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Functional dissociation between lateral and medial entorhinal cortex in memory processes in mice
Behavioural Brain Research, 9 (1983) 111-117 Elsevier
111
Functional dissociation between lateral and medial entorhinal cortex in memory processes in mice
M O N I Q U E G A U T H I E R l, C L A U D E D E S T R A D E l and B E R N A R D S O U M I R E U - M O U R A T 2
~Laboratoire de Psychophysiologie, Universit~ de Bordeaux I, avenue des Facultds, 33405 Talence Cedex, and 2B. Soumireu-Mourat Laboratoire de Neurobiologie des Comportements, Universitd de Provence, Centre de Saint-Jdr6me, 13397 Marseille Cedex 13 (France.) (Received August 18th, 1981) (Revised version received September 9th, 1982) (Accepted March 22nd, 1983)
Key words: lateral entorhinal cortex - medial entorhinal cortex - lesion - appetitive operant conditioning - retention - extinction The effects of lesions of the medial or the lateral entorhinal cortex in mice were examined on acquisition, retention and extinction of an operant-conditioning task in a Skinner box. Compared with the control animals, lesions in the medial entorhinal had no behavioral effects whereas lesions in the lateral entorhinal enhanced retention and increased resistance to extinction but did not change acquisition of this task. These results suggest a functional dissociation between the two parts of the entorhinal cortex.
We have previously shown the involvement of the lateral entorhinal cortex (LEC) in memory processes using lesion [5, 6] or stimulation [7] techniques. However, there is a good deal of evidence that the entorhinal cortex (EC) is not homogeneous. It is divided into a lateral and a medial part [9, 15], each of which sends efferents to different fields of the hippocampus and dentate gyrus [8], and gives rise to fibers of the perforant path with specific electrophysiological characteristics [ 11, 17]. Does the medial entorhinal cortex (MEC) play the same role in memory processes as the LEC or does a behavioural differentiation exist between these two parts? The present study focused on the effects of lateral versus medial entorhinal cortex lesions on operant-conditioning tasks in mice. Fifty-four male mice of BALB/c strain served as subjects. At 8 weeks of age (1 week before surgery) they were individually housed with ad libitum access to food and water. Under deep anaesthesia, 36 animals received a radiofrequency bilateral lesion of the entorhinal cortex, either in the lateral part (18 animals: 2.8 mm posterior to bregrna, 3.0 mm lateral to the midline, 4.9 mm below the skull, with a 12 ° angle from the midline), or in the medial part (18 animals: 2.7 mm posterior to bregma, 2.8 mm lateral to the midline, 4.9 mm below the skull). The 0166-4328/83/$03.00 © 1983 Elsevier Science Publishers B.V.
112 lesions were made by passing high frequency current (500 kHz, 0.35 mA) for 3 sec through an electrode (0.35 mm in diameter, 0.1 mm baretip). Six animals were sham-operated: the electrode was lowered in the MEC (3 animals) or in the LEC (3 animals) but no current was passed. At the end of the experiments, the brains were removed and standard histological techniques were later used to determine the placement and the size of the lesion. The first experiment took place 15 days after surgery. Thirty-six animals (12 LEC lesioned, 12 MEC lesioned, 6 sham-operated, 6 non-operated) underwent an operant lever-press conditioning task with food reward. The Skinner box previously described [2] was equipped with a device which permitted the removal of any pellet that was not eaten. The lever and the food cup were separated by a partition so that the animal had to turn around to press the lever or to find food. A continuous reinforcement (CRF) schedule was used. Throughout the study all mice were maintained at 82-84~o of their ad libitum weight. Each animal underwent an initial 15-min partial learning session in the Skinner box without pretraining or shaping. Animals were fed 30 min after the first learning session so that their body weights were the same at the beginning of the next session. Retention testing was carried out 24 h later during a 30-min session. After such a partial acquisition session, we have often emphasized [4] that a spontaneous improvement in performance is observed at the beginning of the test session on the next day (reminiscence effect); this improvement is not related to non-associative factors such as motivation or motor activity. Mean responses during the successive 5-min periods of the first and second sessions are presented in Fig. 1. Performances of the medial or lateral entorhinal cortex sham-operated animals remained unchanged throughout the experiment (F(1, 4 ) = 0.12, n.s.). Since these subjects were not significantly different, their scores were pooled and then compared to those of non-operated animals throughout the whole session. As no difference was observed (F(1, 10) = 0.10, n.s.), these two groups were also pooled and served as one control group. During the 15 min of the first session, no difference was observed between the 3 groups (F(2, 33) = 0.76, n.s.) (see Fig. 1). Twenty-four hours later, during the test session, the performance of the MEC lesioned animals was not different from that of the control group (F(1, 22) = 0.20, n.s.). In contrast, a great improvement in performance was seen in the LEC-lesioned group compared to the control group during the first and second 5-rain blocks of the retention session fin'st 5-min block, t = 4.32, P < 0.01; second 5-min block, t = 3.56, P < 0.01). After 20 min of learning, the animals of all the groups reached the same performance levels (fifth 5-min block F(2, 33) = 0.47, n.s.). For the second experiment, all animals were trained in the Skinner box on a CRF schedule 24 h after the previous retention session, until they reached a total of 200 responses [3]. For the next 3 days, they underwent a daily 10-rain
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extinction session. The results were analyzed using a number of responses per 2-rain period, as presented in Fig. 2. Throughout the experiment, the scores of medial or lateral entorhinal cortex sham-operated animals were pooled as they were not statistically different (F(1, 14 < 0.85, n.s.). These animals had the same performance level as the non-operated subjects on the 3 sessions (F(1, 10) < 1.16, n.s.). All these subjects together served as the control group. During the first extinction session, no difference was observed between the 3 groups (F(2, 33) = 1.06, n.s.). A resistance to extinction was found during the second extinction for the LEC-lesioned animals compared to control animals (treatment x block interaction: F(4, 88)--36.42, P < 0 . 0 0 1 ) whereas MEClesioned animals behaved like the control animals (F(4, 88) -- 2.04, n.s.). All the animals had the same performance level during the third session (F(2, 33) = 1.53, n.s.).
The third experiment was designed to clarify the results of the first experiment. The animals, partially food deprived, underwent a complete acquisition session of the same operant conditioning for 30 min. Eighteen naive animals were used for this experiment (6 LEC-lesioned, 6 MEC-lesioned, 6 non-operated animals). The deprivation and the conditioning procedures were the same as described for the first experiment. The continuous acquisition curves presented in Fig. 3 were equivalent for the 3 groups. No difference was seen between the performance of lesioned animals (in medial or lateral EC) and that of non-operated animals (F(2, 15) = 0.22, n.s.).
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Fig. 4 shows, on a frontal section of the mouse brain, the location of the lesions and their average size. The histological analysis showed that the lesions were correctly located in each part of the entorhinal cortex as defined b y neuroanatomical studies [9, 15]. They were similar in extent in the two groups; 30-
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Fig. 4. Frontal section of the mouse brain showing the extent and the location of damage with bilateral lesion of the lateral part (black) or of the medial part of the entorhinal cortex. CC, corpus callosum; CS, colliculus superior; FD, fascia dentata; FR, fissura rhinalis; GC, substantia grisea; GM, nucleus medialis thalami; Hip, hippocampus; IP, nucleus interpeduncularis; NR, nucleus ruber; SN, substantia nigra; Sub, subiculum.
no correlation was observed between the size of the lesion and the behavioral effect. The observed results show a functional dissociation between medial and lateral entorhinal cortices. M E C lesion had no effect on the animals behavior during the retention of a Skinner-box task (CRF conditioning) or the extinction of this task. On the contrary, LEC lesion enhanced retention of C R F conditioning and lead to greater resistance to extinction of this task, but did not change the speed of acquisition of the same task. The changes in retention and extinction observed in LEC-lesioned animals corroborate previous results using the same paradigm [6]. Hyperactivity has already been put forward to explain the behavioral modifications produced by the lesion of LEC [6]. Such hyperactivity could be related to behavioral disinhibition as described after hippocampal lesions. This hypothesis fits well with the enhancement of performance seen during the retention of the operant-conditioning task or with the resistance to extinction observed in the extinction experiment. However, the fact that the lesion did not modify the speed of acquisition during the first acquisition session of the Skinner-box task and during the complete learning session of the same task does not agree with such an hypothesis. We cannot say that LEC-lesioned animals were hyperactive compared to MEC-lesioned animals or to control animals. Another hypothesis can be considered with regard to regeneration phenomena. In immature rats, LEC lesion produces sprouting of cholinergic septohippocampal fibres into the denervated zone of the dentate gyrus whereas M E C lesion does not [ 13]. But in mature animals (which is the case in our experiments)
116 the septo-hippocampal fibres proliferated in the denervated area no matter which part of the EC was lesioned [ 14]. In any case, according to previous data [ 12, 16] our experiments took place at a time when sprouting and functional recovery should be finished. The fact that, in spite of this, we observed behavioral differences between LEC and MEC lesioned animals suggests that we are not dealing with the sequelae of sprouting. The memory hypothesis is able to explain the present results. In LEClesioned animals, the enhancement of performance in retention could be due to a facilitating effect of the lesion on the reminiscence phenomenon. The resistance to extinction seen in the second experiment could be related to better retention of the previously well-learned CRF task. If such is the case, what is then the role played by MEC in memory processes? Lesion experiments are not sufficient to determine the role of a particular structure in a specific function. Interesting results were obtained after electrical stimulation of the LEC [1, 7, 10] and in the same cases it was shown that this cortex was involved in late memory processes. In order to clarify the exact role of MEC and LEC in learning and memory, with respect to their different projections to hippocampus and dentate gyrus, we will now try to compare the effects of post-trial stimulation of these cortices in the same behavioral paradigm as used in the present experiments. REFERENCES 1 Collier, T.J. and Routtenberg, A., Entorhinal cortex electrical stimulation disrupts retention performance when applied after but not during learning, Brain Res., 152 (1978) 411-417. 2 Destrade, C. and Cardo, B., Effects of post-trial hippocampal stimulation on time-dependent improvement of performance in mice, Brain Res., 78 (1974) 447-454. 3 Destrade, C. and Gauthier, M., Facilitation de la r&ention et accrlrration de l'extinction d'un conditionnement oprrant aprrs 16sion du cortex cingulaire chez la souris BALB/c, C.R. Acad. Sci., Paris, 293 (1981) 843-846. 4 Jaffard, R., Destrade, C., Soumireu-Mourat, B. and Cardo, B,, Time-dependent improvement of performance on appetitive tasks in mice, Behav. Biol., 11 (1974) 89-100. 5 Gauthier, M. and Soumireu-Mourat, B., 6-OHDA and radiofrequency lesions of the lateral entorhinal cortex facilitate an operant appetitive conditioning task in mice, Neurosci. Len., 24 (1981) 193-197. 6 Gauthier, M. and Soumireu-Mourat, B., Behavioral effects of bilateral entorhinal cortex lesions in the BALB/c mouse, Behav. Neural Biol., 33 (1981) 419-436. 7 Gauthier, M., Destrade, C. and Soumireu-Mourat, B., Late post-learning participation of entorhinal cortex in memory processes, Brain Res:, 233 (1982) 255-264. 8 Habets, A.M.M.C., Lopes da Silva, F.H. and de Quartel, F.W., Autoradiography of the olfactory-hippocampal pathway in the cat with special reference to the perforant path, Exp. Brain Res., 38 (1980) 257-265. 9 Hjorth-Simonsen, A., Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentata, J. comp. Neurol., 146 (1972) 219-232. 10 Martinez, J.L. Jr., McGaugh, J.L., Hanes, C.L. and Lacob, J.S., Modulation of memory processes induced by stimulation of the entorhinal cortex, Physiol. Behav., 19 (1977) 139-144.
117 11 McNaughton, B.L. and Barnes, C.A., Physiological identification and analysis of dentate granule cell responses to stimulation of the medial and lateral perforant pathways in the rat, J. cornp. Neurol., 175 (1977) 439-454. 12 Myhrer, T., Maze performance in rats with hippocampal perforant paths lesions: some aspects of functional recovery, Physiol. Behav., 15 (1975) 433-437. 13 Nadler, J.V., Cotman, C.W., Paoletti, C. and Lynch, G., Histochemical evidence of altered development of cholinergic fibers in the rat dentate gyrus following lesions. I. Time course after complete unilateral entorhinal lesion at various ages, J. comp. NeuroL, 171 (1977) 561-588. 14 Nadler, J.V., Cotman, C.W., Paoletti, C. and Lynch, G., Histochemical evidence of altered development of cholinergic fibers in the rat dentate gyrus following lesions. II. Effects of partial entorhinal and simultaneous multiple lesions, J. comp. Neurol., 171 (1977) 589-604. 15 Steward, O., Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat, J. comp. Neurol., 3 (1976) 285-314. 16 Steward, O., Loesche, J. and Horton, W.C., Behavioral correlates ofdenervation and reinnervation of the hippocampal formation of the rat: open-field activity and cue utilization following bilateral entorhinal cortex lesion, Brain Res. Bull., 2 (1977) 41-48. 17 Tielen, A.M., Lopes da Silva, F.H. and MiUevanger, W.J., Some physiological differences between the medial and lateral perforant paths systems in the guinea-pig, Progress Report, 7 (1980) 80-82.
111
Functional dissociation between lateral and medial entorhinal cortex in memory processes in mice
M O N I Q U E G A U T H I E R l, C L A U D E D E S T R A D E l and B E R N A R D S O U M I R E U - M O U R A T 2
~Laboratoire de Psychophysiologie, Universit~ de Bordeaux I, avenue des Facultds, 33405 Talence Cedex, and 2B. Soumireu-Mourat Laboratoire de Neurobiologie des Comportements, Universitd de Provence, Centre de Saint-Jdr6me, 13397 Marseille Cedex 13 (France.) (Received August 18th, 1981) (Revised version received September 9th, 1982) (Accepted March 22nd, 1983)
Key words: lateral entorhinal cortex - medial entorhinal cortex - lesion - appetitive operant conditioning - retention - extinction The effects of lesions of the medial or the lateral entorhinal cortex in mice were examined on acquisition, retention and extinction of an operant-conditioning task in a Skinner box. Compared with the control animals, lesions in the medial entorhinal had no behavioral effects whereas lesions in the lateral entorhinal enhanced retention and increased resistance to extinction but did not change acquisition of this task. These results suggest a functional dissociation between the two parts of the entorhinal cortex.
We have previously shown the involvement of the lateral entorhinal cortex (LEC) in memory processes using lesion [5, 6] or stimulation [7] techniques. However, there is a good deal of evidence that the entorhinal cortex (EC) is not homogeneous. It is divided into a lateral and a medial part [9, 15], each of which sends efferents to different fields of the hippocampus and dentate gyrus [8], and gives rise to fibers of the perforant path with specific electrophysiological characteristics [ 11, 17]. Does the medial entorhinal cortex (MEC) play the same role in memory processes as the LEC or does a behavioural differentiation exist between these two parts? The present study focused on the effects of lateral versus medial entorhinal cortex lesions on operant-conditioning tasks in mice. Fifty-four male mice of BALB/c strain served as subjects. At 8 weeks of age (1 week before surgery) they were individually housed with ad libitum access to food and water. Under deep anaesthesia, 36 animals received a radiofrequency bilateral lesion of the entorhinal cortex, either in the lateral part (18 animals: 2.8 mm posterior to bregrna, 3.0 mm lateral to the midline, 4.9 mm below the skull, with a 12 ° angle from the midline), or in the medial part (18 animals: 2.7 mm posterior to bregma, 2.8 mm lateral to the midline, 4.9 mm below the skull). The 0166-4328/83/$03.00 © 1983 Elsevier Science Publishers B.V.
112 lesions were made by passing high frequency current (500 kHz, 0.35 mA) for 3 sec through an electrode (0.35 mm in diameter, 0.1 mm baretip). Six animals were sham-operated: the electrode was lowered in the MEC (3 animals) or in the LEC (3 animals) but no current was passed. At the end of the experiments, the brains were removed and standard histological techniques were later used to determine the placement and the size of the lesion. The first experiment took place 15 days after surgery. Thirty-six animals (12 LEC lesioned, 12 MEC lesioned, 6 sham-operated, 6 non-operated) underwent an operant lever-press conditioning task with food reward. The Skinner box previously described [2] was equipped with a device which permitted the removal of any pellet that was not eaten. The lever and the food cup were separated by a partition so that the animal had to turn around to press the lever or to find food. A continuous reinforcement (CRF) schedule was used. Throughout the study all mice were maintained at 82-84~o of their ad libitum weight. Each animal underwent an initial 15-min partial learning session in the Skinner box without pretraining or shaping. Animals were fed 30 min after the first learning session so that their body weights were the same at the beginning of the next session. Retention testing was carried out 24 h later during a 30-min session. After such a partial acquisition session, we have often emphasized [4] that a spontaneous improvement in performance is observed at the beginning of the test session on the next day (reminiscence effect); this improvement is not related to non-associative factors such as motivation or motor activity. Mean responses during the successive 5-min periods of the first and second sessions are presented in Fig. 1. Performances of the medial or lateral entorhinal cortex sham-operated animals remained unchanged throughout the experiment (F(1, 4 ) = 0.12, n.s.). Since these subjects were not significantly different, their scores were pooled and then compared to those of non-operated animals throughout the whole session. As no difference was observed (F(1, 10) = 0.10, n.s.), these two groups were also pooled and served as one control group. During the 15 min of the first session, no difference was observed between the 3 groups (F(2, 33) = 0.76, n.s.) (see Fig. 1). Twenty-four hours later, during the test session, the performance of the MEC lesioned animals was not different from that of the control group (F(1, 22) = 0.20, n.s.). In contrast, a great improvement in performance was seen in the LEC-lesioned group compared to the control group during the first and second 5-rain blocks of the retention session fin'st 5-min block, t = 4.32, P < 0.01; second 5-min block, t = 3.56, P < 0.01). After 20 min of learning, the animals of all the groups reached the same performance levels (fifth 5-min block F(2, 33) = 0.47, n.s.). For the second experiment, all animals were trained in the Skinner box on a CRF schedule 24 h after the previous retention session, until they reached a total of 200 responses [3]. For the next 3 days, they underwent a daily 10-rain
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extinction session. The results were analyzed using a number of responses per 2-rain period, as presented in Fig. 2. Throughout the experiment, the scores of medial or lateral entorhinal cortex sham-operated animals were pooled as they were not statistically different (F(1, 14 < 0.85, n.s.). These animals had the same performance level as the non-operated subjects on the 3 sessions (F(1, 10) < 1.16, n.s.). All these subjects together served as the control group. During the first extinction session, no difference was observed between the 3 groups (F(2, 33) = 1.06, n.s.). A resistance to extinction was found during the second extinction for the LEC-lesioned animals compared to control animals (treatment x block interaction: F(4, 88)--36.42, P < 0 . 0 0 1 ) whereas MEClesioned animals behaved like the control animals (F(4, 88) -- 2.04, n.s.). All the animals had the same performance level during the third session (F(2, 33) = 1.53, n.s.).
The third experiment was designed to clarify the results of the first experiment. The animals, partially food deprived, underwent a complete acquisition session of the same operant conditioning for 30 min. Eighteen naive animals were used for this experiment (6 LEC-lesioned, 6 MEC-lesioned, 6 non-operated animals). The deprivation and the conditioning procedures were the same as described for the first experiment. The continuous acquisition curves presented in Fig. 3 were equivalent for the 3 groups. No difference was seen between the performance of lesioned animals (in medial or lateral EC) and that of non-operated animals (F(2, 15) = 0.22, n.s.).
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Fig. 2. Effects of the MEC or LEC lesions on performance seen during three 24-h-delayed extinction
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Fig. 4 shows, on a frontal section of the mouse brain, the location of the lesions and their average size. The histological analysis showed that the lesions were correctly located in each part of the entorhinal cortex as defined b y neuroanatomical studies [9, 15]. They were similar in extent in the two groups; 30-
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Fig. 4. Frontal section of the mouse brain showing the extent and the location of damage with bilateral lesion of the lateral part (black) or of the medial part of the entorhinal cortex. CC, corpus callosum; CS, colliculus superior; FD, fascia dentata; FR, fissura rhinalis; GC, substantia grisea; GM, nucleus medialis thalami; Hip, hippocampus; IP, nucleus interpeduncularis; NR, nucleus ruber; SN, substantia nigra; Sub, subiculum.
no correlation was observed between the size of the lesion and the behavioral effect. The observed results show a functional dissociation between medial and lateral entorhinal cortices. M E C lesion had no effect on the animals behavior during the retention of a Skinner-box task (CRF conditioning) or the extinction of this task. On the contrary, LEC lesion enhanced retention of C R F conditioning and lead to greater resistance to extinction of this task, but did not change the speed of acquisition of the same task. The changes in retention and extinction observed in LEC-lesioned animals corroborate previous results using the same paradigm [6]. Hyperactivity has already been put forward to explain the behavioral modifications produced by the lesion of LEC [6]. Such hyperactivity could be related to behavioral disinhibition as described after hippocampal lesions. This hypothesis fits well with the enhancement of performance seen during the retention of the operant-conditioning task or with the resistance to extinction observed in the extinction experiment. However, the fact that the lesion did not modify the speed of acquisition during the first acquisition session of the Skinner-box task and during the complete learning session of the same task does not agree with such an hypothesis. We cannot say that LEC-lesioned animals were hyperactive compared to MEC-lesioned animals or to control animals. Another hypothesis can be considered with regard to regeneration phenomena. In immature rats, LEC lesion produces sprouting of cholinergic septohippocampal fibres into the denervated zone of the dentate gyrus whereas M E C lesion does not [ 13]. But in mature animals (which is the case in our experiments)
116 the septo-hippocampal fibres proliferated in the denervated area no matter which part of the EC was lesioned [ 14]. In any case, according to previous data [ 12, 16] our experiments took place at a time when sprouting and functional recovery should be finished. The fact that, in spite of this, we observed behavioral differences between LEC and MEC lesioned animals suggests that we are not dealing with the sequelae of sprouting. The memory hypothesis is able to explain the present results. In LEClesioned animals, the enhancement of performance in retention could be due to a facilitating effect of the lesion on the reminiscence phenomenon. The resistance to extinction seen in the second experiment could be related to better retention of the previously well-learned CRF task. If such is the case, what is then the role played by MEC in memory processes? Lesion experiments are not sufficient to determine the role of a particular structure in a specific function. Interesting results were obtained after electrical stimulation of the LEC [1, 7, 10] and in the same cases it was shown that this cortex was involved in late memory processes. In order to clarify the exact role of MEC and LEC in learning and memory, with respect to their different projections to hippocampus and dentate gyrus, we will now try to compare the effects of post-trial stimulation of these cortices in the same behavioral paradigm as used in the present experiments. REFERENCES 1 Collier, T.J. and Routtenberg, A., Entorhinal cortex electrical stimulation disrupts retention performance when applied after but not during learning, Brain Res., 152 (1978) 411-417. 2 Destrade, C. and Cardo, B., Effects of post-trial hippocampal stimulation on time-dependent improvement of performance in mice, Brain Res., 78 (1974) 447-454. 3 Destrade, C. and Gauthier, M., Facilitation de la r&ention et accrlrration de l'extinction d'un conditionnement oprrant aprrs 16sion du cortex cingulaire chez la souris BALB/c, C.R. Acad. Sci., Paris, 293 (1981) 843-846. 4 Jaffard, R., Destrade, C., Soumireu-Mourat, B. and Cardo, B,, Time-dependent improvement of performance on appetitive tasks in mice, Behav. Biol., 11 (1974) 89-100. 5 Gauthier, M. and Soumireu-Mourat, B., 6-OHDA and radiofrequency lesions of the lateral entorhinal cortex facilitate an operant appetitive conditioning task in mice, Neurosci. Len., 24 (1981) 193-197. 6 Gauthier, M. and Soumireu-Mourat, B., Behavioral effects of bilateral entorhinal cortex lesions in the BALB/c mouse, Behav. Neural Biol., 33 (1981) 419-436. 7 Gauthier, M., Destrade, C. and Soumireu-Mourat, B., Late post-learning participation of entorhinal cortex in memory processes, Brain Res:, 233 (1982) 255-264. 8 Habets, A.M.M.C., Lopes da Silva, F.H. and de Quartel, F.W., Autoradiography of the olfactory-hippocampal pathway in the cat with special reference to the perforant path, Exp. Brain Res., 38 (1980) 257-265. 9 Hjorth-Simonsen, A., Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentata, J. comp. Neurol., 146 (1972) 219-232. 10 Martinez, J.L. Jr., McGaugh, J.L., Hanes, C.L. and Lacob, J.S., Modulation of memory processes induced by stimulation of the entorhinal cortex, Physiol. Behav., 19 (1977) 139-144.
117 11 McNaughton, B.L. and Barnes, C.A., Physiological identification and analysis of dentate granule cell responses to stimulation of the medial and lateral perforant pathways in the rat, J. cornp. Neurol., 175 (1977) 439-454. 12 Myhrer, T., Maze performance in rats with hippocampal perforant paths lesions: some aspects of functional recovery, Physiol. Behav., 15 (1975) 433-437. 13 Nadler, J.V., Cotman, C.W., Paoletti, C. and Lynch, G., Histochemical evidence of altered development of cholinergic fibers in the rat dentate gyrus following lesions. I. Time course after complete unilateral entorhinal lesion at various ages, J. comp. NeuroL, 171 (1977) 561-588. 14 Nadler, J.V., Cotman, C.W., Paoletti, C. and Lynch, G., Histochemical evidence of altered development of cholinergic fibers in the rat dentate gyrus following lesions. II. Effects of partial entorhinal and simultaneous multiple lesions, J. comp. Neurol., 171 (1977) 589-604. 15 Steward, O., Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat, J. comp. Neurol., 3 (1976) 285-314. 16 Steward, O., Loesche, J. and Horton, W.C., Behavioral correlates ofdenervation and reinnervation of the hippocampal formation of the rat: open-field activity and cue utilization following bilateral entorhinal cortex lesion, Brain Res. Bull., 2 (1977) 41-48. 17 Tielen, A.M., Lopes da Silva, F.H. and MiUevanger, W.J., Some physiological differences between the medial and lateral perforant paths systems in the guinea-pig, Progress Report, 7 (1980) 80-82.