Behavioural Brain Research, 50 (1992) 53-68 9 1992 Elsevier Science Publishers B.V. All rights reserved. 0166-4328/92/$05.00

53

BBR01331

Spatial deficits and hemispheric asymmetries in the rat following unilateral and bilateral lesions of posterior parietal or medial agranular cortex V o n R. K i n g ~ a n d J a m e s V. C o r w i n b aDepamnent of Psychology, University of IVisconsin, Madison, 1VI 53706 (USA) and bDepartment of Psychology, Northern Illinois University, Dekalb, IL 60115 (USA) (Received 5 February 1992) (Revised version received 25 May 1992) (Accepted 26 May 1992)

Key words: Egocentric; Allocentric; Prefrontal; Parietal; Cortex; Asymmetry; Hemispatial

Studies of spatial behavior in both the human and non-human primate have generally focused on the role of the posterior parietal and prefrontal cortices and have indicated that destruction of these regions produce allocentric and egocentric deficits, respectively. The present study examined the role of the rodent analogs of these regions, the posterior parietal (PPC) and medial agranular (AGm) cortices, in egocentric and allocentric spatial processing, and whether spatial processing in rodents is organized in a hemispatial and/or lateralized manner as has been found in the primate. Eighty male rats receiving either a unilateral or bilateral lesion of AGm or PPC were examined on an egocentric (adjacent arm) or an allocentric (cheeseboard) maze task. The results indicated that PPC and AGm have dissociable spatial functions. Bilateral AGm destruction resulted in egocentric spatial deficits, and unilateral AGm operates demonstrated an intermediate deficit. In contrast, bilateral PPC operates demonstrated a severe deficit in allocentric processing. In addition, there were lateralized differences in the performance of unilateral PPC operates. While right PPC lesions resulted in a significant deficit on the allocentric task, no such deficit was seen in left PPC operates. In addition, neither unilateral AGm nor unilateral PPC operates demonstrated a hemispatial impairment on either the egocentric or allocentric tasks.

INTRODUCTION

The perception of space is a highly complex function and it is therefore not surprising that a number of brain areas have been implicated in the control of spatial behavior. Studies of the neural mechanisms of spatial behavior in primates have generally focused on cortical areas, in particular, the prefrontal and posterior parietal ( P P C ) c o r t i c e s 46'53. Behavioral, electrophysiological, and anatomical studies have established that PPC (generally considered to be Brodmann's areas 5 and 7) plays an essential role in the perception of space in the primate. The role of PPC in spatial function appears to be related to the perception of allocentric and extrapersonal s p a c e 4'54. I n particular, patients with a right parietal lesion show a deficit on a map reading (allocentric) task, but no deficit on a personal orientation

Correspondence: V.R. King, Dept. Psychology, 1202 West Johnson, University of Wisconsin-Madison, Madison, WI 53706, USA.

task requiring individuals to touch different parts of the body 54. In addition, PPC lesions in the monkey produce deficits on allocentric and extrapersonal tasks ineluding a landmark reversal task 4s, complex string pattern identification6~ cage finding57, and a spatial sequencing task requiring the use of external cues a. Evidence also supports the role of the dorsolateral prefrontal area of the primate (generally considered to be Brodmann's areas 6, 8, 9, 10, 44, 45 and 46) in spatial behavior. In contrast to the role of the PPC in allocentric and extrapersonal spatial processing, prefrontal cortex appears to be involved in the perception of personal and egocentric space. Human patients with left anterior frontal lesions showed deficits on a personal orientation task (i.e. touching body areas based on a human body map), while no such deficit was seen on a map navigation task requiring use ofextrapersonal cues 54. In non-human primates, Poh148 demonstrated that monkeys with bilateral ablation of anterior frontal areas had deficits on a place reversal (egocentric) task but not a landmark reversal (allocentric) task, although

54 it should be noted that Brody and Pribram 3 demonstrated both extrapersonal and personal spatial deficits in monkeys with frontal lesions. Taken together, these findings suggest an allocentric-egocentric dissociation for the PPC and prefrontal cortices in the primate. The role of neocortical areas in rodent spatial behavior has been less thoroughly investigated, though both PPC and area 8 have been proposed to have rodent analogs. In particular, medial agranular cortex (AGm), the rodent analog of a r e a 840,49,50 , has behavioral, anatomical and electrophysiological characteristics similar to area 8 of the primate 8"9:7"49'5~ As with the primate, a number of studies have demonstrated that A G m functions in spatial behavior. Bilateral prefrontal lesions which include AGm result in deficits on a variety of spatial tasks (see refs. 32 and 33 for reviews). In addition, it has been well established that unilateral lesions of AGm cause severe hemispatial neglects'9'6~. Posterior parietal cortex has been proposed to have a rodent analog as well (also termed PPC), though the anatomical and behavioral data supporting the similarity between rodent and primate PPC is more limited. This paucitY of data is due in part to a lack of electrophysiological and anatomical data necessary for a precise areal definition of PPC. Using Krieg's classic cytoarchitectonic and myeloarchitectonic description of rodent cortex 3s, Kolb and Walkey 36 define area 7 as a 2-mm-wide strip of cortex beginning 2 mm lateral to the midline and situated between area 3 (somatosensory cortex) and area 18 (visual cortex). Single-unit recordings in this area revealed the presence of place cells similar to that found in the hippocampus 6. In addition, bilateral lesions of PPC result in acquisition deficits on both the Morris water and radial-arm m a z e s 14'26'28'36. In addition, Dimattia and Kesner ~5 demonstrated that PPC-lesioned animals not only had a deficit on the Morris water maze relative to control operates, but also had more severe deficits than rats with lesions of the hippocampus further supporting the role of this area in spatial behavior. While such studies support the role of A G m and PPC in spatial function, a number of questions about the cortical representation of space in the rodent remain unanswered. In particular, unilateral lesions of parietal and frontal areas in human and non-human primates have been shown to d.isrupt both simple detection of contralateral stimuli and more complex spatial behavior in both a lateralized 24'44"45 and hemispatial fashion ~'2"22. Recent studies in the rodent have shown both hemispatial and lateralized deficits in the neglect produced by unilateral A G m lesions 8"~~ and lateralized differences in open field behavior following both unilateral A G m and parietal lesions ~'55. However, only

one study has thus far examined the effects of unilateral lesions on the more complex spatial tasks typically used to test for spatial deficits following bilateral lesions. In this ease, deficits on the Morris water maze were found following fight but not left-sided PPC lesions combined with corpus callosum section 42. Data on whether the spatial representation in the rodent is hemispatial or lateralized is therefore very limited and requires further examination of the effects of unilateral lesions on complex spatial tasks. In addition to the lack of data on how space may be represented in rodent cortex, there is a paucity of evidence on whether the allocentric-egocentric or peripersonal-extrapersonal dichotomy proposed foithe primate may also be present in the rodent. In support of this dichotomy, Kesner et al. 27 found that PPClesioned rats had deficits on an allocentric task requiring rats to use extrapersonal cues for accurate navigation to a reward and AGm-lesioned rats had deficits on an egocentric task requiring the animal to discriminate the nearest from the farthest arms on a radial arm maze. In contrast, Kolb and his colleagues 34'4~ reported severe deficits following medial prefrontal lesions on the Morris water and radial arm mazes, but very mild or no deficits following a PPC lesion. These findings led to the conclusion that not only is there no egocentric-allocentric dichotomy between PPC and AGm, but also that A G m plays a greater role in spatial perception than PPC, though PPC may have a special function in accurate locomotion to targets 32. Examination of the effects of unilateral lesions on spatial behavior is therefore an important step in understanding how space is represented in rodent cortex. Therefore, the current study examined the effects of unilateral as well as bilateral AGm and PPC lesions on egocentric (adjacent arm task in a radial arm maze) and allocentric (cheeseboard) tasks. Such an investigation is not only useful in clarifying whether an allocentricegocentric dichotomy of function exists but is also useful in determining whether space is represented in a lateralized or hemispatial fashion in rodent cortex.

RADIAL ARM MAZE

Materials and methods Subjects Subjects were 40 male Long-Evans hooded rats ordered from Harlan Industries and weighing 300-350 g at the time of testing. Upon arrival the animals were housed in individual cages in a colony room on a 12:12 h

55 light-dark cycle. All rats were handled for approximately 14 days prior to behavioral testing in order to reduce struggling and 'freezing' which could interfere with behavioral testing. All rats had free access to water and were maintained at 80-85 ~ of free feeding weight throughout the experiment with the weights adjusted for normal growth. Once the weights were stable at the 80-85~o level, presurgical maze training began.

Apparatus attd environment A wooden eight arm radial maze was used to test for egocentric spatial ability z7. Each arm was 60 cm long and 9 cm in width. The walls of the arms were 5 cm in height. The choice area was an octagon 40 cm in width. The maze floor was painted flat black and the walls of the arms were flat brown. The maze was located a meter above the floor in the middle of a well lit room. The room contained a number of distinctive cues (e.g. a shelfwith a nufiaber of different objects on it, the door, a poster, etc.) which remained in the same position relative to the maze throughout the experiment.

Presurgical trahlhlg Subjects were habituated to the radial arm maze for 4 - 5 days by baiting all 8 arms of the maze with onehalf of a 'Froot-Loop' and allowing animals to explore the maze until all arms were visited. Presurgical training ensured that the subjects had explored all maze arms to approximately the same extent and also ensured that subjects ran rapidly down the maze arms for reinforcement.

Surgical procedures Following the last day of habituation, subjects received a lesion of one of the following cortical areas: (1) right A G m (RAGm) (n= 5), (2) left A G m (LAGm) (n = 5), (3) bilateral A G m (BAGm) (n = 5), (4) right PPC (RPPC) (n = 5), (5)left P P C (LPPC) (n = 5), (6) bilateral P P C (BPPC) ( n - 5 ) or (7) unilateral lateral agranular cortex (AGI, n = 10), which served as a surgical control group. For all subjects, surgery was performed within 48 h of the end of habituation training. The animals were anesthetized with sodium pentobarbital (65 mg/kg, i.p.) and when totally unresponsive, as determined by the absence of a corneal reflex, placed in a stereotaxic apparatus using blunt tipped ear bars. A bone flap was then removed over the appropriate brain region. For the A G m operates, the cortex extending from 2 mm posterior to 5 mm anterior to bregma and 2 mm lateral to the sagittal sinus was removed via gentle subpial aspiration with a fine gauge pipette, taking care not to damage the contralateral hemisphere. These lesions are

similar to those used in previous studies of spatial behavior (e.g. refs. 8, 37). However, in the study by Kesner et al. 27 which demonstrated an egocentric deficit in AGm-lesioned animals, lesions extended caudally only to bregma, leaving intact the most caudal aspect of AGm. Lesions of P P C were produced by aspiration of cortex overlying the corpus callosum and extended from 2 to 6 mm posterior to bregma and from 3 mm to 6 mm lateral to the sagittal sinus. Lesions included area 7 as defined by Kolb and Walkey 36. Unilateral lesions of lateral agranular cortex (AGI) served as control lesions and extended from 2 mm to 4 mm lateral and from 5 mm anterior to 2 mm posterior to bregma. The AGI lesions were adjacent to the A G m lesions in their medial extent and to P P C lesion in their posterior extent. These AGI operates served as a control for the effects of general cortical damage. In addition, because unilateral AGI lesions were at least as large as PPC and A G m lesions (see Results below), the unilateral AGI groups controlled for the possibility that any deficits found in subjects with A G m lesions compared to subjects with P P C lesions could be a function of lesion size rather than lesion locus. For all lesion groups, after all tissue was removed and hemostasis was achieved, the wound was gently packed with gelfoam and the incision sutured closed. The subjects were kept warm and monitored for postsurgical complications and then returned to the colony.

Postsurgical behavioral testing Assessment of egocentric spatial ability began within 48 h of surgery with the experimenter 'blind' with respect to the subjects' lesion locus. The paradigm employed was acquisition of the adjacent arm task which has been shown to be disrupted by bilateral A G m lesions but not P P C or sham lesions z7. Training consisted of placing the animal at the end of one arm of the radial arm maze and allowing it to visit only one other arm during a trial. Only the two arms adjacent to the start arm were baited. Beginning each daily trial from a different arm should make an allocentric solution (i.e. associate the reinforcement site with various environmental cues) to this task very difficult. In order to efficiently solve this task the animal had to learn an egocentric strategy (i.e. go to nearest arm(s) relative to its initial position in the maze). After being placed in the start arm, the animal was allowed to visit one arm (i.e. move down the length of the arm to the bait well) before it was removed from the maze and placed back in the home cage for I min. Animals were given five such trials per day. For each trial, the arm visited as well as the latency to reach the end of the arm was recorded. Visits to adjacent arms were scored as correct responses

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AGm

PPC

Fig. 1. Reconstruction of the largest (dark outline) and smallest (stipple) lesions for AGm, PPC, and control (AGI) groups on the radial arm maze task. A: reconstructions of left (L) and right (R) unilateral AGm, PPC, and AGI (control) lesions; and B: reconstruction of bilateral AGm and PPC lesions.

while visits to the remaining six arms were recorded as errors. The start arm was randomly determined on each trial, with the exception that animals were started from a different arm during each of the five daily trials. Animals were trained for 90 trials (5 trials per day for 18 days).

brain diagrams 4v without knowledge of the behavioral data. Lesion size was computed by overlaying each diagram with a grid of 1-cm squares and counting the number of squares either fully within or contacting the perimeter of the lesion representation.

Results Histology After training was complete, animals were overdosed with an i.p. injection of sodium pentobarbital (150 mg/ kg) and perfused transcardially with normal saline followed by 10% formalin. Brains were removed and fixed in 10% formalin. Forty-/Lm frozen sections were then taken, keeping every tenth section for staining with Cresyl violet. The thalamus was examined for any signs of gliosis, shrinkage of nuclei or calcification. Lesion extents were traced onto a series of standard coronal

Histology Examination of PPC, A G m and control (AGI) operates indicated that lesions removed the intended cortical areas and in the case of unilateral operates were limited to one hemisphere. As indicated in Fig. 1, PPC lesions removed the entire extent of area 7 (as defined by Kolb and Walkey36). In addition, PPC lesions caused slight damage medially to the retrosplenial cortex. Laterally, the lesions generally resulted in incom-

58 plete removal of PPC leaving approximately 1 mm of PPC intact, although several lesions did extend far enough laterally to damage areas 39 and 40. PPC lesions caused slight damage to somatosensory cortex anteriorly and visual cortex posteriorly. Ventrally, all PPC lesions resulted in damage to the underlying white matter. In one case the white matter was penetrated resulting in slight damage to the hippocampus. Although lesions of PPC in the current study were situated more caudally than in other studies of the effects of PPC lesions on spatial behavior z7"36, there is considerable overlap with lesions in these studies. In addition, the lesions in the current study are more consistent with the anatomical definition of PPC 36 than in those studies. Examination ofthalamic nuclei indicated slight to moderate areas of gliosis in the lateral posterior and lateral dorsal nuclei of the thalamus, although there was no indication of degeneration in the lateral geniculate nucleus. Therefore, although these lesions impinged on visual cortex, this damage was not extensive enough to result in any detectible retrograde degeneration in the thalamus. Examination of A G m lesions indicated rather homogenous lesions. As can be seen from Fig. 1, A G m lesions began slightly posterior to the frontal pole and encroached to varying degrees on retrosplenial cortex posteriorly. Laterally, AGm lesions generally result in some damage to AGI, although in most cases the damage was slight. Ventrally, most A G m lesions caused slight damage to the white matter (most often the cingulum). It is important to note that there was no obvious difference in the behavioral performance of those animals with lesions that included damage to white matter and those that did not. With the exception of one bilateral operate with slight unilateral damage to the underlying eaudate, A G m lesions did not penetrate the white matter. In addition, all A G m lesions encroached on the dorsal cingulate cortex to varying degrees with two lesions extending ventrally to damage the ventral anterior cingulate cortex. Examination of the thalamus indicated no evidence of shrinkage, gliosis, or calcification in any nuclei. Examination of control lesions (Fig. 1) indicated a similar anterior-posterior extent to that seen in A G m operates (e.g. beginning just caudal to the frontal pole and extending to the level of the retrosplenial cortex). Medially, most control lesions resulted in slight damage to AGm. As with A G m operates, examination of thalamic nuclei gave no indication of shrinkage, gliosis, or calcification. Analysis of variance indicated significant differences among the groups for lesion size (F6.32 = 3.3, P < 0.05). Subsequent Tukey's analysis comparing left A G m with

right A G m operates and left PPC with right PPC operates indicated no significant differences, suggesting any lateralized differences found in either the unilateral AGm or PPC groups was not due to the amount of cortex removed. In contrast, while control operates did not differ significantly from either left or fight AGm operates, controls did have larger lesions than both right and left PPC operates (P's < 0.05). Because A G m and PPC lesions removed the intended area, no comparisons of lesion size were made between these two groups. Behavior To determine if left and right control (AGI) operates could be combined into a single group, these groups were compared on all the variables of interest in the behavioral tests discussed below. These comparisons revealed no significant differences. Because no significant differences emerged between left and right AGI operates for the behavioral and lesion size measures, these groups were combined into a single control group for the analyses of behavioral data below. Behavioral training began 2 days following surgery. Most studies using such maze tasks have a longer period between surgery and the onset of training. However, with the exceptions of BPPC operates demonstrating a tendency to drag their hindlimbs during the first 3-4 days of testing and BPPC and BAGm operates demonstrating dexterity deficits in manipulating reinforcement during the first 2-3 days of testing, there was no evidence of a negative effect of the surgical procedure. In addition, a group • trial block ANOVA conducted on mean response time per trial resulted in no significant main or interaction effects and further indicates the lack of a detrimental effect of beginning training this soon after surgery. Percentage correct. All of the analyses are broken down into 9 trial blocks of 10 trials each (number of trials during a 2-day period). Initially, a group • trial block ANOVA was conducted on the percentage of correct responses to determine if any of the lesions resulted in a significant deficit on this task. This analysis indicated significant main effects for group (F6,32=5.7, P < 0 . 0 5 ) and trial block (Fs,256=11.7, P