Reexamination of functional subdivisions of the rodent prefrontal cortex

EXPERIMENTAL

79,434-45 1 (1983)

NEUROLOGY

Reexamination of Functional Subdivisions of the Rodent Prefrontal Cortex HOWARD EICHENBAUM, Department

of Biology,

Received

May

RAE ANN Welles/q

27, 1982;

CLEGG,

College, revision

AND

Wellesley, received

AIJ&ON

FEELEYI

Massachusetts

September

I,

02181

1982

Selective patterns of behavioral deficits were observed on tests of spatial or olfactory learning after different cortical lesions in rats. The results clearly distinguished fimctional subdivisions of the rodent prefrontal cortex: Rats with lesions of the prefrontal cortex that primarily involve the dorsal bank of the rhinal sulcus were impaired selectively and exhibited increased perseveration of responses in a go, no-go odor discrimination task. In contrast, rats with lesions of the region of prefrontal cortex situated along the medial cortical wall were impaired selectively and exhibited increased perseveration of responses in a spatial delayed alternation task. These behavioral deficits were similar in magnitude and quality to those found in monkeys after discrete ablations of frontal lobe regions that are argued to be homologous prefrontal subdivisions.

INTRODUCTION Anatomical tracing studies have provided evidence for structural homologies in lower animals of the primate prefrontal areas. Description of functional homologies, however, have been only partially realized. This appears due to the failure of investigators to discover clearcut behavioral roles for frontal cortex in lower mammals similar to those described for primates, a failure often attributed to poor development of the frontal system in lower mammals. This study is a reexamination of these issues, with regard to the role of the frontal cortex in learning by rodents. The results clearly distinguish functional differences of subdivisions of the rodent prefrontal cortex and suggest a new view of approaches to the evolution of the prefrontal cortex. Abbreviations: MD-nucleus medialis dorsalis, MW-frontal cortex on the shoulder and medial wall, RS-frontal cortex on the dorsal bank of the rhinal sulcus, DRL-differential reinforcement of low response rate, SC-sham-operated control. ’ This work was supported by National Science Foundation grant BNS 77-24405. We thank Dr. Neal Cohen for his comments on the manuscript. 434 00 14-4886/83/020434-18.$03.00/O Copyright 0 1983 by Academic Press, Inc. All rights of reproduction in any form reserved.

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Efforts to trace the evolutionary origins of prefrontal cortex have focused on a search among species for both anatomic homologies and for similarities in the behavioral consequences of lesions of the prefrontal neocortex (25, 34,35). These will be discussed in turn. With regard to anatomic homologies of frontal cortex, it is important to note that whereas the primate prefrontal cortex is characterized by a prominent granular appearance of the fourth layer, the prefrontal neocortex of subprimates is entirely agranular. This factor renders it impossible to make a cross-class homology purely on cytoarchitectural grounds. Rose and Woolsey (48) suggested that the mammalian prefrontal cortex, like other cortical divisions, could be defined with respect to the projection field of the primate thalamic associate [in this case, nucleus medialis dorsalis (MD)] and that comparisons of the appropriate thalamic nuclei could be used in the determination of cortical homologies. Using this criterion, there is evidence for homology of prefrontal cortex among several species. Thus, a distinctly similar pattern of subdivisions of the MD and their cortical projections has been found in several species of mammals (34). Of particular importance to the present paper, the pattern of MD subdivisions and projections to cortex in the rat arc strikingly similar to those of primates. In rats, a histologically distinct lateral segment of the MD projects preferentially to the frontal cortex of the shoulder and medial wall (MW) and the central subnucleus of the MD selectively projects to the frontal cortex along the dorsal bank of the rhinal sulcus (RS) (9, 28, 31); in primates, the lateral, parvocellular segment of the MD projects to the dorsolateral prefrontal cortex, and the central, magnocellular component of the MD projects to the orbital prefrontal subfield (24). Let us now turn to possible similarities between primates and rodents in the behavioral consequences of lesions of the prefrontal cortex. Since Jacobson’s (20) original description in monkeys of rather general learning deficits that follow total prefrontal ablation, a number of investigators have fractionated the pattern of deficits into distinct abnormalities that are related to the cortical subfields described above. Thus, in primates, lesions of the dorsolateral subfield have different behavioral consequences from lesions of the orbital frontal cortex. Damage to the dorsolateral frontal cortex surrounding the principal sulcus produces impairments (i) in delayed response tasks, in which the location of a reward cue must be remembered across a delay in the absence of the cue, (ii) in delayed alternation tasks, in which the location of a reward on any particular trial is reversed from its location on the previous trial, and (iii) in spatial reversal learning tasks, in which a learned response to a particular position must be reversed (5, 36). Learning is not impaired in tasks that do not depend on spatial cues [e.g., (15, 37)]. Such results suggested that the dorsolateral prefrontal cortex is selectively involved in learning and memory of location. Furthermore, animals with

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these lesions were not significantly impaired in the original place discrimination, or in a conditional position response or a go, no-go nonspatial alternation (15). Thus the performance deficit is maximal when the relevant cue is spatial and when the response demands reversal of a prepotent choice. By contrast, numerous studies demonstrated that large lesions of the orbitofrontal cortex produce severe impairments in both the learning of spatial and nonspatial visual, tactile, and auditory discriminations and in various tasks which involve no exteroceptive cue but demand witholding of prepotent responses, such as extinction of a bar-press response or differential reinforcement of low response rate (DRL) (12, 49). The latter consequence of orbitofrontal ablation led to the view that lesions of this prefrontal area produced impairments which are cue-independant (36). Another study, however, demonstrated that partial orbitofrontal cortex lesions differentiate deficits in specific sensory discrimination and tasks which involve no exteroceptive cue (3). Rosenkilde (49) concluded that deficits in discrimination learning involving exteroceptive cues are restricted to the inferior prefrontal convexity. It is notable that performance deficits are not observed in simple simultaneous discriminations, but are maximal in go, no-go differentiation and in early reversals of a simultaneous discrimination, i.e., in discriminations which require reversal of a prepotent response (3,4, l&22,36). This deficit involves an inability to suppress both “go” and “no-go” responses (33). These data have led investigators to suggest a dorsal-to-ventral anatomical topography relating specific subdivisions of prefrontal cortex to a series of cue modes (48, 59): dorsal-most cortex seems to be involved selectively in spatial tasks. The lateral aspect of both the dorsal and ventral surface seem primarily involved in tasks of a variety of exteroceptive modes, including tasks based on spatial cues. Finally, the medial-orbital cortex is critical only to certain tasks with no exteroceptive cue. The consistent factor is that the deficits that follow any specific lesion are largest or are observed only in tasks which require the inhibition or reversal of prepotent responses. In recent years a number of investigators have examined the correspondence between the effects of dorsolateral prefrontal or orbitofrontal cortex lesions in primates and MW or RS lesions in rodents. Several studies found that damage to the MW in rats, like damage to dorsolateral prefrontal cortex in monkeys, impairs spatial learning. After MW lesions, impairments have been observed in spatial delayed alternation in a T maze (62) spontaneous alternation in a T maze (8) spatial reversal (7, 25, 41), spatial delayed response (25) and spatial go, no-go alternation (2 1). This spatial deficit appears to be selective to MW lesions and does not occur in rats with RS lesions (25, 41, 42). The evidence for a similar functional correspondence between the rodent RS and primate orbitofrontal cortex is less convincing. To our knowledge,

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the effect of selective RS ablation on visual, auditory, or tactile discrimination learning has not been tested. Instead, investigators have focused on evaluations of response disinhibition in tasks which have no external cues. Thus Neill(39) reported mildly impaired DRL performance in rats with RS lesions and Kolb et al. (25) reported retarded extinction in such animals, much like the effects found in monkeys with lesions of the orbitofrontal cortex. Nonneman et al. (42), however, observed superior DRL performance and normal bar-press extinction in rats with RS lesions, and as Kolb et al. (25) point out, “the perseverative tendency in monkeys with orbitofrontal lesions is considerably stronger than that in rats with RS lesions” [p. 779 in (42)]. Furthermore, it is unclear whether the disinhibition or perseveration in extinction and DRL are distinct features of RS lesions. In a replication of their extinction test, Kolb et al. (25) found that rats with RS and MW lesions failed to significantly differ in performance. The latter result, Kolb et al. (25) argue, was not so much due to good performance by the RS group, but was the product of mild perseveration by rats with MW lesions. Deficits in DRL performance by rats with MW lesions were also observed by Numan et al. (43) and Rosenkilde and Divac (50). The tendency for perseveration or disinhibition in rats with MW lesions was also observed by Kolb et al. (25) in spatial reversal and delayed response. It appears that tests for perseveration and behavioral disinhibition in extinction and DRL distinguish lesions of the orbital prefrontal cortex in primates, but the evidence for the importance of the homologous rodent brain structure is weak. This observation led Markowitsch et al. (34), in their comparative analysis, to conclude that the rat may have a relatively undeveloped frontal system. If there is phylogenetic continuity of a functionally important prefrontal cortex, then there must be some other behavioral role of this system which we have yet to identify as equally important to rodents and primates. So far, no behavioral task has proved powerfully and selectively sensitive to lesions of the rodent homologue of the orbitofrontal cortex. A comparison of sensory afferent fibers to the frontal cortex in different species indicates that the primate medial MD and orbital frontal cortex receive heavy sensory inputs from the temporal lobe polysensory region, but in rats the only direct source of sensory input to the medial MD and RS (13,29) comes from the olfactory cortex. Our research has demonstrated the functional role of olfactory inputs to this system (10). Small lesions of the MD or RS, but not the MW, severely impaired odor discrimination learning and retention, but did not significantly alter odor thresholds or impair the ability to detect odors. The magnitude of the discrimination impairment was related to stimulus similarity and familiarity. The results suggest that this task might provide a more sensitive measure of the behavioral effects of RS lesions than do tests of DRL or bar-press extinction. The combination of

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this test and a spatial learning task provides a test battery for functional dissociation of RS and MW lesions in the first experiment in the present study. EXPERIMENT Double Dissociation

of Functional

1 Prefrontal

Subdivisions

Teuber (58) argued that some of the strongest evidence for structure-function relationships comes from experiments that demonstrate dissociable patterns of behavioral deficit after damage to two separate brain structures, i.e., “double dissociation.” In separate experiments, lesions of the MW and RS have previously been associated with different behavioral impairments. But none of these demonstrated powerful and selective deficits in the same animals. In the present experiment, rats were tested for retention of both a delayed spatial alternation and an odor discrimination after partial prefrontal lesions. Methods Subjects. Twenty-one adult male Norwegian hooded rats (Charles River, Wilmington, Massachusetts) were maintained on a 23.75-h water deprivation schedule with food available ad libitum. They were trained during the light part of a 12: 12-h lightdark cycle. Ail subjects were trained preoperatively on a Y-maze spatial delayed alternation and two go, no-go olfactory discriminations. Apparatus and Procedure. The Y maze was composed of three lo-cm wide and l-m long arms, with g-cm high walls and a Plexiglas top. The arms were positioned in equiangular orientation. Two goal arms had l-cm deep water reward cups at their ends. After initial familiarization with the Y maze, 48h water-deprived rats were rewarded with 0.1 ml water only on trials in which they alternated goal arm choice. Correction trials were conducted after errors. Training continued at 60-s inter-trial intervals for 50 trials per day until a criterion of 27 correct choices were made in a 30-trial block. The next day, subjects began training in the odor discrimination task described elsewhere (10). Briefly, rats were trained in an instrumental chamber that was continuously exhausted by a forced clean-air stream that flowed out through a small port on one wall of the chamber. Initially, the subjects were shaped to press a paddle placed behind the port to obtain 0.05ml water rewards. In subsequent discrimination training, odor stimuli, generated at 4% of saturation (20°C) by a glass and Teflon flow-dilution olfactometer, were presented through holes in the paddle. On half of the trials an arbitrarily assigned positive stimulus was presented and a paddle press within 5 s resulted

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in reward. On negative trials the other odor was presented and no reward was delivered regardless of response. Positive and negative trials were in random order with a limit of three repetitions of the same trial type. Rats were trained preoperatively in discriminations of methyl salicylate vs. octane and eugenol vs. guiacol, each to the criterion of 27 correct of 30 consecutive trials. Within 1 week after completion of training, the rats were matched for overall trials to criterion and assigned to one of three operative treatment groups (N = 7 for each): MW, RS, and sham-operated control (SC). After a 1-week postsurgical recovery, the rats resumed the water deprivation schedule and were retrained to criterion (or 200 trials maximum per problem) in delayed alternation. Subsequently all the animals were retrained in the preoperative odor discrimination sequence, and in a discrimination between phenethyl alcohol and geraniol. Surgery Rats were anesthetized with Chloropent (Fort Dodge, Inc. 0.4 ml/ 1OOg), and cortical ablations were carried out by subpial aspiration during direct observation under a dissection microscope. The MW lesions were made by bilateral removal of the medial cortex extending from 1 to 6 mm posterior to the tip of the frontal poles and approximately 1 mm deep from the top of the brain. Bilateral lesions of the RS were made after detachment of the dorsal aspect of the origin of the temporal muscle. The lesions began at the frontal pole and included the cortex dorsal to the rhinal sulcus extending posteriorly approximately 3 mm. The SC operations included only anesthesia, incisions, and elevation of the temporal muscle.

Results Histology. Our analysis of the extent of cortical lesions was based on descriptions of MD projections and cortical cytoarchitecture by Krettek and Price (28). Except in the largest lesions, the damage to the MW did not include the entire projection field of the lateral MD (Fig. 1). In all cases, there was significant damage to the so-called shoulder cortex; generally the lesion included most of the medial precentral area and dorsal part of the anterior cingulate region, but never did the lesion extend as far anteriorly as the lateral MD projects. Lesions of the RS were also generally subtotal, in most cases substantially damaging the agranular insular and lateral orbital region, but sparing the depths of the dorsal bank of the rhinal sulcus. None of the animals suffered damage in the cortex contiguous to the two MD projection targets, i.e., the prelimbic, medial orbital, and ventrolateral orbital regions. In some cases there was unilateral damage dorsally to the sensorimotor cortex. In a few cases there was superficial damage to the pyriform cortex subjacent to the rhinal sulcus, but postoperative performance was unrelated to such damage in any task.

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FIG. 1. Reconstructions of medial wall (MW) and rhinal sulcus (RS) lesions of experiment 1. Blackened area indicates extent of smallest lesions; darkly stippled area indicates extent of me dium lesions; lightly stippled area indicates extent of largest lesion.

Behavior. Analyses of the postoperative trials to criterion revealed a striking double dissociation of impairments after selective prefrontal lesions (Fig. 2). In a comparison of the performance of experimental groups in the maze task versus their average performance in the three odor discriminations, analysis of variance revealed highly significant group (fl2, 18) = 18.89, P < 0.001) and task @‘(I, 18) = 13.54, P < 0.002) differences. Moreover, the group by task interaction was also highly significant (fl2, 18) = 40.65, P < 0.001). Post hoc Scheffe tests revealed that the MW group required significantly more trials to acquire the maze task than either the RS group (P < 0.001) or the SC group (P < O.OOl), which did not differ significantly from each other. The MW group also required more trials on the maze task than they did in their average performance on odor discrimination problems (P < 0.01). In contrast, the RS group required more trials to learn the odor discrimination problems than trials to learn the maze (P < 0.001) and were impaired significantly in odor discrimination compared with both the MW

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SPatial alternation MW

SC

RS

110

100

SO g w t 8 200 2 I: 5 E

160

100

60

MW odor

SC discrimination

RS

FIG. 2. Postoperative learning of delayed spatial alternation and three odor discrimination problems. Mean f SE of trials to criterion for MW, sham-operated control (SC), and RS groups. Open bars = octane vs. methyl salicylate, diagonal lines = eugenol vs. guiacol, solid bars = phenethyl alcohol vs. geraniol.

group (P < 0.001) and the SC group (P < O.OOl), which did not differ significantly from each other. A second analysis of variance comparing the performance of experimental groups with the three odor problems also revealed that the RS subjects were significantly impaired in odor discrimination learning (I;r2, 18) = 23.125, P < 0.001). Furthermore, post hoc SchefE tests revealed that the RS group scores were significantly higher than both the MW and SC scores (PA 0.01) for each problem. Despite incomplete removal of either cortical region, the lesions produced substantial effects on learning. In a previous study (10) the degree of odor discrimination impairment was found to be significantly correlated with the extent of damage to the RS. In the present experiment, however, this relationship could not be quantified because nearly all subjects with RS lesions failed each odor discrimination problem. Degree of impairment in the maze task was greatest in the MW subjects with the largest lesions, but the Spear-

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man correlation (r = .643) of extent of lesion and performance was not significant. In an effort to analyze potential lesion-induced response biases, a further analysis of the delayed alternation task focused on the nature of errors committed. Perseverative errors, counted as repetitive incorrect responses during correction trials, averaged 32.0 among subjects with MW lesions, 1.3 among subjects with RS lesions, and .014 in control subjects. Analysis of variance indicated highly significant group differences (F( 1, 12) = 20.97, P < 0.001) and post hoc Scheffe tests revealed that the MW group made significantly more perseverative errors than both the RS group (P < 0.05) and the SC group (P < 0.05) who did not differ significantly from each other. EXPERIMENT

2

Response Bias following Lesions of the Dorsal Bank of the Rhinal Sulcus Perseveration and behavioral disinhibition of unreinforced responses is commonly observed to follow frontal lesions in subprimate species including dogs (27) cats (34), rabbits (1 l), and rats (25). Indeed, these alterations in response tendency are frequently seen after lesions of limbic structures including the septal nuclei and hippocampus. In a further examination of the odor discrimination deficit that follows lesions of the RS, we also evaluated error tendencies in a modified version of our discrimination task. It is possible that disinhibition or perseveration might have contributed to the increased numbers of errors made by subjects with RS lesions. The odor discrimination task used in our’ previous study ( 10) involves a go, no-go response choice, and may be sensitive to lesion-produced behavioral disinhibition. Nearly all errors for each treatment group were errors of commission. Thus, our measures of performance deficits could not differentiate between errors resulting from disinhibition and those caused by an impairment of discrimination. In

FIG.

3. Reconstructions of rhinal sulcus lesions of Experiment 2. See caption of Fig. 1.

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our second experiment, we altered the reward contingencies of the task in order to reduce the response bias of normal rats and allow a direct quantification of response bias in brain-damaged subjects. The strong bias toward errors of commission observed in normal subjects seemed directly related to the asymmetrical reinforcement contingency; rewards were given only after “go” responses to the positive stimulus. In the present experiment, reinforcements were provided after the correct response to either stimulus. This procedural change resulted in the elimination of response bias preoperatively, thus ahowing direct measurement of postoperative response bias and differential assessment of disinhibition and discrimination deficits. Methods Apparatus and Procedure. Except for modifications related to the reinforcement contingencies, the olfactory discrimination apparatus and procedures were identical to those used in the previous experiment. On half of the trials an arbitrarily assigned positive odor was presented for 5 s during which a paddle press resulted in reward. On negative trials another odor was presented and a reward was delivered if the paddle-press response was withheld for the 5-s trial period. In addition, a correction procedure was applied during odor discrimination training. Thus, after an error, the trial was repeated until the correct response was given. Fifteen rats were trained in discriminations of methyl salicylate vs. octane and eugenol vs. guiacol, each to a criterion of 27 correct of 30 consecutive trials. Correction trials were included in the measure of trials to criterion. Within 1 week after completion of training, the rats were matched for total trials to acquire both discriminations and assigned to one of two op erated treatment groups, RS, (N = 8) or sham-operated controls (SC, N = 5). Bilateral lesions of the RS and sham-operated control procedures were as in Experiment 1. After a l-week postsurgical recovery, the rats resumed the water deprivation schedule and were retrained to criterion (or 200 trials maximum per problem) in the preoperative sequence. Additionally, each rat was trained on a discrimination between phenethyl alcohol and geraniol. Results and Discussion Histology. As in Experiment 1, lesions of the RS were subtotal, sparing the depths of the dorsal bank of the rhinal sulcus (Fig. 3). In general the lesions in this experiment were larger, in some cases there was damage dorsally to sensorimotor cortex or medial cortex unilaterahy. As in Experiment 1, in a few cases there was superficial damage to the pyriform cortex underlying the RS, but in no case was there damage to the olfactory bulb or lateral olfactory

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Trials to Criterion (Mean k SE) and Response Bias Index (Mean + SE) for Three Individual Odor Discrimination Problems Octane vs. methyl salicylate Group RS: Group SC:

trials index trials index

146.5 -11.3 91.8 2.6

f + + f

21.3 15.0 22.4 13.8

Eugenol vs. guiacol 198.4 20.9 68.2 8.0

+ f f +

1.6 26.4 15.1 5.6

Phenethyl alcohol vs. geraniol 163.9 37.0 117.6 31.8

k f + +

21.4 8.9 34.7 15.5

tract. Minor olfactory cortical damage was unrelated to postoperative performance in any task. This finding was not surprising because only complete olfactory bulb ablations or major interuption of the olfactory input anterior to the cortex results in odor discrimination impairments (6, 51). Behavior. Analysis of variance of the postoperative scores indicated that subjects with damage to the RS required significantly more trials than control subjects to attain criterion performance in odor discrimination learning (F’( 1, 11) = 26.28, P < 0.001, Table 1). The analysis of variance revealed neither a significant trend in performance for successive discrimination problems nor an interaction of the magnitude of the deficit among problems. In an effort to clarify the source of the poor performance of rats with RS lesions, three separate analyses were applied to measure alterations in the tendency to produce errors of commission vs. errors of omission, i.e., response bias, and to measure the tendency to repeat, i.e., to perseverate, previous responses. Response bias was determined for each discrimination problem pre- and postoperatively. An index of bias was calculated as the difference between errors of commission and errors of omission, with a positive index indicating more errors of commission. Although the bias index varied widely across subjects initially, the procedural modifications eliminated response bias by the end of preoperative training. After surgery, a small bias toward errors of omission was observed in RS but not SC subjects. The index shifted positively for both experimental groups for the succeeding two problems (Table 1). Analysis of variance indicated no group difference in response index (F( 1, 11) = 0.06), or interaction of magnitude of the index within groups across problems (F(2, 22) = 0.40), but did suggest an increasing trend in the index toward errors of commission for successive problems (F(2, 22) = 3.19, P < 0.055). Because of the large degree of variability in individual indices and relatively small number of subjects, the nonparametric Wilcoxon test (twotailed) was also applied to clarify the significance of the trend in index. A

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TABLE 2 Average Correction Errors (&SE) and Correction Error Runs (*SE) for Errors of Commission and Errors of Omission Group RS

Correction errors Correction runs

Group SC

Commission

Omission

Commission

Omission

32.1 + 6.9 9.3 + 1.5

13.1 z!z4.4 4.7 f 1.3

12.1 + 3.1 5.3 + 1.5

4.3 + 1.5 2.0 + 0.7

paired comparison of bias indices for the combined SC and RS groups indicated a significantly more positive index for the last problem compared with the first (T= 15, P < 0.05). In further analyses of the postoperative data, perseveration was measured in two ways. By one measure, “correction errors” were defined as repetitive incorrect responses after an error, i.e., errors made during the correction procedure. The average number of correction errors of commission and correction errors of omission were counted separately to allow an evaluation of response bias within the correction errors. In addition, we counted the average number of each type of correction error run, defined as a sequence of more than one correction error (Table 2). Analysis of variance was applied to determine group differences in number and type of correction errors. Rats with RS lesions made about three times as many correction errors as control subjects (F(1, 11) = 9.29, P < 0.02). Both RS and SC groups made considerably more commission than omission type errors (fll, 11) = 4.87, P < 0.05), but there was no significant interaction of error type between experimental groups (F( 1, 11) = 0.84. The analysis of correction error runs yielded similar results. Thus, rats with RS lesions required more correction runs than control subjects (F(1, 11) = 7.53, P < 0.05) and there were in general more runs of errors of commission (F( 1,ll) = 5.85, P < 0.05), but the experimental groups did not differ significantly in their response bias. In the other evaluation of perseveration, “response-following” perseverative errors were defined as incorrect responses which were the same in type (go or no-go) as the immediately preceeding response, whether that response was correct or not (Table 3). Analysis of variance was performed on the average number of response-following and “response-switching” errors (errors which differed in type from the previous response, i.e., nonperseverative errors). Overall, rata with RS lesions made about three times as many errors as control subjects (F(1, 11) = 18.29, P < 0.001). Both experimental groups made many more response-following than response-switching errors (F(1, 11) = 74.84, P < O.OOl), but the effect was much larger for rats with RS

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Average Response-Following and Response-Switching Errors (*SE)

Response-following Response-switching

Group RS

Group SC

66.6 f 1.3 6.2 * 1.2

22.9 f 4.9 2.4 f 0.2

lesions than for controls. Thus there was a significant interaction between experimental group and error type (F( 1, 11) = 18.15, P < 0.001). The present results, combined with those of our previous study (lo), indicate a profound and consistent impairment in go, no-go odor discrimination after selective lesions of the RS in rats. The deficit is apparent with both asymmetrical and symmetrical reward contingencies, although, comparing among experiments, the scores of sham-operated control subjects were somewhat elevated in the symmetrical reward condition. The analyses of errors in Experiment 2 indicate that although perseverative errors are the predominant error type for all subjects, response-following errors are selectively elevated in rats with RS lesions. The lesion-produced perseveration can be distinguished from a general behavioral disinhibition by the following two facts. First, our comparisons of both the response bias index and the types of correction errors indicated that the relative frequency of commission to omission errors was not altered by the RS lesion. Second, unlike rats with MW lesions, rats with RS lesions did not perseverate in the spatial alternation task in Experiment 1, i.e., their perseveration is selective to the go, no-go discrimination task. GENERAL

DISCUSSION

Task-SpeciJic Perseveration after Partial Prefrontal Ablations

Based on the anatomic evidence, Nauta (38) suggested that we should view the frontal lobe “at once as a ‘sensory’ and ‘effector’ mechanism” (p. 137). Thus one might expect to find that behavioral deficits that follow prefrontal ablations would depend both on the cue and response demands of the task. In rats, the pattern of data observed in this and other studies similarly indicates that selective partial ablations of the prefrontal cortex result in response perseveration within cue-specific learning deficits. Thus, lesions of the putative homologue of the primate dorsolateral cortex, the MW, selectively impair performance in spatial alternation, delayed response, and reversal tasks. In striking contrast, lesions of the putative homologue of the primate lateral orbitofrontal cortex, the RS, selectively impair go, no-go

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discrimination in at least one specific sensory mode, olfaction. It is not known whether this deficit extends to other sensory modes. The two MD projection cortices are contiguous (28). To insure that the damage in each case was isolated to only one region, the lesions were made subtotal by design. It is possible that complete lesions would have caused more global effects, including deficits in both tasks. The double dissociation of behavioral alterations produced by these lesions, however, indicates that different tinctions may be associated selectively with the cortical regions involved. It is notable that RS lesions in rats do not cause a deficit in the delayed alternation task, although such deficits are commonly observed to follow orbitofrontal lesions in monkeys (14). Also, there remains no strong behavioral evidence for a rodent homologue of primate medial orbital cortex, the prefrontal subdivision associated with performance in extinction and DRL (see Introduction). As in monkeys, the performance impairment associated with lesions of each prefrontal region is characterized by perseveration of dominant response tendencies. In the present study, the response abnormality associated with each lesion was selectively observed in one task, rats with MW lesions perseverate their choices only in the spatial task and rats with RS lesions perseverate responses only in the odor discrimination task. As shown in Experiment 2, rats with RS lesions, like monkeys with orbitofrontal lesions, are impaired in the suppression of both “go” and “no-go” responses. These data provide strong evidence for rodent behavioral homologues of the primate dorsolateral and lateral orbital prefrontal regions, and indicate that the leaming deficits observed after these partial prefrontal lesions in both species can be characterized as task-specific perseveration.

Comparative Aspectsof the Role of the Frontal Lobe in OlJaction The present successful use of the olfactory sensory modality in the functional analysis of the role in the RS can be related to the considerable anatomic, electrophysiologic, and behavioral data that indicate a pathway from olfactory cortex to the MD and the frontal lobe. As demonstrated in the rat, deep cells of the pyriform cortex and olfactory tubercle project selectively to the central segment of the MD (16, 17,29,52,53). This segment of the MD projects specifically to the RS (28, 31) which also receives direct aBerent fibers from pyriform and lateral entorhinal cortices (13, 29, 47, 6 1). In the monkey, the prorhinal cortex, which is a target of the olfactory bulb, projects to a part of the frontal cortex that is responsive to odor stimulation (45). Electrical stimulation of the olfactory bulb drives neurons of the central segment of the MD in the rat (26), rabbit (19), and monkey (2), and the orbital frontal region of the rat (61) and monkey (55, 63).

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Behavioral evidence also indicates an important functional role for parts of the frontal cortex in odor-guided behavior. Thus in addition to the present data, other studies showed that damage to the MD or RS but not the MW results in impairments in odor discrimination in rats (10, 54). Hamsters with lesions of the RS or MD but not the MW have diminished or altered odor preferences and alterations in subtle aspects of odor-guided sexual behavior (5 1). In dogs (1) and monkeys (57), lesions of the ventrolateral part of the orbital frontal cortex result in defective odor discrimination performance. Impaired odor-discrimination performance is also demonstrated by humans with Korsakoff s syndrome (23) which is associated with damage to the MD (60), or to the orbital frontal cortex (46). The deficit has been observed in tasks with very different response demands: go, no-go (10, 54, 57), simultaneous discrimination (57) and verbal “same/different” judgements of sequentially presented stimuli (23, 46). Furthermore, some experiments suggested that the above described prefrontal olfactory pathway is modality specific. Thus Slotnick and Kaneko (54) found that rats with lesions of the central MD were impaired in reversal learning with odor but not visual cues. Potter and Butters (46) found that humans with orbital frontal damage were poor at odor but not visual discrimination. In primates, there also appears to be an anatomic separation of orbital cortex subdivisions involved in purely olfactory rather than polysensory processes. Thus, Tanabe et al. (56) and Yarita et al. (63) showed that the neocortical region responsive to olfactory bulb stimulation was restricted to a posterior portion of the orbital surface. But other behavioral experiments demonstrated deficits in the auditory, visual, and tactile modalities after damage to the orbital region of monkeys. In particular, Butter (3) demonstrated a severe bar-press extinction deficit in monkeys with selective lesions of a frontal region later described by Yarita et al. (63) to be a focus of olfactory input. There is currently no evidence on the stimulus specificity of the discrimination impairment in rats with RS lesions. Also, little is known about the nonolfactory cortical sensory afferent fibers to the RS. Afferent input from the anterior cortical amygdala or central MD may provide an indirect pathway from other modalities (29). Unlike monkeys, the rat central MD and RS (29, 32) receive cortical sensory afferent fibers only from olfactory cortex. This species difference is particularly interesting, because rats develop learning sets considerably faster when trained with olfactory cues, compared with their performance in the visual or auditory modalities (30,40, 55). It is clear that the olfactory-frontal pathway, refered to by Nauta (38) as “a basic anatomical ‘flow diagram’ of telencephalic signal processing,” is completely evolved in rodents and therefore may provide the best mode for comparative investigations of the functional role of the RS.

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Rats also perform impressively in the spatial tasks (44). As demonstrated here, specific partial prefrontal ablations disrupt performance in the spatial and olfactory modes selectively. Thus, from a comparative viewpoint, we suggest that specific subdivisions of the prefrontal cortex may have evolved as the neocortical components of separate functional pathways for the expression of dominant sensory modalities. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

W. F. 1974. Effect of ablating the frontal lobes, hippocampi, and occip ito-temporo-par&al (excepting pyriform areas) lobes on positive and negative olfactory conditioned responses. Am. J. Physiol. 128: 754-771. BENJAMIN, R. M., AND J. C. JACKSON. 1974. Unit discharges in mediodorsal nucleus of sqnirrel monkey evoked by eleetricaJ stimulation of olfactoq bulb. Brain Res. 75: 18 l- 19 1. BUTTER, C. M. 1969. Perseveration in extinction and in discrimination reversal tasks following selective frontal ablations in Macaca mulatta. Physiol. Behav. 4: 163-171. BUTTER, C. M., M. MIS-, AND H. E. ROSVOLD. 1963. Conditioning and extinction of a food-rewarded response after selective ablations of frontal cortex in rhesus monkeys. Exp. Neural. 7: 65-75. BUTTERS, N., D. PANDYA, K. SANDERS,AND P. DYE. 197 1. Behavioral deficits in monkeys after selective lesions within the middle third of sulcus prineipalis. J. Camp. Physiol. Psychol. 76: 8-14. DEVOR, M. 1973. Components of mating disweiated by lateral olfactory tract transeotions in male hamsters. Brain Res. 64: 437-441. DIVAC, I. Frontal lobe system and spatial reversal in the rat. 197 1. Neuropsychology 9: 175-183. DIVAC, I., R. G. E. WIKMARK, AND A. GADE. 1975. Spontaneous alteration in rats with lesions in the frontal lobes: an extension of the frontal lobe syndrome. Physiol. Psychol. 3: 39-42. DOMESICK, V. B. 1972. Thalamic relationships of the medial cortex in the rat. Brain Behav. Evol. 6: 457-483. EI~HENBALJM, H., K. J. SHEDLACK, AND K. W. ECKMANN. 1980. TbalamoeortieaJ meehanisms in odor guided behavior. I. Effects of lesions of the mediodomal thalamus and frontal cortex on olfactory discrimination in the rat. Brain Behav. Evol. 17: 255-275. EICHENBAUM, H., H. P~-R, J. P-RF, AND C. M. Burrow. 1974. Effects of frontal cortex lesions on differentiation and extinction of tbe classically conditioned nictitating membrane response in rabbits. J. Comp. Physiol. Psychol. 86: 179-186. FUSTER, J. M. 1980. The Pr&ontal Cortex. Anatomy, Physiology, and Neuropsychologv of the Frontal Lobe. Raven Press, New York. GERFEN, C. R., AND R. M. CLAV~ER. 1979. Neural inputs to the prefrontal agranular insular cortex in the rat: horse&i& peroxidase study. Brain Res. Bull. 4: 347-353. GOLDMAN, P. S. 197 1. Functional development of the prefrontal cortex in early life and the problem of neuronal plasticity. Exp. Neurol. 32: 366-387. GOLDMAN, P. S., H. E. ROSVOLLI, B. VEST, AND T. W. GALKIN. 1971. Analysis of the delayed alternation deficit produced by dorsolateraJ prefrontal lesions in the rhesus monkey. J. Comp. Physiol. Psychol. 77: 212-220. HABERLY, L. B., AND J. L. PRICE. 1979. Association and commissural fiber systems of the olfactory system of the rat. .I Comp. Neurol. 178: 71 l-740. ALLEN,

450

EICHENBAUM,

CLEGG, AND FEELEY

17. HEIMER, L. 1972. Olfactory connections of the diencephaloo in the rat. Bruin Behuv. Evol. 6: 484-523.

IVERSEN, S. D., AND M. MISHKIN. 1970. Perseverative interference in monkeys following selective lesions of the inferior prefrontal convexity. Exp. Bruin Res. 11: 376-386. 19. JACKSON, J. C., AND R. M. BENJAMIN. 1974. Unit discharges in the mediodorsal nucleus of the rabbit evoked by electrical stimulation of the olfactory bulb. Brain Res. ‘15: 193-20 I. 20. JACOBSEN,C. F. 1935. Functions of the frontal association area in primates. Arch. Neural. Psychiatr. 33: 558-569. 21. JOHNSTON,V. S., M. HART, AND W. HOWELL. 1974. The nature of the medial wall deficit in the rat. Neuropsychology 12: 495-503. 22. JONES,B., AND M. M~SHKIN. 1972. Limbic lesions and the problem of stimulwreinforco meats associations. Exp. Neural. 36,362-377. 23. JONES,B. P., H. R. MOSKOWITZ, AND N. M. BUTTERS. 1975. Olfactory discrimination in alcoholic Korsakoff patients. Neuropsychology 13: 173- 179. 24. KIEVET, J., AND H. G. J. M. KUYPERS. 1977. organization of thalamo-cortical connectivity of the frontal lobe of the monkey. Exp. Brain Res. 29: 299-322. 25. KOLB, B., A. J. NONNEMAN, AND R. K. SINGH. 1974. Double dimociatioo of spatial impairments and perseveration following selective prefrontal lesions in rats. J. Comp. Physiol. PsychoI. 87: 772-780. 26. KOMISARUK, B. R., AND C. BEYER. 1972. Responses of diencephahc neurons to olfactory bulb stimulation, odor, and arousal. Brain Res. 36: 153-170. 27. KONORSKI, J. 1972. Some hypotheses concerning the functional organization of prefrontal cortex. Acta Neurobiol. Exp. 32: 595-614. 28. Kam-ra~, J. E., AND J. L. PRICE. 1977. The cortical projections of the mediodomal nucleus and adjacent thalamic nuclei in the rat. J. Comp. Neural. 171: 157-192. 29. KRETTEK, J. E., AND J. L. PRICE. 1977. Projections from the amy8daloid complex to the cerebral cortex and thalamus in the rat and cat. J. Comp. Neural. 172: 687-722. 30. LANGWORTHY, R. A., AND J. W. JENNINGS. 1972. odd ball, abstract, olfactory learning in laboratory rats. Psycho/ Rec. 22: 487-490. 31. LEONARD, C. M. 1969. The prefrontal cortex of the rat. I. Cortical projection of the medicxlorsai nucleus. II. Effereot connections. Bruin Res. 12: 321-343. 32. LEONARD, C. M. 1972. Connections of the mediodorsal nuclei. Brain Behav. Evol. 6: 524-541. 33. MCENANEY, K. W., AND C. M. BUTTER. 1969. Perseveration of responding and ooo-respooding in monkeys with orbital frontal ablations. J. Comp. Physiol. Psycho/.68: 558-56 1. 34. MARK~~ITSCH, H. J., AND M. PRETZEL. 1977. Comparative analysis of prefrontal learning functions in rats, cats, and monkeys, Psycho/. Bull. 84: 817-837. 35. MASTERSON, B., AND L. C. SKEEN. 1972. origins of anthropoid intelligence: prefrontal system and delayed alternation in hedgeho& tree shrew and bushbaby. J. Comp. Physiol. Psychol. 81: 423-433. 36. MISHKIN, M. 1964. Perseveration of central sets after frontal lesions in monkeys. Paga 219-241 in J. M. WARREN AND K. AKERT, (Eds..), The Frontal Granular Cortex and Behavior. McGraw-Hill, N.Y. 37. MISHKIN, M., AND F. J. MANNING. 1978. Nonspatial memory after selective prefrontal lesions in monkeys. Brain Res. 143: 3 13-323. 38. NAUTA, W. J. H. 1972. Neural associations of the frontal cortex. Acta Neurobiol. Exp. 32: 125-140. 39. NEILL, D. B. 1976. Frontal-striatal control of behavioral inhibition in the rat. Brain Res. 105: 89-103. 40. NIGROSH, B. J., B. M. SLOTNICK, AND J. A. NEVIN. 1975. Olfactory discrimination, reversal learning and stimulus control in rats. J. Comp. Physiol. Psychol. 89: 285-294. 18.

RODENT

PREFRONTAL

CORTEX

451

4 1. NOIWEMAN, A. J., AND B. KOLB. 1979. Functional recovery after serial ablation of prehontal cortex in the rat. Physiol. Behav. 22: 895-904. 42. NONNEMAN, A. J., J. VOIGT, AND B. E. KOLB. 1974. Comparisons of behavioral e&cts of hippocampd and prefrontal cortex lesions in the rat. .I Comp. Physiol. Psychol. 87: 249-260. 43. NUMAN, R., A. R. SEIFERT,AND J. F. LUBAR. 1975. Effects of media-cortical frontal lesions on DRL performance in the rat. Physiol. PsychoI. 3: 390-394. 44. OLTON, D. S., AND R. J. SAMUELSON. 1976. Rememberance of places past: spatial memory in rats. J. Exp. Psycho/. 2: 97-l 16. 45. POUR, H., AND W. J. H. NAUTA. 1979. A note on the problem of olfactory associations of the orbitofrontal cortex in the monkey. Neuroscience 4: 36 l-367. 46. POTTER, H., AND N. M. BIJTTERS. 1980. An assessmentof olfactory deficits in patients with damage to prefrontal cortex. Neuropsychofogy 14: 621-628. 47. REEP, R. L., AND S. S. WINANS. 1982. Afferent connections of the dorsal and ventral agranular insular cortex in the hamster, Mesocricetus aurutus. Neuroscience 7: 1265- 1288. 48. ROSE, J. E., AND C. N. WOOLSEY. 1948. The orbitofrontal cortex and its connections with the mediodomal nucleus in rabbit, sheep, and cat. Res. Pd. Assoc. Nerv. Ment. Dis. 27: 210-232. 49. ROSE-E, C. E. 1979. Functional heterogeneity of the prefrontal cortex in the monkey: a review. Behav. Neural Biol. 25: 301-345. 50. RO~ENKILDE, C. E., AND 1. DIVAC. 1975. DRL performance following anteromediaI cortical ablations in rats. Brain Res. 95: 142-146. 51. SAFOUKY, R. M., AND H. EICHENBAUM. 1980. Thalamo-cottical mechanisms in odor guided behavior. II. Effects of lesions of the mediodorsal thalamus and frontal cortex on odor preferences and sexual behavior in the hamster. Bruin Behuv. Evol. 17: 276-290. 52. Scorn, J. W., AND C. M. LEONARD. 1971. The olfactory connections of the lateral hypothalamus in the rat, mouse and hamster. J. Comp. Neural. 172: 331-334. 53. SIEGEL, A., T. F~JKUSHIMA, R. MEIBACH, L. BURKE, H. EDINGER, AND S. WEINER. 1977. The origin of the atIem.nt supply to the mediodomal thalamic nucleus: enhancement of HRP transport by selective lesions Bruin Res. 135: 1 l-23. 54. SLQTNICK, B. M., AND N. WKO. 198 1. Role of mediodomal thalamic nucleus in olfactory discrimination learning in rats. Science 214: 9 l-92. 55. SLOTNICK, B..M., AND H. M. KATZ. 1974. Olfactory learning set formation in rats. science 185: 796-798. 56. TANABE, T., M. 11~0, AND S. F. TAGAKI. 1975. Discrimination of odors in olfactory bulb, pyriform-amygdaloid areas, and orbitohontal cortex of the monkey. .I. Neurophysiol. 38: 1284-1296. 57. TANABE, T., H. YARITA, M. 11~0, Y. OOSHIMA, AND S. F. TAGAK~. 1975. An olfactory projection area in orhito-frontal cortex of the monkey. J. Neurophysiol. 38: 1269-1283. 58. TEUBER, H.-L. 1955. Physiolo&al psychology. Annu. Rev. Psychol. 6: 267-296. 59. TEUBER, H.-L. 1972. Unity and diversity of frontal lobe functions. Actu Neurobiol. Exp. 32: 615-656. 60. VIOR, M., R. D. ADAMS, AND G. H. COLLINS. 197 1. The Wemicke-KorsukoffSyndrome. Davis, Philadelphia. 6 1. WIEGAND, S. J., AND J. L. PRIME. 1980. Olfactory neoeortieal areas in the rat. Sot. Neurosci. Abstr. 6: 307. 62. WIKMARK, R. G. E., I. DIVAC, AND R. WEISS. 1973. Retention of spatial delayed alternation in rats with lesions in the frontal lobes. Bruin Behuv. Evol. 8: 329-339. 63. YAR~TA, H., M. 11~0, T. TANABE, S. KOGCJRE,AND S. F: TAGAK~. 1980. A transthahumc olfactory pathway to orbitofrontal cortex in the monkey. J. Neurophysiof. 43: 69-85.