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The effects of fornix lesions on latent learning in the rat
Physiology & Behavior, Vol. 24, pp. 817-822. Pergamon Press and Brain Research Publ., 1980. Printed in the U.S.A.
The Effects of Fornix Lesions on Latent Learning in the Rat MICHAEL
J. O W E N A N D S. R. B U T L E R
D e p a r t m e n t o f A n a t o m y , Medical School, Vincent Drive, Birmingham, B I 5 2T J, England R e c e i v e d 9 O c t o b e r 1979 OWEN, M. J. AND S. R. BUTLER. The effects offornix lesions on latent learning in the rat. PHYSIOL. BEHAV. 24(5) 817-822, 1980.--Rats with fornix lesions and sham-operated controls were trained to press a lever for 0.9% NaC! while thirsty and then tested under extinction conditions when not thirsty. Sham-operated controls which were sodium depleted during extinction testing made twice as many responses as non-depleted controls, an effect attributed to latent learning. However, no such difference was observed between the sodium depleted and the non-depleted subjects which had received fornix lesions, suggesting that fornix lesions abolish this type of latent learning. This effect is predicted by both cognitive map and contextual retrieval models of hippocampal function. Hippocampus
Fornix lesions
Latent learning
TWO explanations have recently been proposed for the behavioural deficit which follows bilateral lesions of the hippocampus. O'Keefe and Nadel [37] have proposed that the rat hippocampus functions as a cognitive map and that the abnormal behaviour of lesioned animals reflects the disruption of this mapping system. The second view is that a functionally intact hippocampus is essential for the process of contextual retrieval [16,25]. Both these hypotheses predict that lesions which disrupt hippocampal function will preclude latent learning. The present study was designed to test these predictions. According to the cognitive map theory, latent learning results from the action of the hippocampal cognitive-mapping system which allows the development of internal maps of experienced environments. Hirsh's exposition of the contextual retrieval hypothesis proposes that latent learning depends in particular on the retrieval of information relevant to the motivational state of the moment, a process for which functional integrity of the hippocampus is held to be essential [16]. In the classical type of latent learning experiment, first performed in Tolman's laboratory [2,47], rats are given preliminary exposure to a maze while neither hungry nor thirsty. They subsequently learn faster than rats which have not experienced the maze when required to run it for food or water under the appropriate conditions of deprivation. This is held to indicate that they use information gained during the ostensibly non-reinforced pre-exposure period. Two studies have examined the effects of hippocampal lesions on latent learning. Means [31] found some evidence for latent learning in hippocampal rats in terms of a reduction in trials to criterion but not in errors to criterion. Kimble and
Greene [24] also reported that there was no reduction in the number of errors after pre-exposure in lesioned rats. However, both these studies found only a small latent learning effect even in the operated control groups. This raises a general problem of interpretation concerning latent learning in maze running experiments. Muenzinger and Conrad [33] discovered that relatively long periods of non-reinforced preexposure were needed if true latent learning (i.e., of the correct path through the maze) was to be demonstrated. Improved maze learning seen after relatively short periods of pre-exposure was not the result of learning the correct path but has been attributed by Mackintosh [29] to habituation of fear or startle responses to what would otherwise have been a novel environment. Although the procedures and mazes used by Means and by Kimble and Greene differed in various ways from each other and from those used by Muenzinger and Conrad, the possibility remains that the small effect seen in the control animals of the former investigators was due to general habituation to the apparatus rather than true latent learning. Indeed Means' data led him to this conclusion. Moreover neither the cognitive map theory nor the contextual retrieval hypothesis predict any effect of hippocampal lesions on the habituation of reactions to general features of the apparatus which precedes exploration. Thus existing reports do not provide clear evidence of the effects of hippocampal disruption on latent learning and hence do not constitute adequate tests of these two explanations of the hippocampal deficit. Latent learning can be reliably demonstrated in normal animals using a technique developed by Krieckhaus and Wolf [27] which is not open to the same ambiguities of in-
1This work was supported by a MRC studentship to M. J. Owen. 2The authors wish to thank Mrs. Wendy McKenna for excellent histological assistance, Professor P. B. Bradley of the MRC Neuropharmacology Unit and Dr. Glyn Thomas of the Department of Psychology at the University of Birmingham for providing some of the equipment used in this study, and Mrs. Polly Fontijn for typing the manuscript. :~Requests for reprints should be sent to Michael J. Owen, Department of Anatomy, Medical School, Vincent Drive, Birmingham, B 15 2TJ.
C o p y r i g h t © 1980 B r a i n R e s e a r c h P u b l i c a t i o n s Inc.--0031-9384/80/050817-06502.00/0
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OWEN AND BUTLER
terpretation as the procedures using mazes. Krieckhaus and Wolf trained rats which were thirsty but not sodium deficient to press a lever for a solution containing sodium ions. Animals which were subsequently satiated for water but made sodium deficient pressed significantly more times under extinction conditions than those which although satiated for water were not made sodium deficient. Additional controls in this study and in a subsequent replication [22] ruled out several alternative explanations and favour the interpretation that the rats had learned that lever pressing led to the receipt of sodium even though they had no need for sodium at the time. This is regarded as an example of latent learning. The purpose of the present study was to determine the effects of hippocampal disruption on latent learning, using this apparently more robust procedure. Fornix lesions were used as a means of producing functional disruption of the hippocampus with minimal extra-hippocampal damage [12, 30, 38].
TABLE 1 t,EVER PRESSING BY I N D I V I D U A L SHAM-OPERATED { ' O N T R O I SUBJECTS
Subgroup
PTA*
EXT,
Sodium depleted (Formalin injected)
372.3 377.2 422.6 245.8 290.0 231.1 381.7
57 94 58 27 50 32 63
15.3 24.9 13.7 II .0 17.2 13.8 16.5
Mean
308.9
54.4
16.1
Non-depleted (saline injected)
313.7 356.0 541.7 486.6 218.6 311.7 369.1
27 16 55 28 15 24 15
8.6 4.5 10.2 5.8 6.9 7.7 4. I
Mean
371.1
25.7
METHOD
Sub.je¢'ts The subjects were 24 male albino rats (Ashwistar) weighing 150-200 g at the time of surgery. The animals were housed individually with a 12 hr light-12 hr dark cycle. They were assigned randomly to a fornix lesion group (n= 10) and a sham-operated control group (n= 14).
EXT/PTA J'~"
6.8
*PTA, pretest average, refers to average presses/hr before the extinction test. CEXT refers to number of lever presses during 1 hr extinction.
Sur~,ery and Histology Prior to surgery, all the rats were anaesthetized with 0.1 ml/100 g of IMMOBILON (Reckitt and Coleman). Lesions were placed stereotaxically in a Kopf apparatus using the coordinates of K6nig and Klippel [26]. A hole approximately 3 mm in diameter was drilled in the midline of the skull 6.2 mm anterior to the ear-bars without damaging the sagittal sinus. Lesions were produced by thermocoagulation using two electrodes. The electrodes were constructed from 0.4 mm diameter stainless steel insect pins which were insulated except for 1.5 mm at the tip which was not ground down. They were held 2.5 mm apart in a double electrode carriage, positioned symmetrically on either side of the midline (judged from the sagittal sinus), and then lowered until their tips were 6.2 mm anterior and 5.5 mm dorsal to the interaural line. Radiofrequency electric current of 15 mA was then passed between them for 25 sec. This procedure was designed to place the tips of the two electrodes in the opposite lateral extremities of the fornix. The use of radiofrequency current permitted coagulation of the area between the electrode tips by a single application of current and without the necessity for multiple lesions. A further reason for using radiofrequency current rather than electrolysis is that it is said to be more efficient at destroying white matter [10]. It was necessary to approach the fornix dorsally rather than laterally as is usual (e.g., [12, 35, 38]) because this minimised the possibility of damage to stria terminalis, whose integrity is essential if sodium appetite is to be elicited [6]. The same procedure was adopted for the sham-operations except that the electrodes stopped 7 mm dorsal to the interaural line, and no current was passed. The animals were allowed 10 days recovery after surgery before behavioural testing began. Following testing, all the animals were sacrificed, perfused intracardially with physiological saline followed by I(~. formol saline solution, and their brains removed and fixed in 10% formol saline solution for several days. The
brains were embedded in wax, cut, mounted and stained with luxoi fast blue and cresyl violet.
Apparatus All training took place in a standard Lehigh Valley Skinner box in a chamber that was light proof and partially soundproof. A single bar was situated 7.5 cm to the left of a water dispenser which was situated centrally on the front wall of the inner chamber. Drops of liquid (0.05 ml) were delivered to the dispenser cup by means of a solenoid. During training sessions the box was illuminated and the ventilating fan provided a masking noise. Programming and recording equipment were located in an adjacent room.
Pro~'edure Each subject was placed on a water deprivation schedule with continuous access to food (Heygate and Sons Ltd., Modified Rat/Mouse Breeding Diet Cube; sodium content 0.6%). All the rats were trained to barpress for 0.9% NaCI. Immediately after acquisition of the barpress the subjects were given 1/2 hr training on a CRF schedule, again for 0.9% NaC1. In the next phase of the experiment the animals were given three consecutive daily sessions of 1 hr on a VI60 schedule. Twenty-three hours separated each training session. At the end of its daily run from the first day of training up to and including session 2 of VI60, each rat was given free access to tap water for 1 hr. At the end of the third session of VI60 training rats from both operation groups were assigned randomly to one of two subgroups. Half the rats from each group were injected subcutaneously in the dorsal thorax with 2.5 ml of 1.5% formalin to induce sodium depletion [57]. The remaining animals were given a control injection of 2.5 ml of 0.9% NaC1. All subjects were lightly anaesthetized with ether prior to injection. Immediately after injection all the
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FORNIX LESIONS AND LATENT LEARNING TABLE 2 LEVER PRESSING BY INDIVIDUALFOP,NIX LESIONED SUBJECTS Subgroup
PTA*
EXTP
EXT/PTA ×1°°
Sodium depleted (Formalin injected)
373.3 678.6 833.7 666.3 732.0
76 54 141 35 15
20.3 8.0 16.9 5.3 2.0
Mean
656.8
Non-depleted (saline injected)
909.4 561.7 756.9 780.9 520.0
Mean
705.8
64.2 85 23 164 104 49 85.0
10.5 9.3 4.1 21.7 13.3 9.4 11.6
*PTA, pretest average, refers to average presses/hr before extinction test. tEXT refers to number of lever presses during 1 hr extinction.
animals were bathed in warm water to remove salts from the body surface and placed in washed cages with ad lib distilled water but no food. The latter procedures minimized the possibility of contact with sodium between the time of induction of sodium depletion and subsequent testing. Twenty-three hours later the subjects, half of which were deficient in sodium and none of which was deficient in water, were placed in a washed Skinner box and allowed to barpress for 1 hr under extinction conditions. RESULTS Beha vioural Table 1 shows the number of lever-presses by the shamoperated control subjects during the 1 hr extinction period. The sodium depleted subjects pressed the lever more often than the non-depleted animals, averaging 54.4 presses compared with an average of 25.7 presses by the non-depleted group. This difference was statistically significant (p~0.01, Mann-Whitney, two-tailed). The rate of lever-pressing during the extinction testing can also be expressed as a percent of each animal's average rate of lever-pressing prior to extinction testing (PTA). When this measure of performance is used the sodium depleted group are again seen to have pressed significantly more often (mean=16.1%) than the non-depleted group (mean=6.8%) Co=0.002, Mann-Whitney, two-tailed). Table 2 shows the same data for the subjects with fornix lesions. There is no significant difference in lever-pressing rates between the sodium-depleted and non-depleted groups, which ever measure is taken. Comparison between the operation groups reveals that the fornix lesioned animals lever-pressed at a significantly higher rate prior to extinction testing (mean PTA=681.1) than the sham-operated control group (mean PTA=351.3) (0<0.002, Mann-Whitney, two-tailed). Of the animals who had not been treated with formalin, those with fornix lesions pressed significantly more often (mean=85.0) than the shamoperated controls (mean=25.7) during extinction testing (0<0.05, Mann-Whitney, two-tailed). However there is no
FIG. 1. Representative fornix lesions from formalin-injected (upper) and saline-injected (lower) sub-groups. Maximum and minimum extents of damage are represented by stippled and cross hatched areas, respectively.
significant difference between these two groups when extinction scores are expressed as a percent of each animal's PTA. Among sodium-depleted animals those with fornix lesions did not press significantly more often than the shamoperated controls (mean=54.4) during extinction testing. Indeed in relation to their PTA sham-operated controls pressed more often (mean= 16.1%) than the fornix lesioned animals (mean= 10.5%) although this difference was not significant. Anatomical The maximum and minimum lesions for both sub-groups of fornix lesioned animals are shown in Fig. I. While all fornix lesions were large (at least 70% of the fibres were destroyed at this coronal level) in all of the lesioned animals the extreme lateral parts of the fimbriae were spared. This was the inevitable consequence of the attempt not to inflict damage to the stria terminalis in any animal. All the fornix lesioned animals received slight thalamic damage, which was largely confined to the most anterior part of the anterior nuclear group. Bilateral destruction of the cingulum occurred in 8 of the lesioned animals. This structure suffered slight unilateral damage in one animal and was spared in another. These animals both belonged to the
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()WEN ~ N D IBLI'I'I,ER
t'ormalin-injected sub-group and their behavioural performances were within the range of those of the saline-injected animals with fornix lesions. All of the fornix-lesioned animals suffered bilateral transection of the stria medullaris as well as damage to the corpus callosum overlying the area of fornix-damage. DISCUSSION
The present study set out to determine the effects of disrupting hippocampal function on latent learning. Rats were trained to press a lever for saline while thirsty and then tested under extinction conditions when not thirsty. The sham-operated controls rendered sodium deficient by formalin injection prior to testing made twice as many responses as the saline-injected controls during extinction testing, an effect attributed to latent learning. However, no such difference was seen between the formalin- and the salineinjected subjects which had received fornix lesions. Before we discuss the theoretical implications of these results we shall consider whether they really reflect the abolition of latent learning by fornix lesions. One alternative interpretation might be that the lesioned animals suffered damage to the neural mechanisms mediating sodium appetite. Thus it might be argued that "after lesions to the fornix the formalin-injected rats did not show elevated rates of barpressing during extinction testing because a sodium appetite had not been induced. However it is unlikely that fornix lesions disrupt sodium appetite since it can be elicited normally in rats with lesions of the h'ippocampus [23,32] and also of the septum [5,55]. It is also unlikely that the lesioned group suffered damage to any structures outside the fornix with a significant role in sodium appetite. Although the lesioned group consistently sustained damage to the corpus callosum, sodium appetite can be elicited normally in neodecorticate animals [56] so one would not expect lesions of the corpus callosum to abolish it. In addition, the stria medullaris was consistently damaged in the lesioned group and this would have completely destroyed those axonal connections of the septum and preoptic hypothalamus which contribute to the stria medullaris [14,15]. Since lesions in these areas also cause no deficit in sodium appetite [5,55] it seems likely that sodium appetite was elicited normally in the lesioned animals. It is unlikely that extra-fornical damage was responsible for a more direct effect on learning ability. Complete section of the corpus callosum does not result in learning deficits in the rat 13, 7, 28, 44] so it is unlikely that the comparatively small callosal lesions suffered by the lesioned rats in the present study contributed to their impairment. Little is known about the effects of stria medullaris damage on behaviour, although deficits have been seen in some tasks involving punishment [43,48] and at least one of these is not sensitive to fornix lesions [43]. However, against this must be weighed numerous reports of the effects of fornix lesions in which partial or complete damage occurred to the stria medullaris in some of the subjects. In none of these cases did combined lesions of the stria medullaris and fornix result in different behavioural sequelae from those of fornix lesions alone. These include a variety of behavioural tests such as position reversal, several different avoidance tasks, measures of exploration, spatial discrimination, DRL and spontaneous alternation [4, 8, 9, 19, 21, 35] as well as a detailed analysis of behaviour during extinction in an operant chamber [39]. It therefore seems likely that it was the damage to the fornix in the present study that was responsible for
the abolition of latent learning. It is conceivable that sodium depletion produces b e havioural effects that are unrelated to the animal's previous reinforcement with saline, and that these effects operate differently after fornix lesions. We can rule out the possibility that the elevated response rate shown by intact animals after sodium depletion is the result of a general increase in drive on the basis of controls performed by Krieckhaus and Wolf [27]. It remains a logical possibility that animals with fornix lesions are particularly sensitive to the debilitating effects of sodium depletion with the result that any latent learning by these animals was masked. This is important in view of the involvement of the hippocampal formation in the pituitary-adrenal system. However damage to the hippocampus or fornix does not seem to impair the corticosterone response to either stressors or deprivation (see [401 for review). Therefore it seems unlikely that the animals with fornix lesions would have been any less able than normals to cope with the systemic consequences of formalin injection. The higher pressing rate of the fornix lesioned rats which carried over to extinction testing has been frequently reported after hippocampal lesion s [ 13, 20, 41 ]. I t is the refore necessary to consider the possibility that the amount of latent learning achieved by an animal is inversely related to its response rate prior to testing. If this were true, the failure of the animals with fornix lesions to demonstrate latent learning might have been a result of their greater pretest response rates rather than a direct effect of the lesion on a learning mechanism. However, the variance in each group enables this possibility to be examined, and inspection of the tables reveals no evidence for an inverse relationship between pretest response rates and the amount of latent learning. Indeed if anything, the reverse appears to be the case; there is a trend towards greater latent learning among the shamoperated animals with high pretest response rates. This is in agreement with data from the only other study of this kind of latent learning in normal animals for which pretest response rates of individual animals are reported [49]. It therefore seems unlikely that the absence of latent learning after fornix lesions was a consequence of high response rates; rather it would appear to be a direct consequence of the lesion. The present task required animals to use stimuli that had no direct motivational significance (i.e., reinforcing consequences) at the time they were perceived. Normal animals use stimuli of this kind in a number of behavioural situations [16]. The inability to use such "contextual cues" has been proposed as comprising the centre of the hippocampal deficit [16,25], and the result of the present study is thus in accord with recent evidence supporting this view [17, 18, 50, 51,52, 53, 54]. Another explanation of the hippocampal deficit is that it reflects the disruption of a cognitive mapping system 137] which is responsible for the internal representation of spatial relationships in the animal's environment. In many ways this theory is similar to the contextual retrieval hypothesis. For the purposes of the present discussion the main difference is that the cognitive map theory maintains that information which is not directly associated with reward can still be stored but only in this internal map. In the present experiment sodium was always present in the same place during the initial acquisition period, when it had no motivational significance, and the failure of the rats to use this information after the hippocampal system was disrupted is thus in accord with the predictions of the cognitive map theory.
FORNIX LESIONS AND L A T E N T L E A R N I N G
821
The absence of latent inhibition and the attenuation of blocking seen after hippocampal disruption [42, 45, 46] provide further examples of lesioned animals showing abnormal behaviour when required to deal with stimuli that have no direct motivational significance. These findings have been interpreted as supporting the view first proposed by Douglas [11] that the hippocampus forms part of a neural system which is responsible for "gating-out" stimuli so that the animal ceases to attend to them once their lack of motivational significance has been established [45,46]. However such a view is clearly not adequate to explain the results of the present study. The phenomenon of latent learning suggests that the way in which normal animals can deal with stimuli which are not directly relevant to their present needs involves more than a gating-out process. Normal animals seem able to store information even though it has been gated-out for the purposes of present behaviour and to use it when it becomes relevant. This additional mnemonic process is evidently dependent on the functional integrity of the hippocampus. If a motivationally non-significant stimulus is to be gated-out the animal must first determine that the stimulus has been received before, and that it had no motivational consequences. These facts must be registered, stored and retrieved from memory before gating-out can occur. The most parsimonious interpretation seems to be that the inability to gate-out motivationally non-significant stimuli seen after hippocampal disruption is a consequence of a break-
down in some stage of mnemonic side of this operation. This view is in line with those of authors who h a v e recently suggested that the disinhibitory effects of hippocampal lesions are secondary to a more fundamental information processing deficit [1, 51, 52, 54]. A further question remains: How long must the delay be between perceiving a stimulus and recognizing its relevance to a state of motivation if a lesioned animal is to be unable to use it to guide behaviour? In the present study lesioned animals failed when the interval between receipt of sodium and the need to press for it was 24 hr, but two pieces of recent evidence suggest that even if the interval is of the order of a few seconds such animals will still be impaired. Mikulka and Freeman [32] found that a 10 sec delay between response and reward seriously retarded acquisition by hippocampal rats of a position habit in a Y-maze. O'Keefe and Black [36] examined the ability of rats with fornix lesions to use distal cues to solve a T-maze problem. These workers concluded that lesioned animals do not have difficulty using distal cues per se, but are unable to use those which cannot be perceived immediately before or during reinforcement. It therefore seems likely that the kind of stimuli that animals without a functioning hippocampus can use as cues to guide behaviour are limited to those whose perception is accompanied or immediately followed by reinforcement. Indeed both the cognitive map theory and the contextual retrieval hypothesis predict that lesioned rats should behave much as early S-R learning theory predicts for normal animals [16, 36, 37].
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822 25. Kinsbourne, M. and F. Wood. Short-term memory and the amnesic syndrome. In: Short-term Memory, edited by D. Deutsch and J. A. Deutsch. New York: Academic Press, 1975, pp. 258293. 26. Krnig, J. F. R. and R. A. Klippel. The Rat Brain: A Stereotaxic' Atlas of the Forebrain and Lower Parts of the Brain Stem. Baltimore: Williams and Wilkins, 1963. 27. Krieckhaus, E. E. and G. Wolf. Acquisition of sodium by rats: Interaction of innate mechanisms and latent learning. J. comp. physiol. Psychol. 65: 197-201, 1%8. 28. Levinson, D. M. and C. L. Sheridan. Monocular acquisition and interocular transfer of two types of pattern discrimination in hooded rats. J. comp. physiol. Psyehol. 67: 468--472, 1969. 29. Mackintosh, N. J. The Psychology ~[Animal Learning. London: Academic Press, 1974. 30. Mahut, H. A selective spatial deficit in monkeys after transection of the fornix. Neuropsychologia 10: 65-74, 1972. 31. Means, L. W. Latent learning in rats with hippocampal lesions. Psychon. Sci. 16: 51-52, 1969. 32. Mikukla, P. J. and F. G. Freeman. The effects of reinforcement delay and hippocampal lesions on the acquisition of a choice response. Behav. Biol. 15: 473--477, 1975. 33. Muenzinger, K. F. and D. G. Conrad. Latent learning observed through negative transfer. J. comp. physiol. Psychol. 46: 1-8, 1954. 34. Murphy, H. M. and T. S. Brown. Effects of hippocampal lesions on simple and preferential consummatory behaviour in the rat. J. comp. physiol. Psychol. 72: 404-415, 1970. 35. Okaiche, H., H. Anchel, H. Barbaree and A. H. Black. Punishment of runaway behaviour in rats with fornix lesions. Physiol. Behav. 21: 503-509, 1978. 36. O'Keefe, J. and A. H. Black. Single unit and lesion experiments on the sensory inputs to the hippocampal cognitive map. In: Functions ~t the Septohippocampal System. CIBA Foundation Symposium 58. North-Holland: Elsevier. Excerpta Medica, 1978, pp. 179-191. 37. O'Keefe, J. and L. Nadel. The Hippocampus as a Cognitive Map. London: Oxford University Press, 1978. 38. O'Keefe, J., L. Nadel, S. Keightley and D. Kill. Fornix lesions selectively abolish place learning in the rat. Expl Neurol. 48: 152-166, 1975. 39. Osborne, B. and A. H. Black. A detailed analysis of behaviour during the transition from acquisition to extinction in rats with fornix lesions. Behav, Biol. 23: 271-290, 1978. 40. Osborne, B., T. Sivakumaran and A. H. Black. Effects of fornix lesions on adrenocortical responses to changes in environmental stimulation. Behav. Neural Biol. 25: 227-241, 1979. 41. Rabe, A. and R. K. Haddad. Effect of selective hippocampal lesions in the rat on acquisition, performance and extinction of bar pressing on a fixed ratio schedule. Expl Brain Res. 5: 259266, 1968.
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42. Rickert, E. J., T. L. Bennett, P. Lane and J. French. Hippocampectomy and the attenuation of blocking. Behav. Bi~d. 22: I47-160, 1978. 43. Ross, J. F. and S. P. Grossman. Transection of stria medullaris or stria terminalis in the rat: Effects on aversively controlled behaviour. J. eomp. physiol. Psychol. 91: 907-917, 197% 44. Sheridan, C. L. lnterocular transfer of brightness and pattern discriminations in normal and corpus callosum-sectioned rats. J. comp. physiol. Psychol. 59: 292-294, 1965. 45. Solomon, R. P. Role of the hippocampus in blocking and conditioned inhibition of the rabbit's nictitating membrane response. J. comp. physiol. Psychol. 91: 407-417, 1977. 46. Solomon, P. R. and J. W. Moore. Latent inhibition and stimulus generalization of the classically conditioned nictitating membrane response in rabbits (Oryctolagus Cuniculus) following dorsal hippocampal ablation..1, eomp. phy.~iol. Psychol. 89: 1192-1203, 1975. 47. Tolman, E. C. and C. H. Honzik. Introduction and removal of reward and maze performance in rats. (Jniv. CahZf: Pubis. Psychol. 4: 257-275, 1930. 48. Van Hosen, G. W., J. M. MacDougall and J. C. Mitchell. Anatomical specificity of septal projections in active and passive avoidance behaviour in rats. J. eomp. physiol. Psyehol. 68: 80-89, 1%0. 49. Weisinger, R. S., S. C. Woods and J. D. Skorupski. Sodium deficiency and latent learning. Psychon. Sci. 19: 30%308, 1970. 50. Winocur, G. Effects of interference on discrimination learning and recall by rats with hippocampal lesions. Physiol. Behav. 22: 339--346, 1979. 51. Winocur, G. and D. Bindra. Effects of additional cues on passive avoidance learning and extinction in rats with hippocampal lesions. Physiol. Behav. 17: 915-920, 1976. 52. Winocur, G. and A. H. Black. Cue-induced recall of a passive avoidance response by rats with hippocampal lesions. Physiol. Behav. 21: 39-44, 1978. 53. Winocur, G. and M. Kinsbourne. Contextual cueing as an aid to Korsakoff Amnesics. Neuropsyehologia 16: 671-682, 1978. 54. Winocur, G. and J. Olds. Effects of contextual manipulation on memory and reversal learning in rats with hippocampal lesions. J. comp. physiol. Psychol. 92: 312-321, 1978. 55. Wolf, G. Hypothalamic regulation of sodium intake: Relations to preoptic and tegmental function. Am. J. Physiol. 213: 14331438, 1967. 56. Wolf, G., L. V. DiCara and J. J. Braun. Sodium appetite in rats after neocortical ablation. Physiol. Behav. 5: 1265-1269, 1970. 57. Wolf, G. and E. Steinbaum. Sodium appetite elicited by subcutaneous formalin: mechanism of action. ,1. comp. physiol. Psychol. 59: 335-339, 1965.
The Effects of Fornix Lesions on Latent Learning in the Rat MICHAEL
J. O W E N A N D S. R. B U T L E R
D e p a r t m e n t o f A n a t o m y , Medical School, Vincent Drive, Birmingham, B I 5 2T J, England R e c e i v e d 9 O c t o b e r 1979 OWEN, M. J. AND S. R. BUTLER. The effects offornix lesions on latent learning in the rat. PHYSIOL. BEHAV. 24(5) 817-822, 1980.--Rats with fornix lesions and sham-operated controls were trained to press a lever for 0.9% NaC! while thirsty and then tested under extinction conditions when not thirsty. Sham-operated controls which were sodium depleted during extinction testing made twice as many responses as non-depleted controls, an effect attributed to latent learning. However, no such difference was observed between the sodium depleted and the non-depleted subjects which had received fornix lesions, suggesting that fornix lesions abolish this type of latent learning. This effect is predicted by both cognitive map and contextual retrieval models of hippocampal function. Hippocampus
Fornix lesions
Latent learning
TWO explanations have recently been proposed for the behavioural deficit which follows bilateral lesions of the hippocampus. O'Keefe and Nadel [37] have proposed that the rat hippocampus functions as a cognitive map and that the abnormal behaviour of lesioned animals reflects the disruption of this mapping system. The second view is that a functionally intact hippocampus is essential for the process of contextual retrieval [16,25]. Both these hypotheses predict that lesions which disrupt hippocampal function will preclude latent learning. The present study was designed to test these predictions. According to the cognitive map theory, latent learning results from the action of the hippocampal cognitive-mapping system which allows the development of internal maps of experienced environments. Hirsh's exposition of the contextual retrieval hypothesis proposes that latent learning depends in particular on the retrieval of information relevant to the motivational state of the moment, a process for which functional integrity of the hippocampus is held to be essential [16]. In the classical type of latent learning experiment, first performed in Tolman's laboratory [2,47], rats are given preliminary exposure to a maze while neither hungry nor thirsty. They subsequently learn faster than rats which have not experienced the maze when required to run it for food or water under the appropriate conditions of deprivation. This is held to indicate that they use information gained during the ostensibly non-reinforced pre-exposure period. Two studies have examined the effects of hippocampal lesions on latent learning. Means [31] found some evidence for latent learning in hippocampal rats in terms of a reduction in trials to criterion but not in errors to criterion. Kimble and
Greene [24] also reported that there was no reduction in the number of errors after pre-exposure in lesioned rats. However, both these studies found only a small latent learning effect even in the operated control groups. This raises a general problem of interpretation concerning latent learning in maze running experiments. Muenzinger and Conrad [33] discovered that relatively long periods of non-reinforced preexposure were needed if true latent learning (i.e., of the correct path through the maze) was to be demonstrated. Improved maze learning seen after relatively short periods of pre-exposure was not the result of learning the correct path but has been attributed by Mackintosh [29] to habituation of fear or startle responses to what would otherwise have been a novel environment. Although the procedures and mazes used by Means and by Kimble and Greene differed in various ways from each other and from those used by Muenzinger and Conrad, the possibility remains that the small effect seen in the control animals of the former investigators was due to general habituation to the apparatus rather than true latent learning. Indeed Means' data led him to this conclusion. Moreover neither the cognitive map theory nor the contextual retrieval hypothesis predict any effect of hippocampal lesions on the habituation of reactions to general features of the apparatus which precedes exploration. Thus existing reports do not provide clear evidence of the effects of hippocampal disruption on latent learning and hence do not constitute adequate tests of these two explanations of the hippocampal deficit. Latent learning can be reliably demonstrated in normal animals using a technique developed by Krieckhaus and Wolf [27] which is not open to the same ambiguities of in-
1This work was supported by a MRC studentship to M. J. Owen. 2The authors wish to thank Mrs. Wendy McKenna for excellent histological assistance, Professor P. B. Bradley of the MRC Neuropharmacology Unit and Dr. Glyn Thomas of the Department of Psychology at the University of Birmingham for providing some of the equipment used in this study, and Mrs. Polly Fontijn for typing the manuscript. :~Requests for reprints should be sent to Michael J. Owen, Department of Anatomy, Medical School, Vincent Drive, Birmingham, B 15 2TJ.
C o p y r i g h t © 1980 B r a i n R e s e a r c h P u b l i c a t i o n s Inc.--0031-9384/80/050817-06502.00/0
,~1~
OWEN AND BUTLER
terpretation as the procedures using mazes. Krieckhaus and Wolf trained rats which were thirsty but not sodium deficient to press a lever for a solution containing sodium ions. Animals which were subsequently satiated for water but made sodium deficient pressed significantly more times under extinction conditions than those which although satiated for water were not made sodium deficient. Additional controls in this study and in a subsequent replication [22] ruled out several alternative explanations and favour the interpretation that the rats had learned that lever pressing led to the receipt of sodium even though they had no need for sodium at the time. This is regarded as an example of latent learning. The purpose of the present study was to determine the effects of hippocampal disruption on latent learning, using this apparently more robust procedure. Fornix lesions were used as a means of producing functional disruption of the hippocampus with minimal extra-hippocampal damage [12, 30, 38].
TABLE 1 t,EVER PRESSING BY I N D I V I D U A L SHAM-OPERATED { ' O N T R O I SUBJECTS
Subgroup
PTA*
EXT,
Sodium depleted (Formalin injected)
372.3 377.2 422.6 245.8 290.0 231.1 381.7
57 94 58 27 50 32 63
15.3 24.9 13.7 II .0 17.2 13.8 16.5
Mean
308.9
54.4
16.1
Non-depleted (saline injected)
313.7 356.0 541.7 486.6 218.6 311.7 369.1
27 16 55 28 15 24 15
8.6 4.5 10.2 5.8 6.9 7.7 4. I
Mean
371.1
25.7
METHOD
Sub.je¢'ts The subjects were 24 male albino rats (Ashwistar) weighing 150-200 g at the time of surgery. The animals were housed individually with a 12 hr light-12 hr dark cycle. They were assigned randomly to a fornix lesion group (n= 10) and a sham-operated control group (n= 14).
EXT/PTA J'~"
6.8
*PTA, pretest average, refers to average presses/hr before the extinction test. CEXT refers to number of lever presses during 1 hr extinction.
Sur~,ery and Histology Prior to surgery, all the rats were anaesthetized with 0.1 ml/100 g of IMMOBILON (Reckitt and Coleman). Lesions were placed stereotaxically in a Kopf apparatus using the coordinates of K6nig and Klippel [26]. A hole approximately 3 mm in diameter was drilled in the midline of the skull 6.2 mm anterior to the ear-bars without damaging the sagittal sinus. Lesions were produced by thermocoagulation using two electrodes. The electrodes were constructed from 0.4 mm diameter stainless steel insect pins which were insulated except for 1.5 mm at the tip which was not ground down. They were held 2.5 mm apart in a double electrode carriage, positioned symmetrically on either side of the midline (judged from the sagittal sinus), and then lowered until their tips were 6.2 mm anterior and 5.5 mm dorsal to the interaural line. Radiofrequency electric current of 15 mA was then passed between them for 25 sec. This procedure was designed to place the tips of the two electrodes in the opposite lateral extremities of the fornix. The use of radiofrequency current permitted coagulation of the area between the electrode tips by a single application of current and without the necessity for multiple lesions. A further reason for using radiofrequency current rather than electrolysis is that it is said to be more efficient at destroying white matter [10]. It was necessary to approach the fornix dorsally rather than laterally as is usual (e.g., [12, 35, 38]) because this minimised the possibility of damage to stria terminalis, whose integrity is essential if sodium appetite is to be elicited [6]. The same procedure was adopted for the sham-operations except that the electrodes stopped 7 mm dorsal to the interaural line, and no current was passed. The animals were allowed 10 days recovery after surgery before behavioural testing began. Following testing, all the animals were sacrificed, perfused intracardially with physiological saline followed by I(~. formol saline solution, and their brains removed and fixed in 10% formol saline solution for several days. The
brains were embedded in wax, cut, mounted and stained with luxoi fast blue and cresyl violet.
Apparatus All training took place in a standard Lehigh Valley Skinner box in a chamber that was light proof and partially soundproof. A single bar was situated 7.5 cm to the left of a water dispenser which was situated centrally on the front wall of the inner chamber. Drops of liquid (0.05 ml) were delivered to the dispenser cup by means of a solenoid. During training sessions the box was illuminated and the ventilating fan provided a masking noise. Programming and recording equipment were located in an adjacent room.
Pro~'edure Each subject was placed on a water deprivation schedule with continuous access to food (Heygate and Sons Ltd., Modified Rat/Mouse Breeding Diet Cube; sodium content 0.6%). All the rats were trained to barpress for 0.9% NaCI. Immediately after acquisition of the barpress the subjects were given 1/2 hr training on a CRF schedule, again for 0.9% NaC1. In the next phase of the experiment the animals were given three consecutive daily sessions of 1 hr on a VI60 schedule. Twenty-three hours separated each training session. At the end of its daily run from the first day of training up to and including session 2 of VI60, each rat was given free access to tap water for 1 hr. At the end of the third session of VI60 training rats from both operation groups were assigned randomly to one of two subgroups. Half the rats from each group were injected subcutaneously in the dorsal thorax with 2.5 ml of 1.5% formalin to induce sodium depletion [57]. The remaining animals were given a control injection of 2.5 ml of 0.9% NaC1. All subjects were lightly anaesthetized with ether prior to injection. Immediately after injection all the
819
FORNIX LESIONS AND LATENT LEARNING TABLE 2 LEVER PRESSING BY INDIVIDUALFOP,NIX LESIONED SUBJECTS Subgroup
PTA*
EXTP
EXT/PTA ×1°°
Sodium depleted (Formalin injected)
373.3 678.6 833.7 666.3 732.0
76 54 141 35 15
20.3 8.0 16.9 5.3 2.0
Mean
656.8
Non-depleted (saline injected)
909.4 561.7 756.9 780.9 520.0
Mean
705.8
64.2 85 23 164 104 49 85.0
10.5 9.3 4.1 21.7 13.3 9.4 11.6
*PTA, pretest average, refers to average presses/hr before extinction test. tEXT refers to number of lever presses during 1 hr extinction.
animals were bathed in warm water to remove salts from the body surface and placed in washed cages with ad lib distilled water but no food. The latter procedures minimized the possibility of contact with sodium between the time of induction of sodium depletion and subsequent testing. Twenty-three hours later the subjects, half of which were deficient in sodium and none of which was deficient in water, were placed in a washed Skinner box and allowed to barpress for 1 hr under extinction conditions. RESULTS Beha vioural Table 1 shows the number of lever-presses by the shamoperated control subjects during the 1 hr extinction period. The sodium depleted subjects pressed the lever more often than the non-depleted animals, averaging 54.4 presses compared with an average of 25.7 presses by the non-depleted group. This difference was statistically significant (p~0.01, Mann-Whitney, two-tailed). The rate of lever-pressing during the extinction testing can also be expressed as a percent of each animal's average rate of lever-pressing prior to extinction testing (PTA). When this measure of performance is used the sodium depleted group are again seen to have pressed significantly more often (mean=16.1%) than the non-depleted group (mean=6.8%) Co=0.002, Mann-Whitney, two-tailed). Table 2 shows the same data for the subjects with fornix lesions. There is no significant difference in lever-pressing rates between the sodium-depleted and non-depleted groups, which ever measure is taken. Comparison between the operation groups reveals that the fornix lesioned animals lever-pressed at a significantly higher rate prior to extinction testing (mean PTA=681.1) than the sham-operated control group (mean PTA=351.3) (0<0.002, Mann-Whitney, two-tailed). Of the animals who had not been treated with formalin, those with fornix lesions pressed significantly more often (mean=85.0) than the shamoperated controls (mean=25.7) during extinction testing (0<0.05, Mann-Whitney, two-tailed). However there is no
FIG. 1. Representative fornix lesions from formalin-injected (upper) and saline-injected (lower) sub-groups. Maximum and minimum extents of damage are represented by stippled and cross hatched areas, respectively.
significant difference between these two groups when extinction scores are expressed as a percent of each animal's PTA. Among sodium-depleted animals those with fornix lesions did not press significantly more often than the shamoperated controls (mean=54.4) during extinction testing. Indeed in relation to their PTA sham-operated controls pressed more often (mean= 16.1%) than the fornix lesioned animals (mean= 10.5%) although this difference was not significant. Anatomical The maximum and minimum lesions for both sub-groups of fornix lesioned animals are shown in Fig. I. While all fornix lesions were large (at least 70% of the fibres were destroyed at this coronal level) in all of the lesioned animals the extreme lateral parts of the fimbriae were spared. This was the inevitable consequence of the attempt not to inflict damage to the stria terminalis in any animal. All the fornix lesioned animals received slight thalamic damage, which was largely confined to the most anterior part of the anterior nuclear group. Bilateral destruction of the cingulum occurred in 8 of the lesioned animals. This structure suffered slight unilateral damage in one animal and was spared in another. These animals both belonged to the
,~20
()WEN ~ N D IBLI'I'I,ER
t'ormalin-injected sub-group and their behavioural performances were within the range of those of the saline-injected animals with fornix lesions. All of the fornix-lesioned animals suffered bilateral transection of the stria medullaris as well as damage to the corpus callosum overlying the area of fornix-damage. DISCUSSION
The present study set out to determine the effects of disrupting hippocampal function on latent learning. Rats were trained to press a lever for saline while thirsty and then tested under extinction conditions when not thirsty. The sham-operated controls rendered sodium deficient by formalin injection prior to testing made twice as many responses as the saline-injected controls during extinction testing, an effect attributed to latent learning. However, no such difference was seen between the formalin- and the salineinjected subjects which had received fornix lesions. Before we discuss the theoretical implications of these results we shall consider whether they really reflect the abolition of latent learning by fornix lesions. One alternative interpretation might be that the lesioned animals suffered damage to the neural mechanisms mediating sodium appetite. Thus it might be argued that "after lesions to the fornix the formalin-injected rats did not show elevated rates of barpressing during extinction testing because a sodium appetite had not been induced. However it is unlikely that fornix lesions disrupt sodium appetite since it can be elicited normally in rats with lesions of the h'ippocampus [23,32] and also of the septum [5,55]. It is also unlikely that the lesioned group suffered damage to any structures outside the fornix with a significant role in sodium appetite. Although the lesioned group consistently sustained damage to the corpus callosum, sodium appetite can be elicited normally in neodecorticate animals [56] so one would not expect lesions of the corpus callosum to abolish it. In addition, the stria medullaris was consistently damaged in the lesioned group and this would have completely destroyed those axonal connections of the septum and preoptic hypothalamus which contribute to the stria medullaris [14,15]. Since lesions in these areas also cause no deficit in sodium appetite [5,55] it seems likely that sodium appetite was elicited normally in the lesioned animals. It is unlikely that extra-fornical damage was responsible for a more direct effect on learning ability. Complete section of the corpus callosum does not result in learning deficits in the rat 13, 7, 28, 44] so it is unlikely that the comparatively small callosal lesions suffered by the lesioned rats in the present study contributed to their impairment. Little is known about the effects of stria medullaris damage on behaviour, although deficits have been seen in some tasks involving punishment [43,48] and at least one of these is not sensitive to fornix lesions [43]. However, against this must be weighed numerous reports of the effects of fornix lesions in which partial or complete damage occurred to the stria medullaris in some of the subjects. In none of these cases did combined lesions of the stria medullaris and fornix result in different behavioural sequelae from those of fornix lesions alone. These include a variety of behavioural tests such as position reversal, several different avoidance tasks, measures of exploration, spatial discrimination, DRL and spontaneous alternation [4, 8, 9, 19, 21, 35] as well as a detailed analysis of behaviour during extinction in an operant chamber [39]. It therefore seems likely that it was the damage to the fornix in the present study that was responsible for
the abolition of latent learning. It is conceivable that sodium depletion produces b e havioural effects that are unrelated to the animal's previous reinforcement with saline, and that these effects operate differently after fornix lesions. We can rule out the possibility that the elevated response rate shown by intact animals after sodium depletion is the result of a general increase in drive on the basis of controls performed by Krieckhaus and Wolf [27]. It remains a logical possibility that animals with fornix lesions are particularly sensitive to the debilitating effects of sodium depletion with the result that any latent learning by these animals was masked. This is important in view of the involvement of the hippocampal formation in the pituitary-adrenal system. However damage to the hippocampus or fornix does not seem to impair the corticosterone response to either stressors or deprivation (see [401 for review). Therefore it seems unlikely that the animals with fornix lesions would have been any less able than normals to cope with the systemic consequences of formalin injection. The higher pressing rate of the fornix lesioned rats which carried over to extinction testing has been frequently reported after hippocampal lesion s [ 13, 20, 41 ]. I t is the refore necessary to consider the possibility that the amount of latent learning achieved by an animal is inversely related to its response rate prior to testing. If this were true, the failure of the animals with fornix lesions to demonstrate latent learning might have been a result of their greater pretest response rates rather than a direct effect of the lesion on a learning mechanism. However, the variance in each group enables this possibility to be examined, and inspection of the tables reveals no evidence for an inverse relationship between pretest response rates and the amount of latent learning. Indeed if anything, the reverse appears to be the case; there is a trend towards greater latent learning among the shamoperated animals with high pretest response rates. This is in agreement with data from the only other study of this kind of latent learning in normal animals for which pretest response rates of individual animals are reported [49]. It therefore seems unlikely that the absence of latent learning after fornix lesions was a consequence of high response rates; rather it would appear to be a direct consequence of the lesion. The present task required animals to use stimuli that had no direct motivational significance (i.e., reinforcing consequences) at the time they were perceived. Normal animals use stimuli of this kind in a number of behavioural situations [16]. The inability to use such "contextual cues" has been proposed as comprising the centre of the hippocampal deficit [16,25], and the result of the present study is thus in accord with recent evidence supporting this view [17, 18, 50, 51,52, 53, 54]. Another explanation of the hippocampal deficit is that it reflects the disruption of a cognitive mapping system 137] which is responsible for the internal representation of spatial relationships in the animal's environment. In many ways this theory is similar to the contextual retrieval hypothesis. For the purposes of the present discussion the main difference is that the cognitive map theory maintains that information which is not directly associated with reward can still be stored but only in this internal map. In the present experiment sodium was always present in the same place during the initial acquisition period, when it had no motivational significance, and the failure of the rats to use this information after the hippocampal system was disrupted is thus in accord with the predictions of the cognitive map theory.
FORNIX LESIONS AND L A T E N T L E A R N I N G
821
The absence of latent inhibition and the attenuation of blocking seen after hippocampal disruption [42, 45, 46] provide further examples of lesioned animals showing abnormal behaviour when required to deal with stimuli that have no direct motivational significance. These findings have been interpreted as supporting the view first proposed by Douglas [11] that the hippocampus forms part of a neural system which is responsible for "gating-out" stimuli so that the animal ceases to attend to them once their lack of motivational significance has been established [45,46]. However such a view is clearly not adequate to explain the results of the present study. The phenomenon of latent learning suggests that the way in which normal animals can deal with stimuli which are not directly relevant to their present needs involves more than a gating-out process. Normal animals seem able to store information even though it has been gated-out for the purposes of present behaviour and to use it when it becomes relevant. This additional mnemonic process is evidently dependent on the functional integrity of the hippocampus. If a motivationally non-significant stimulus is to be gated-out the animal must first determine that the stimulus has been received before, and that it had no motivational consequences. These facts must be registered, stored and retrieved from memory before gating-out can occur. The most parsimonious interpretation seems to be that the inability to gate-out motivationally non-significant stimuli seen after hippocampal disruption is a consequence of a break-
down in some stage of mnemonic side of this operation. This view is in line with those of authors who h a v e recently suggested that the disinhibitory effects of hippocampal lesions are secondary to a more fundamental information processing deficit [1, 51, 52, 54]. A further question remains: How long must the delay be between perceiving a stimulus and recognizing its relevance to a state of motivation if a lesioned animal is to be unable to use it to guide behaviour? In the present study lesioned animals failed when the interval between receipt of sodium and the need to press for it was 24 hr, but two pieces of recent evidence suggest that even if the interval is of the order of a few seconds such animals will still be impaired. Mikulka and Freeman [32] found that a 10 sec delay between response and reward seriously retarded acquisition by hippocampal rats of a position habit in a Y-maze. O'Keefe and Black [36] examined the ability of rats with fornix lesions to use distal cues to solve a T-maze problem. These workers concluded that lesioned animals do not have difficulty using distal cues per se, but are unable to use those which cannot be perceived immediately before or during reinforcement. It therefore seems likely that the kind of stimuli that animals without a functioning hippocampus can use as cues to guide behaviour are limited to those whose perception is accompanied or immediately followed by reinforcement. Indeed both the cognitive map theory and the contextual retrieval hypothesis predict that lesioned rats should behave much as early S-R learning theory predicts for normal animals [16, 36, 37].
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