Panel C) were analyzed for overall changes across treatment groups and age as well as changes within each treatment group considered separately. The overall analysis revealed a highly significant effect from Age (F (2163) = 46.57, P < 0.001, LO* = 0.27), successive Stages of Testing (F(1/63) = 74.70, P < 0.001, w2 = 0.22) and the interaction of Age X Stages (F(2163) = 19.03, P < 0.001, o2 = 0.11). Neither the effect of surgery nor any of the remaining interactions were significant (every F < 1). The pronounced age differences in retention between tests were more apparent when each treatment was considered separately. Specifically among the control subjects, significant levels were obtained from Age (F (2121) = 16.17, P < 0.001, u2 = 0.26), changes from the

initial test to the test 1 wk later (F (1/21) = 12.31, P < 0.001, w2 = 0.16). Similar significant effects were obtained from the sham subjects considered separately, although the strengths of the respective relationships were not as marked: Age (F (2121) = 4.26, P < 0.05, 0 2 = 0.10), TestIRe- test (F (1121) = 15.15, P < 0.001, w2 = 0.16), Age X TestIRetest (F (2121) =

4.15, P < 0.05, w2 = 0.07). In the lesioned subjects 'the most dramatic changes emerged between tests as measured by the w2 statistic: Age (F(2121) = 15.04, P < 0.001, w* = 0.19), TestIRetest (F (1121) = 59.62, P < 0.001, wh 0.34), Age X TestJRetest (F (2121 = 15.62, P < 0.001, w2 = 0.17). A posteriori t-tests for dependent groups indicated significant mean differences from the second to the third retention tests in the 18-20 day-old subjects under each treatment. Only the 30-32 day-old surgical subjects differed significantly (P < 0.05) in latencies between retention tests among that age level while none of the latency differences among the adult treatments were reliable, although the surgical adults approached the acceptable level of a Type I error (0.05 < P < 0.10).

Panel D contains the mean latencies of the second retention test one week after initial training. Prior to this test all of the 18-20 control and lesioned subjects received a shock series as did seven of the 18-20 day-old shams. Among the 30-32 day-old subjects, four of the controls, six of the shams and five of the lesioned subjects required the shock series prior to the final retention test. At the adult age level, three controls, two shams and six lesioned subjects had the series of five shocks. Analysis of latencies on this test revealed only significant effects from Age (F (2163) = 7.14, P < 0.005, o 2 = 0.12) and Surgery (F (2163) = 8.56, P < 0.001, w2 = 0.15) while the interaction between these variables was nonsignificant (F < 1).

The most obvious impression from this experiment is the overriding effect of age. Performance at each stage of testing as well as the retention deficits occurring during the interpolated 7-day rest interval suggest that differences among subjects can be most readily attributed to age. The effects from the surgical manipulation were rather minimal and must be inferred primarily from differences in the strength of the relationships between independent and dependent variables when the three treatments were analyzed separately. Although a main surgical effect emerged on the final retention test (Panel D), this finding must be qualified because performance at that level was most assuredly con- founded by the age differences accumulated from earlier stages of training and retention. Accordingly, measurement of DM prefrontal deficits on acquisition and retention of passive avoidance is obscured by differences in passive avoidance performance specific to age.

EXPERIMENT IV: EFFECTS OF DORSOMEDIAL LESIONS ON RETENTION OF PREOPERATIVELY ACQUIRED PASSIVE AVOIDANCE AND ITS STABILITY

IN YOUNG AND ADULT RATS

Method

The overall design of this experiment was identical to Experiment I11 except that the surgical treatments were administered after acquisition of passive avoidance to comparable levels among the age groups. Subjects were 72 naive male albino Sprague-Dawley rats, bred in our colony, of ages 18-20, 30-32 and l O O f days when training began. The weaning history and laboratory maintenance of the subjects were the same as described above. As in Experiment 111, avoidance training consisted of placing the subject on the white side of the avoidance chamber followed by a series of five shocks on the black side after a spontaneous cross- through response. Each subject was then immediately removed to the white side with the guillotine door raised for the first retention test lasting to a maximum of 180 s. Subjects that crossed through to the black side received a second shock series followed by a second retention test, while subjects having 180 s latencies were briefly taken out of the white side and returned for the second test. Those subjects failing to remain on the white side for a t least 120 s during the second retention test were discarded from the experiment and replaced with naive rats.

Eight subjects at each age level received DM lesions of the prefrontal cortex on the same day as initial passive avoidance training and testing. The surgical procedure was identical to that described above. Eight additional rats from each age level served as sham controls. The remaining eight rats a t the three ages served as nonoperated controls and rested in their home cages in the interim between training and retesting. After 7 days of recovery or rest, subjects were retested for retention of passive avoidance by placement in the white compartment and recording cross- through latencies up to 180 s. Subjects that passed into the black side received a shock series followed by a final retention test. Subjects meeting the 180 s maximum latency were taken out of the white side momentarily and replaced for the final retention test. Subjects were adults when they wTre perfused and their brains removed, sectioned and stained with cresyl violet.

Results

Histology. The extent of lesion damage was nearly identical to that reported in Fig. 5.

Behavioral data. Figure 7 contains panels showing successive retention at the various stages of the experiment. Presurgical retention after the shock series (Panel A) resulted in none of the 24 youngest subjects ob-

3 - Acta Neurobiologiae Experimentalis

taining criterion, while three of the 30-32 days and six of the adults had 180 s latencies. Analysis of the data from the first retention revealed a significant effect only from Age (F (2/63) = 17.01, P < 0.001, w2 = 0.32). Presurgical retention after the second shock series (when appropriate) is depicted in Panel B. In this experiment, an age effect remained even after the second shock series (F (2/63) = 5.60, P < 0.01, w2 = 0.1 2).

1 8 - 1 0 $ "'32 $ ADULT

150

Fig. 7. Mean retention latencies a t state of testing in Kxperiment IV control (C) , sham operated (Sh) lesioned (Su) subjects of the three

each for

and age

S U R G I C A L TREATMENT levels.

The surgical treatments were administered following the second retention test, and testing resumed after the elapse of 7 days recovery or rest. Panel C shows the mean cross-through latencies of the first postsurgical test of retention. Comparisons among age groups in the test indicated only a significant effect of Age (F (2163) = 42.75, P < 0.001, w2 = 0.50). Since presurgical age differences were apparent (Panel B), the comparison between pre- and postsurgical changes in retention is highly critical. Overall analysis of retention just prior to surgery and the first postsurgical test resulted in the expected Age effect (F(2163) =

= 32.17, P < 0.001, w2 = 0.20), but neither Surgery (F < 1) nor the Age X Surgery interaction were reliable sources of variation. The effect of the two stages (i.e., pre- and postsurgical) of retention tests (F(1/63) =

= 75.26, P < 0.001, w2 = 0.22) and the interaction of Age X Stages of

Testing (F(2163) = 24.19, P < 0.001, w2 = 0.14) were both significant. Further examination of the retention loss after surgery was made by analyzing the treatment conditions separately. Among the control subjects, significant effects were obtained from Age (F(2121) = 15.34, P < 0.01, w2 = 0.19), Stages of Testing (F(1121) = 27.30, P < 0.01, w2 = 0.24) and Age X Stages interaction (F(2121) = 11.19, P < 0.01, u2 = 0.19). Similarly, strong relationships emerged in the separate analysis of pre- and postsurgical retention latencies in the sham subjects: Age (F(2121) = 12.73, P < 0.01, w2 = 0.24), Stages of Testing (F(1121) = 28.73, P < 0.001, w2 =

= 0.17) and Age X Stages (F(2121) = 10.63, P < 0.01, w2 = 0.15). However, among the surgical subjects, only the effect of Age retained the strong relationship noted under the other treatments: Age (F(2121) = 27.48, P < 0.001, w2 = 0.29), Stages of Testing (F(1121) = 5.78, P < 0.05 w2 =

= 0.14) and Age X Stages (F(2121) = 4.84, P < 0.05, 0 2 = 0.06). Com- parisons between retention tests among age levels using t-tests showed significant differences (P < 0.01) for all 18-20 age groups, while only the surgical 30-32 day old group had significantly different (P < 0.01) latencies between tests and none of the adult comparisons were significant.

A shock series prior to the final test (Panel D) was required for all of the 18-20 day pups. Among the 30-32 day subjects, four of the controls, three of the shams, and five of the surgical subjects received the series of five shocks before the final test. Two adults from each treatment condition did not attain the 180 s criterion and were given shocks prior to the final test. Analysis of the latencies during the final test revealed only that Age was a significant source of variance (F(2163) = 13.93, P < 0.001, w2 = 0.26).

The results of this experiment were not dramatically different from Experiment I11 - i.e., age emerged as the most salient variable in accounting for performance during the successive retention tests. Indeed, presurgical training failed to result in comparable retention at the second retention test (Panel B), which had occurred at the similar, although postsurgical, stage for the manipulations in Experiment 111. The first postsurgical retention test (Panel C) did reveal overall attenuated latencies and seemingly marked retention loss. However, differences between pre- and postsurgical retention appear generally invariant across surgical treatments and limited to age-related deficits. As in Experiment 111, surgical effects are suggested only by variations in the strength of the independentldependent variable relationship measured by the 0 2 statistic.

I

GENERAL DISCUSSION

A major finding emerging from the overall comparison between both types of behavior is that prefrontal effects appear more salient than

age in the control of active avoidance, while age overrides the effects of DM injury in passive avoidance. The lack of striking disruptions inter- acting with age within either response class suggests that once subjects acquire behavioral capabilities in ontogeny, gross distortions in performance specific to age do not appear after cortical injury of the type presently employed. Upon closer scrutiny, the data suggest more subtle differences in DM effects and age that may be characterized as an exaggeration of deficits as a function of age. Specifically, both the short- and long-term impairments of active avoidance behavior as well as the lack of stimulus control 30 days after surgery in Experiment I1 were more pronounced in the pups. Similarly, in both passive avoidance experiments, the statistical interactions and measures of robustness in the independenudependent variable relationships tended to support the impression that surgical effects resulted in more pronounced long term retention deficits in the younger groups. Accordingly, predictions regard- ing the behavioral effects of age on both types of response requirements were confirmed, but the effects of DM injury emerged within the pre- vailing influence of the task-specific expectancies.

The time of surgical intervention within each response class attempted to distinguish DM effects on to-be-acquired behavior vs. already-established behavior. Within the active avoidance experiments, different effects emerged depending on when the lesions were administered. All subjects that received lesions prior to acquisition training showed severe disruption in immediate post-surgical avoidance acquisition. However, when subjects had presurgical acquisition training, post-surgical avoidance levels revealed some impairment, although lesioned subjects did attain the criterion avoidance level. Further, the 30 day interval resulted in differential influences on avoidance levels, depending on when lesion intervention occurred. After initially failing to avoid reliably, surgical subjects of both ages successfully recovered avoidance responsivity to permit reacquisition of the criterion level 30 days later. Conversely, subjects with lesions interpolated after initial acquisition showed avoidance levels that attained postsurgical criterion, but then three of the pups and one adult were severely disrupted when retrained 30 days later. Indeed, recovery of avoidance levels in Experiment I was invariant across ages, while the regression of avoidance responding during the 30 days after testing in Experiment I1 was more pronounced in the pups. Accordingly, the relative juxtaposition of lesion intervention resulted in a paradox with respect to active avoidance levels. The respective impairments in discriminative cue utilization in mediating the avoidance contingency was reflected by long-term recovery from surgery effects before any avoidance training and long-term interference when lesions occurred after

initial training. Moreover, the interference of avoidance levels after 30 days may be related to a disfunction in cue utilization that is sensitive to critical periods in development. Under both manipulations, despite attaining acquisition of active avoidance, short- and long-term measurement of generalization revealed little stimulus control, although the disruption of stimulus control was more pronounced during the immediate postsurgical generalization test, as indicated in Fig. 3. Considera- tion of the passive avoidance experiments indicates that the dominant age-related effects obscured possible distinctions in lesion effects arising from the arrangement of acquisition and surgery sequence in Experi- ments I11 and IV.

To further examine the results of these experiments, a comparison of the response requirements specific to active and passive avoidance is appropriate. In passive avoidance, learning involves several characteristics that should be implicated by prefrontal lesions. First there is the obvious spatial component of requiring subjects to consistently associate areas of the chamber with conditioned aversiveness or safety. Further, each acquisition trial requires subjects to orient along the spatial dimen- sion, which is essentially a discriminative delay component. A third characteristic of passive avoidance in the present context is the response inhibitory component generated from maturational influences. Although some evidence of lesion effects emerged in the passive avoidance experiments, the third characteristic of age-related deficits in response inhibition, predicted from previous findings, emerged as most salient, and striking surgical differences were obscured.

A similar analysis of the components of active avoidance reveals somewhat different characteristics. The spatial component is attenuated in two-way active avoidance, since subjects must shuttle between compartments and the sole discriminative cue for the aversive stimulus is the tone. In addition, the active motor response has been found to be relatively invariant across ages. In our experiments, the surgery effects were indicated by the lack of postsurgical stimulus control in both experiments and by the 30 day regression in avoidance behavior following interpolated lesions in Experiment 11. Moreover, this regression was more pronounced in the younger subjects. I t is well documented that stimulus control will not be acquired without the presence of some discriminative element during training (e.g., 18). The discriminative aspect in two-way active avoidance that is critical for eventual acquisition of stimulus control involves the implicit contrast between the silent period of the intertrial interval (ITI) and the tone-on period of CS action. Thus, the delay of the IT1 (CS-) and the presence of the tonal warning signal (CSS) during avoidance training constitutes the usual definition of in-

terdimensional discrimination training (6, 40). The present evidence of little postsurgical stimulus control in lesioned subjects of both experiments suggests a deficit in mediation of the contrasting delay period of the IT1 and CS onset. This suggestion is supported by the indication of retarded initial acquisition (Experiment I) and reacquisition (Experi- ment 11) of avoidance behavior in the lesioned animals. That is, avoidance levels decreased, but were not obliterated. However, stimulus control, presumably resulting from interdimensional discriminative influences, was not spared.

This discriminative interpretation of stimulus control deficits after DM lesions is also applicable to the age differences obtained in the lesioned pups within each active avoidance experiment. The evidence of recovery and regression in the respective experiments may be interpreted in the context of related strategy changes and tissue plasticity or compensation after lesions. Since the prefrontal area is relatively late in maturing and commitment to specific functions may be slower compared to other brain areas, there may be a critical period of maximizing inter- ventive manipulations. In Experiment I, the initial deficit in avoidance levels in the pups lesioned a t 20-21 days showed eventual recovery or compensation after 30 days. Conversely, the pups with more severe behavioral regression after 30 days were not lesioned until 27-28 days of age. The data from the pups are most intriguing since they 'indicate differences in lesion effects in a direction similar to that obtained in behavioral studies (e.g., 2) showing differential cue saliency in complex avoidance CSi as a function of age. Accordingly, this interpretation, em- phasizing a deficit in discriminative ability after DM lesions, supports previous behavioral evidence of age-related change in the mediation of discriminable cues.

Finally, aspects of these experiments, especially relating lesion effects on avoidance levels across both ages, may be considered in light of prefrontal homologies. The interpretation of the present data as resulting from impairments in cue utilization, in conjunction with such studies in alimentary reflexes as Eukaszewska (31), is consistent with findings in other species. More specifically, a recent study by Brennan, Kowalska and Zielinski (3) reported marked changes in auditory control after prefrontal injury in dogs. Of interest to present concerns was their evidence of hypersensitivity to reinforcement density after medial prefrontal lesions, such that medial subjects responded in all-or-nothing fashion depending upon the reinforcement availability. In addition, there are similar prefrontal data indicating deterioration of avoidance behavior in cats to CS+, while inhibition of CS- was retained (43, 44). Accordingly, our emphasis on the discriminative functions of avoidance behavior is ap-

propriately supported from other species with homologous injuries. The present data showing comparable gradients of control of active avoidance across ages, as well as little evidence of lesion-generated disruption of response inhibitory task requirements across ages, indicate additional evidence for prefrontal implication of discriminative behavior.

Portions of this research were supported by Grant 21-71510 from the Research Foundation of State University of New York. The authors wish to thank Mr. Vin- cent Mariano for his assistance in collecting data for Experiment I11 and IV.

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Accepted 5 January 1977

James F. BRENNAN, State University of New York, College at Buffalo, Buffalo, New York 14222, USA.

Evelyn A. POWELL, Kent State University, Kent, Ohio, USA.

John P. VICEDOMINI, University of Kentucky, Lexington, Kentucky, USA.

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