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Long-term deficits in water maze spatial conditional alternation performance following retrohippocampal lesions in rats
63
Behavioural Brain Research, 32 (1989) 63-67 Elsevier BBR 00880
Long-term deficits in water maze spatial conditional alternation performance following retrohippocampal lesions in rats C h a r l e s R. G o o d l e t t , J o h n M . N i c h o l s , R o b e r t W . H a l l o r a n a n d J a m e s R. W e s t Alcohol and Brabz Research Laboratory, Department of Anatomy. University of lowa, Iowa City, 1.4 52242 (U.S.A.) (Received 20 January 1988) (Revised version received 19 May 1988) (Accepted 1 June 1988) Key words: Retrohippocampal lesion; Water maze; Rat
The effects of large bilateral retrohippocampal lesions on long-term performance of conditional spatial alternation, incorporating a strong working memory component, were examined using a T-maze task motivated by swim-escape. The lesions, which included entorhinal cortex, subiculum, pre- and parasubiculum and invaded the molecular layer of the dentate gyrus, completely eliminated the previously acquired conditional alternation learning, and performance failed to recover with 40 days oftesting. These findings support the contention that retrohippocampal structures are an important and necessary component of the neural circuitry mediating working memory.
INTRODUCTION
The entorhinal cortex provides one of the major afferents to the hippocampal formation 13'14'1s, and serves as a link between the neocortex and the hippocampus 11,16,17 AS such, it is not surprising that bilateral damage to the entorhinal cortex in rats produces behavioral deficits in spatial learning in many of the same tasks that are disrupted by hippoeampal lesions 4'7'8'12. Nevertheless, studies of the extent of recovery from entorhinal cortex lesions have produced equivocal results. Tasks requiring working memory 6, in which appropriate behavior depends on utilization of information about specific items or events that occur in a given context over relatively short periods of time, are sensitive to damage to the hippoeampal formation and associated structures
such as the entorhinal cortex. Olton and his colleagues7,8, using the radial maze, found that bilateral damage produced enduring deficits in the performance of working memory tasks. Loesehe and Steward 4 found comparable long-term deficits in rewarded alternation performance in a T-maze. However, recovery of rewarded alternation performance after about 30 days of postoperative training has been reported I~ Likewise, spatial navigation in the Morris water maze is impaired by entorhinal cortex lesions ~2, but we have found that substantial recovery of place navigation occurs with extended postoperative training 2. Since the appetitive Working memory tasks have yielded somewhat equivocal findings concerning the long-term effects of entorhinal cortex lesions, we developed a water maze conditional
Correspondence: C.R. Goodlett, Alcohol and Brain Research Laboratory, Department of Anatomy, University of Iowa, Iowa City, IA 52242, U.S.A. 0166-4328/89/$03.50 9 1989 Elsevier Science Publishers B.V. (Biomedical Division)
64 alternation procedure to determine the extent of behavioral recovery in an aversively-motivated spatial working memory task. The water maze provides several experimental advantages over food- or water-rewarded procedures, including elimination of the need for deprivation, reduction of the confounding effects of local olfactory cues, and the opportunity to manipulate motivational conditions of the task by altering water temperature. We have found that water maze working memory tasks are acquired more slowly by intact rats than comparable appetitive tasks 3. However, conditional ('win-shift') spatial alternation (but not spatial alternation over consecutive trials) can be reliably learned by intact rats. Thus, we used a conditional alternation procedure in the water maze to examine extended postoperative retention performance of rats with large bilateral retrohippocampal lesions including the entorhinal cortex and subiculum. Male rats were obtained from Sasco-King Laboratories at 55-65 days of age and maintained in group cages with ad libilum food and water throughout the experiment. Behavioral training was conducted using a white circular water tank, 121 cm diameter, filled to within 8 cm of the rim with 21 ~ water which was made opaque by dissolving 1500 ml of powdered milk. A T-maze was partially immersed in the water, extending 10 cm above the surface of the water. The start stem (72 cm long) and the two goal arms (each 38 cm long) were made of clear Plexiglas, and the cul-de-sacs (10 cm long) at the end of each goal arm were made of black Plexiglas. All alleys were 18 cm wide, and an escape ladder could be placed in the end ot~ the cul-de-sac of each arm, hidden from view from the start stem or choice area. The rats were given two days of swim-escape pretraining in the maze, 10 trials per day in which one arm was blocked and the escape ladder present at the end ot" the other arm. On these trials, the rats had to swim from the start area to the end of the unblocked arm. The rats were forced to escape from each arm 5 times each day, with the order determined by a random sequence. The conditional alternation training used the procedure previously described 3. Briefly, the rats
were given 8 trials per day, with each trial consisting of a forced ('information') run, in which one arm was blocked and escape available from the other arm, followed by a choice run, in which both arms were open and escape was available only from the arm previously blocked. The rats were left on the escape ladder for 5 s after each run, and a 6-s interval was maintained between removal from the ladder after the forced run and the start of the choice run. On half of the trials each day the information run was to the left, and the other half to the right, with the order determined by a random sequence each day. Each entry into the incorrect arm (the forced arm on each trial) was counted as an error, and errors, latencies to complete the forced trial and latencies to make a choice on the choice trials were recorded. Operationally, this task involved a strong working memory component, since over the 8 trials of each day, the rats had to maintain information about the direction of the forced trial in order to make an accurate choice on the immediately succeeding choice trial, while keeping the sets of runs temporally distinct 6. All rats were given acquisition training to a criterion of 3 consecutive days of 7/8 correct trials. Upon reaching the acquisition criterion, they were assigned to one of 3 groups: bilateral entorhinal cortex lesions (n = 9), sham operates (n = 9) or unoperated controls (n = 5), balancing for the number of days to criterion. Surgery was performed on the day following the last acquisition day, and retention training began on the fifth day after the last acquisition day. Bilateral entorhinal cortex lesions were performed under ether anesthesia by passing a 1.0-mA DC (anodal) current for 30 s through a Teflon-coated stainless steel electrode exposed only at the tip, 3.0, 5.0 and 6.0 mm ventral to the surface of the brain at each of 3 placements on each side ~9. Sham operations performed under ether anesthesia included bilateral removal of a bone flap, cutting the dura and inserting a needle 2 mm into the cortex at each of the 3 locations on each side. The rats with entorhinal cortex lesions were given 40 days of retention training, while the sham operates and unoperated controls were each given 16 days of retention training. The two control groups were
65 not tested beyond 16 days because it was clear they had returned to presurgical accuracy levels by that time. Only the group with lesions was tested for the extended period, to determine whether behavioral recovery would eventually occur.
At the completion of training the rats given surgery were perfused with 0.9% saline followed by 1% (w/v) paraformaldehyde and 1.25 % (v/v) glutaraldehyde. Coronal sections (40/lm thick) through the rostral hippocampus were processed for acetylcholinesterase (/~ChE) histochemical localization using a modification of the Geneser-Jensen method ~, to confirm the typical reorganization of AChE-positive staining in the dentate gyrus induced by these lesions 5'~5. Horizontal sections (40tim thick) through the posterior forebrain were taken, and every fifth section was stained with Cresyl violet to determine the extent of each lesion. As shown in Fig. 1, the lesions were large and destroyed all of the medial entorhinal cortex (except at the most ventral level). Extensive damage to the presubiculum, parasubiculum and subiculum was present in every case, and overlying occipital cortex was also damaged. In the mid-temporal region, the molecular layer of the dentate gyrus was invaded in all cases, and hippocampal subfield C A l a was partially damaged on at least one side of the brain in 5 cases. The typical
intensification of AChE staining (not shown) in the outer molecular layer and the concomitant clearing and widening of the pale-staining commisural/associational zone following the lesions was observed bilaterally in every case. These lesions were comparable to those reported by Loesche and Steward 4 and Ramirez and Stein l~ As shown in Table I, there were no significant group differences in presurgical acquisition performance, indicating that the balancing procedure effectively equated acquisition performance among groups. The bilateral lesions resulted in deficits in choice accuracy, which did not improve over the 40 days of testing (Fig. 2). Both the sham operates and the unoperated controls showed an increase in errors during the initial stages of retention testing relative to the end of acquisition, but returned to accurate performance levels by the end of the first week (Fig. 2). A repeated measures analysis of variance on daily total error scores during the first 16 days of retention yielded a significant treatment x retention test day interaction [F3o,3oo = 2.25,p < 0.001 ], due to the rapid decline in errors in the two control groups early in retention testing compared to the lasting deficits of the group with lesions. The two control groups committed significantly fewer errors after the second retention test day relative to the group with lesions (Newman-Keuls, p < 0.05). In fact, none of the rats with lesions approached presurgi-
lr.f Fig. 1. Low power photomicrograph of a Cresyl violet-stained horizontal section depicting a typical lesion, shown at a midtemporal level corresponding approximatelyto plate 104 of the atlas of Paxinos and Watson9.
66 TABLE I
Conditional alternation pe~orniance measures during presurgical acquisition There were no significant differences in acquisition performance in the conditional alternation task for the 3 surgical groups (means + S.E.M.).
EC lesions (n = 9) Sham operates (n = 9) Unoperated controls (n = 5)
s
o
Days to acquisition criterion
Total errors to acquisition criterion
Escape latency (s) (forced trials)
14.9 + 1.8
28.6 + 4.0
6.0 + 0.3
15.1 + 1.6
35.4 + 4.4
6.6 + 0.4
16.2 + 3.3
40.2 + 9.3
5.6 + 0.5
~
H
BILATEnAL EC [N-9) SHAM OPERATES (N'g) L$ (N-5)
i.-
8~ to z
2
<= I
;
,;
,;
2'o
L
~o
;s
,'o
RETENTION DAY
Fig. 2. Mean daily number of total errors on the conditional alternation task over the retention test period as a function of treatment.
cal criterion performance levels during the 40 days of testing. The lesions resulted in signifi9 cant increases in escape latencies on the forced trials on the In-st 5 retention test days. Choice latencies on the choice trials were significantly increased in the group with lesions only on the first retention day. The lack of recovery of performance following large, bilateral lesions involving the entorhinal cortex and subiculum in thisconditionai alternation task indicates that these lesions eliminated neural structures necessary for working memory. These fmdings are consistent with those of Loesche and Steward 4 and, more generally, with long-lasting deficits in radial maze performance 6,7,8. The difference between the lack of
recovery of these studies and the recovery of alternation performance around 30days of training reported by Ramirez and Stein 1~ has yet to be accounted for, but may relate to differences between the studies in the length of time the information was required to be maintained in working memory. In addition, the combined damage to the entorhinal cortex plus the subiculum, which eliminates many of the efferent connections of the hippocampal formation as well as the primary cortical afferents ~6, may be much more debilitating than more circumscribed damage to the entorhinal cortex. Nevertheless, it is reasonable to conclude that these large retrohippocampal lesions eliminated the ability to maintain and utilize the spatial information over the short periods of time necessary to direct choice behavior, a capacity reflecting a working memory function that is readily expressed by intact rats. REFERENCES 91 Geneser-Jensen, F.A. and Blackstad, T.W., Distribution of acetylcholinesterase in the hippocampal region of the guinea pig. I. Entorhinal area, parasubiculum, Z. Zellforsch., 114 (1971) 460-481. 2 Goodlett, C.R., Nichols, J.M., Halloran, R.W. and West, J.R., Recovery of performance of spatial navigation but not spatial working memory in water maze tasks following entorhinal cortex lesions, Soc. Neurosci. Abstr., 13 (1987) 1065. 3 Goodlett, C.R., Nonneman, AJ., Valentino, M.L. and West, J.R., Constraints on water maze spatial learning in rats: implications for behavioral studies of brain damage and recovery of function, Behav. Brain Res., in press.
67 4 Loesche, J. and Steward, O., Behavioral correlates of denervation and reinnervation of the hippocampal formation of the rat: recovery of alternation performance following unilateral entorhinal cortex lesions, Brain Res. Bull., 2 (1977) 31-39. 5 Lynch, G., Matthews, D.A., Mosko, S., Parks, T. and Cotman, C., Induced acetylcholinesterase-rich layer in rat dentate gyrus following entorhinal lesions, Brain Res., 42 (1972) 311-318. 6 0 l t o n , D.S., Memory functions and the hippocampus, Neurobiology of the Hippocampus, Academic, London, 1983, pp. 335-402. 7 0 l t o n , D.S., Walker, J.A. and Gage, F.H., Hippocampal connections and spatial discrimination, Brain Bes., 139 (1978) 295-308. 80lton, D.S., Walker, J.A. and Wolf, W.A., A disconnection analysis of hippocampal function, Brain Res., 233 (1982) 241-253. 9 Paxinos, G. and Watson, C., The Rat Brain in Stereotaxic Coordinates, Academic, Sydney, 1986. 10 Ramirez, J.J. and Stein, D.G., Sparing and recovery of spatial alternation performance after entorhinal cortex lesions in rats, Behav. Brain Res., 13 (1984) 53-61. 11 Rosene, D.L. and Van Hoesen, G.W., Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey, Science, 198 (1977) 315-317. 12 Schenk, F. and Morris, R.G.M., Dissociation between
components ofspatial memory in rats after recovery from the effects of retrohippocampal lesions, Exp. Brain Res., 58 (1985) 11-28. 13 Steward, O., Topographic organization ofthe projections from the entorhinal area to the hippoeampal formation of the rat, J. Comp. Neurol., 167 (1976) 285-314. 14 Steward, O. and Scoville, S.A., Ceils of origin of entorhinal cortex afferents to the hippocampal and fascia dentata ofthe rat, J. Comp. NeuroL, 169 (1976) 347-370. 15 Storm-Mathisen, J., Choline aeetyltransferase and acetylcholinesterase in fascia dentata following lesion of the entorhinal afferents, Brain Res., 80 (1974) 181-197. 16 Van Hoesen, G.W., The primate parahippocampal gyrus: new insights regarding its cortical connections, TINS, 5 (1982) 345-350. 17 Van Hoesen, G.W. and Pan@a, D.N., Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices in the rhesus monkey. I. Temporal lobe affercnts, Brain Res., 95 (1975) 1-24. 18 Van Hoesen, G.W. and Pan@a, D.N., Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices in the rhesus monkey. II. Entorhinal cortex efferents, Brain Res., 95 (1975) 39-59. 19 West, J.R., Deadwyler, S., Cotman, C.W. and Lynch, G., Time-dependent changes in commissural field potentials in the dentate gyrus following lesions of the entorhinal cortex in adult rats, Brain Res.; 97 (1975) 215-233.
Behavioural Brain Research, 32 (1989) 63-67 Elsevier BBR 00880
Long-term deficits in water maze spatial conditional alternation performance following retrohippocampal lesions in rats C h a r l e s R. G o o d l e t t , J o h n M . N i c h o l s , R o b e r t W . H a l l o r a n a n d J a m e s R. W e s t Alcohol and Brabz Research Laboratory, Department of Anatomy. University of lowa, Iowa City, 1.4 52242 (U.S.A.) (Received 20 January 1988) (Revised version received 19 May 1988) (Accepted 1 June 1988) Key words: Retrohippocampal lesion; Water maze; Rat
The effects of large bilateral retrohippocampal lesions on long-term performance of conditional spatial alternation, incorporating a strong working memory component, were examined using a T-maze task motivated by swim-escape. The lesions, which included entorhinal cortex, subiculum, pre- and parasubiculum and invaded the molecular layer of the dentate gyrus, completely eliminated the previously acquired conditional alternation learning, and performance failed to recover with 40 days oftesting. These findings support the contention that retrohippocampal structures are an important and necessary component of the neural circuitry mediating working memory.
INTRODUCTION
The entorhinal cortex provides one of the major afferents to the hippocampal formation 13'14'1s, and serves as a link between the neocortex and the hippocampus 11,16,17 AS such, it is not surprising that bilateral damage to the entorhinal cortex in rats produces behavioral deficits in spatial learning in many of the same tasks that are disrupted by hippoeampal lesions 4'7'8'12. Nevertheless, studies of the extent of recovery from entorhinal cortex lesions have produced equivocal results. Tasks requiring working memory 6, in which appropriate behavior depends on utilization of information about specific items or events that occur in a given context over relatively short periods of time, are sensitive to damage to the hippoeampal formation and associated structures
such as the entorhinal cortex. Olton and his colleagues7,8, using the radial maze, found that bilateral damage produced enduring deficits in the performance of working memory tasks. Loesehe and Steward 4 found comparable long-term deficits in rewarded alternation performance in a T-maze. However, recovery of rewarded alternation performance after about 30 days of postoperative training has been reported I~ Likewise, spatial navigation in the Morris water maze is impaired by entorhinal cortex lesions ~2, but we have found that substantial recovery of place navigation occurs with extended postoperative training 2. Since the appetitive Working memory tasks have yielded somewhat equivocal findings concerning the long-term effects of entorhinal cortex lesions, we developed a water maze conditional
Correspondence: C.R. Goodlett, Alcohol and Brain Research Laboratory, Department of Anatomy, University of Iowa, Iowa City, IA 52242, U.S.A. 0166-4328/89/$03.50 9 1989 Elsevier Science Publishers B.V. (Biomedical Division)
64 alternation procedure to determine the extent of behavioral recovery in an aversively-motivated spatial working memory task. The water maze provides several experimental advantages over food- or water-rewarded procedures, including elimination of the need for deprivation, reduction of the confounding effects of local olfactory cues, and the opportunity to manipulate motivational conditions of the task by altering water temperature. We have found that water maze working memory tasks are acquired more slowly by intact rats than comparable appetitive tasks 3. However, conditional ('win-shift') spatial alternation (but not spatial alternation over consecutive trials) can be reliably learned by intact rats. Thus, we used a conditional alternation procedure in the water maze to examine extended postoperative retention performance of rats with large bilateral retrohippocampal lesions including the entorhinal cortex and subiculum. Male rats were obtained from Sasco-King Laboratories at 55-65 days of age and maintained in group cages with ad libilum food and water throughout the experiment. Behavioral training was conducted using a white circular water tank, 121 cm diameter, filled to within 8 cm of the rim with 21 ~ water which was made opaque by dissolving 1500 ml of powdered milk. A T-maze was partially immersed in the water, extending 10 cm above the surface of the water. The start stem (72 cm long) and the two goal arms (each 38 cm long) were made of clear Plexiglas, and the cul-de-sacs (10 cm long) at the end of each goal arm were made of black Plexiglas. All alleys were 18 cm wide, and an escape ladder could be placed in the end ot~ the cul-de-sac of each arm, hidden from view from the start stem or choice area. The rats were given two days of swim-escape pretraining in the maze, 10 trials per day in which one arm was blocked and the escape ladder present at the end ot" the other arm. On these trials, the rats had to swim from the start area to the end of the unblocked arm. The rats were forced to escape from each arm 5 times each day, with the order determined by a random sequence. The conditional alternation training used the procedure previously described 3. Briefly, the rats
were given 8 trials per day, with each trial consisting of a forced ('information') run, in which one arm was blocked and escape available from the other arm, followed by a choice run, in which both arms were open and escape was available only from the arm previously blocked. The rats were left on the escape ladder for 5 s after each run, and a 6-s interval was maintained between removal from the ladder after the forced run and the start of the choice run. On half of the trials each day the information run was to the left, and the other half to the right, with the order determined by a random sequence each day. Each entry into the incorrect arm (the forced arm on each trial) was counted as an error, and errors, latencies to complete the forced trial and latencies to make a choice on the choice trials were recorded. Operationally, this task involved a strong working memory component, since over the 8 trials of each day, the rats had to maintain information about the direction of the forced trial in order to make an accurate choice on the immediately succeeding choice trial, while keeping the sets of runs temporally distinct 6. All rats were given acquisition training to a criterion of 3 consecutive days of 7/8 correct trials. Upon reaching the acquisition criterion, they were assigned to one of 3 groups: bilateral entorhinal cortex lesions (n = 9), sham operates (n = 9) or unoperated controls (n = 5), balancing for the number of days to criterion. Surgery was performed on the day following the last acquisition day, and retention training began on the fifth day after the last acquisition day. Bilateral entorhinal cortex lesions were performed under ether anesthesia by passing a 1.0-mA DC (anodal) current for 30 s through a Teflon-coated stainless steel electrode exposed only at the tip, 3.0, 5.0 and 6.0 mm ventral to the surface of the brain at each of 3 placements on each side ~9. Sham operations performed under ether anesthesia included bilateral removal of a bone flap, cutting the dura and inserting a needle 2 mm into the cortex at each of the 3 locations on each side. The rats with entorhinal cortex lesions were given 40 days of retention training, while the sham operates and unoperated controls were each given 16 days of retention training. The two control groups were
65 not tested beyond 16 days because it was clear they had returned to presurgical accuracy levels by that time. Only the group with lesions was tested for the extended period, to determine whether behavioral recovery would eventually occur.
At the completion of training the rats given surgery were perfused with 0.9% saline followed by 1% (w/v) paraformaldehyde and 1.25 % (v/v) glutaraldehyde. Coronal sections (40/lm thick) through the rostral hippocampus were processed for acetylcholinesterase (/~ChE) histochemical localization using a modification of the Geneser-Jensen method ~, to confirm the typical reorganization of AChE-positive staining in the dentate gyrus induced by these lesions 5'~5. Horizontal sections (40tim thick) through the posterior forebrain were taken, and every fifth section was stained with Cresyl violet to determine the extent of each lesion. As shown in Fig. 1, the lesions were large and destroyed all of the medial entorhinal cortex (except at the most ventral level). Extensive damage to the presubiculum, parasubiculum and subiculum was present in every case, and overlying occipital cortex was also damaged. In the mid-temporal region, the molecular layer of the dentate gyrus was invaded in all cases, and hippocampal subfield C A l a was partially damaged on at least one side of the brain in 5 cases. The typical
intensification of AChE staining (not shown) in the outer molecular layer and the concomitant clearing and widening of the pale-staining commisural/associational zone following the lesions was observed bilaterally in every case. These lesions were comparable to those reported by Loesche and Steward 4 and Ramirez and Stein l~ As shown in Table I, there were no significant group differences in presurgical acquisition performance, indicating that the balancing procedure effectively equated acquisition performance among groups. The bilateral lesions resulted in deficits in choice accuracy, which did not improve over the 40 days of testing (Fig. 2). Both the sham operates and the unoperated controls showed an increase in errors during the initial stages of retention testing relative to the end of acquisition, but returned to accurate performance levels by the end of the first week (Fig. 2). A repeated measures analysis of variance on daily total error scores during the first 16 days of retention yielded a significant treatment x retention test day interaction [F3o,3oo = 2.25,p < 0.001 ], due to the rapid decline in errors in the two control groups early in retention testing compared to the lasting deficits of the group with lesions. The two control groups committed significantly fewer errors after the second retention test day relative to the group with lesions (Newman-Keuls, p < 0.05). In fact, none of the rats with lesions approached presurgi-
lr.f Fig. 1. Low power photomicrograph of a Cresyl violet-stained horizontal section depicting a typical lesion, shown at a midtemporal level corresponding approximatelyto plate 104 of the atlas of Paxinos and Watson9.
66 TABLE I
Conditional alternation pe~orniance measures during presurgical acquisition There were no significant differences in acquisition performance in the conditional alternation task for the 3 surgical groups (means + S.E.M.).
EC lesions (n = 9) Sham operates (n = 9) Unoperated controls (n = 5)
s
o
Days to acquisition criterion
Total errors to acquisition criterion
Escape latency (s) (forced trials)
14.9 + 1.8
28.6 + 4.0
6.0 + 0.3
15.1 + 1.6
35.4 + 4.4
6.6 + 0.4
16.2 + 3.3
40.2 + 9.3
5.6 + 0.5
~
H
BILATEnAL EC [N-9) SHAM OPERATES (N'g) L$ (N-5)
i.-
8~ to z
2
<= I
;
,;
,;
2'o
L
~o
;s
,'o
RETENTION DAY
Fig. 2. Mean daily number of total errors on the conditional alternation task over the retention test period as a function of treatment.
cal criterion performance levels during the 40 days of testing. The lesions resulted in signifi9 cant increases in escape latencies on the forced trials on the In-st 5 retention test days. Choice latencies on the choice trials were significantly increased in the group with lesions only on the first retention day. The lack of recovery of performance following large, bilateral lesions involving the entorhinal cortex and subiculum in thisconditionai alternation task indicates that these lesions eliminated neural structures necessary for working memory. These fmdings are consistent with those of Loesche and Steward 4 and, more generally, with long-lasting deficits in radial maze performance 6,7,8. The difference between the lack of
recovery of these studies and the recovery of alternation performance around 30days of training reported by Ramirez and Stein 1~ has yet to be accounted for, but may relate to differences between the studies in the length of time the information was required to be maintained in working memory. In addition, the combined damage to the entorhinal cortex plus the subiculum, which eliminates many of the efferent connections of the hippocampal formation as well as the primary cortical afferents ~6, may be much more debilitating than more circumscribed damage to the entorhinal cortex. Nevertheless, it is reasonable to conclude that these large retrohippocampal lesions eliminated the ability to maintain and utilize the spatial information over the short periods of time necessary to direct choice behavior, a capacity reflecting a working memory function that is readily expressed by intact rats. REFERENCES 91 Geneser-Jensen, F.A. and Blackstad, T.W., Distribution of acetylcholinesterase in the hippocampal region of the guinea pig. I. Entorhinal area, parasubiculum, Z. Zellforsch., 114 (1971) 460-481. 2 Goodlett, C.R., Nichols, J.M., Halloran, R.W. and West, J.R., Recovery of performance of spatial navigation but not spatial working memory in water maze tasks following entorhinal cortex lesions, Soc. Neurosci. Abstr., 13 (1987) 1065. 3 Goodlett, C.R., Nonneman, AJ., Valentino, M.L. and West, J.R., Constraints on water maze spatial learning in rats: implications for behavioral studies of brain damage and recovery of function, Behav. Brain Res., in press.
67 4 Loesche, J. and Steward, O., Behavioral correlates of denervation and reinnervation of the hippocampal formation of the rat: recovery of alternation performance following unilateral entorhinal cortex lesions, Brain Res. Bull., 2 (1977) 31-39. 5 Lynch, G., Matthews, D.A., Mosko, S., Parks, T. and Cotman, C., Induced acetylcholinesterase-rich layer in rat dentate gyrus following entorhinal lesions, Brain Res., 42 (1972) 311-318. 6 0 l t o n , D.S., Memory functions and the hippocampus, Neurobiology of the Hippocampus, Academic, London, 1983, pp. 335-402. 7 0 l t o n , D.S., Walker, J.A. and Gage, F.H., Hippocampal connections and spatial discrimination, Brain Bes., 139 (1978) 295-308. 80lton, D.S., Walker, J.A. and Wolf, W.A., A disconnection analysis of hippocampal function, Brain Res., 233 (1982) 241-253. 9 Paxinos, G. and Watson, C., The Rat Brain in Stereotaxic Coordinates, Academic, Sydney, 1986. 10 Ramirez, J.J. and Stein, D.G., Sparing and recovery of spatial alternation performance after entorhinal cortex lesions in rats, Behav. Brain Res., 13 (1984) 53-61. 11 Rosene, D.L. and Van Hoesen, G.W., Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey, Science, 198 (1977) 315-317. 12 Schenk, F. and Morris, R.G.M., Dissociation between
components ofspatial memory in rats after recovery from the effects of retrohippocampal lesions, Exp. Brain Res., 58 (1985) 11-28. 13 Steward, O., Topographic organization ofthe projections from the entorhinal area to the hippoeampal formation of the rat, J. Comp. Neurol., 167 (1976) 285-314. 14 Steward, O. and Scoville, S.A., Ceils of origin of entorhinal cortex afferents to the hippocampal and fascia dentata ofthe rat, J. Comp. NeuroL, 169 (1976) 347-370. 15 Storm-Mathisen, J., Choline aeetyltransferase and acetylcholinesterase in fascia dentata following lesion of the entorhinal afferents, Brain Res., 80 (1974) 181-197. 16 Van Hoesen, G.W., The primate parahippocampal gyrus: new insights regarding its cortical connections, TINS, 5 (1982) 345-350. 17 Van Hoesen, G.W. and Pan@a, D.N., Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices in the rhesus monkey. I. Temporal lobe affercnts, Brain Res., 95 (1975) 1-24. 18 Van Hoesen, G.W. and Pan@a, D.N., Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices in the rhesus monkey. II. Entorhinal cortex efferents, Brain Res., 95 (1975) 39-59. 19 West, J.R., Deadwyler, S., Cotman, C.W. and Lynch, G., Time-dependent changes in commissural field potentials in the dentate gyrus following lesions of the entorhinal cortex in adult rats, Brain Res.; 97 (1975) 215-233.