On the role of hippocampal connections in the performance of place and cue tasks: comparisons with damage to hippocampus.

Behavioral changes following interruption of the main connections of hippocampus and closely related areas (entorhinal cortex, mammillary bodies, dentate gyrus) were determined and compared with findings of previous research that involved direct damage to hippocampus. By a within-subjects design, rats were trained to run in a radial maze with a procedure that involved two kinds of learning (place and cue) and two memory functions (working and reference memory). Rats with fimbria-fornix and entorhinal cortex lesions were impaired on both the place and the cue task. Specifically, the animals suffered a general impairment in working memory on both tasks but were impaired in reference memory only on the place task. Animals with lesions of the dentate gyrus and mammillary bodies were able to perform the complex place and cue tasks with minimal problems. In previous research it was found that direct damage to hippocampus (including all cell fields, alveus, fimbria) resulted in impaired performance only on the place task (Jarrard, 1983). Taken together, these findings indicate that interruption of hippocampal input/output pathways and/or damaging some closely related structures has a greater effect on the behaviors studied than does direct damage to hippocampus.

Studies on the cell-type specific expression of RBP-L, a RBP-J family member, by replacement insertion of beta-galactosidase.

The RBP-L gene encodes a DNA binding protein that is structurally related to RBP-J, the mammalian homolog of Drosophila Suppressor of Hairless. Although the RBP-L protein binds the same DNA sequence as RBP-J, the in vivo function of this protein remains largely unknown. In order to investigate the role of this protein, we generated RBP-L mutant mice by targeted disruption involving replacement of the protein-coding sequence in the first exon with an in-frame fusion of the nlacZ cDNA. The homozygous mutant mice appeared morphologically normal and fertile. Unexpectedly, we found the possible existence of additional promoter(s) downstream of the first exon whose activity was not fully disrupted in the mutant mice. The promoter upstream of the first exon is regulated in a cell type-specific manner so that transcription is active in neurons but almost inactive in lung where the downstream promoter is active. The specific expression of the beta-galactosidase fusion protein was detected in layer VI of the cerebral cortex, in the pyramidal cell layer of the hippocampus, and in the granule cell layer of the dentate gyrus. Furthermore, we found that the upstream promoter activity in neurons might be regulated by some neuronal activity.

Learning behaviour in chronic vitamin E-deficient and -supplemented rats: radial arm maze learning and passive avoidance response.

The effects of long-term vitamin E deficiency and supplementation on learning behaviour were investigated. Rats were fed vitamin E-deficient [VE(-)], -supplemented [VE(+)], or control standard food beginning after the age of 4 weeks. They were trained in an eight-arm radial maze learning task at the age of 17 months, and in a step-through passive avoidance response (PAR) task at the age of 25 months. In the radial maze task, both VE(-) and VE(+) animals required as many trials to reach the learning criterion as control animals. Scopolamine injection (0.25-0.5 mg/kg) after acquisition of the task decreased the number of correct choices dose-dependently; however, the degree of the drug effect on VE(-) and VE(+) rats did not differ from that on control rats. On the other hand, VE(-) animals showed significantly lower rate of avoidance response and VE(+) animals tended to show higher rate of avoidance response in the PAR task than did control animals. These results suggest that long-term vitamin E deficiency or supplementation does not influence general ability to acquire and maintain memory tasks in rats, but that it may affect learning behaviour, depending on the kind of task in which animals were trained.

Effects of fimbria-fornix lesions on avoidance tasks with temporal elements in rats.

Sidman schedule active avoidance, passive avoidance, and multiple avoidance (continuous alternation of active and passive avoidance) tasks were given to fimbria-fornix (FF)-lesioned (n = 10) and control (n = 10) rats to assess the effects of fimbria-fornix lesions on unsignaled avoidance learning with temporal cognition requirement. Active avoidance required subjects to make running responses, and passive avoidance required them to stop running and remain immobile on a running wheel. The tasks could be achieved purely by temporal cues, and no spatial elements were involved. Animals in the FF group performed the active, passive, and multiple avoidance tasks as well as control animals, showing no deficits by lesions in either the number of running responses nor the number of shocks received, although animals in the FF group displayed a greater negative transfer in passive avoidance when they received the active training before the passive training. The results indicate that fimbria-fornix lesions do not impair avoidance tasks when the tasks do not require spatial information, even if temporal information and/or inhibition are necessary to perform the tasks.

Scopolamine impairs both working and reference memory in rats: a replication and extension.

Rats were trained to run in a spatial, radial maze for sucrose reward using a procedure that permitted determination of two memory functions [working memory (WM) and reference memory (RM)]. Injections of saline, 0.1, 0.4, and 0.8 mg/kg of scopolamine hydrobromide were administered using a Latin-square design; a single dose (0.4 mg/kg) of scopolamine methylbromide served as a control for peripheral drug effects. The smallest dose of scopolamine (0.1 mg/kg) had no measurable effect on performance, but as the dose was increased to 0.4 and 0.8 mg/kg there were increases in both WM and RM errors, in errors of omission, and increases in running time. These results support the view that the effects of scopolamine on performance in the radial maze is not specific for working memory, but rather the effects are more general in nature.

[Punished behavior in hippocampectomized rats (author's transl)].

Hippocampectomized rats were compared with the controls on punishment training in a L-shaped alley. Five measures of running time were taken; startbox latency A (from the placement in the startbox to the door), startbox latency B(from the door to the runway), runway running time, goalbox entry time and goalbox time. The postshock running time of controls was significantly longer than the preshock one in all measures. Hippocampals showed no hesitation in both startbox latencies, but did show hesitation in the other three measures just as the controls did. The controls spent a long time in the startbox from which they were unable to see outside stimuli until reaching the startbox door. These results support the spatial cognition theory of hippocampal function rather than the distant cue theory.

[The effects of a fimbria-fornix lesion on distance discrimination in rats].

In order to study the role of hippocampus in spatial learning, fimbria-fornix (FF) lesioned and control rats, eight each, were trained for a distance discrimination task in a rectangular test box (120 x 60 x 35 cm). A rat was placed in a start box at one of the corners of the test box, and then released to choose the bottle that contained food reward. Two bottles, at the distance of 50 cm, were placed along the walls, one short and the other long, on either side of the start box, and to find the reward the rat had to discriminate the distance, i.e., short vs. long wall of the test box. Results showed that control rats were able to make the discrimination, while FF rats were not. The finding suggests that hippocampus plays an important role in processing distance information in general, and distance discrimination in particular.

[The use of geometrical information and featural information in fimbria-fornix-lesioned rats].

Fimbria-fornix-lesioned (FF) rats (n = 10) and control rats (n = 10) were trained for the food-searching task in a rectangular box with four kinds of featural panels. In Experiment 1, food was placed at the fixed corner in front of the fixed panel so that both geometrical information (the shape of the rectangular box) and featural information (panels at the corners) were available for the rat. Control rats could find the food, but they sometimes searched at the diagonal corner of the food. Food location and its diagonal location were equivalent in relation to the longer and shorter sides of the box. FF rats could find food, only when the featural panel that showed the location of food was in front of them. From Experiments 2A and 2B which controlled geometrical information and featural information respectively, it is indicated that control rats could use geometrical information and featural information independently, but that FF rats could use only featural information. These results suggest that the hippocampus plays an important role in processing geometrical information, but not featural information.

[Effects of shock experience on aversiveness caused by the scream of other rats: overshadowing tests of the association assumption].

Distress responses of rats like screams are aversive for other rats. This study was conducted to determine some of the conditions affecting these aversive properties. Eighteen rats were trained to press a lever to obtain food on a FR4 schedule, then assigned to Shock-experienced group (SE). Overshadow group (OS), and Control group (CNT). SE received three 1-second shocks (1 mA) a day for two days in a grid-floor box. The procedure for OS was the same as that for SE except that a 40-W lamp was lit 30 seconds before the onset of the shock. CNT received neither lights nor shocks. During the next eight days, rats received FR4 schedule with the same procedure as for training except that lights (40 W) or screams (65 dB) were presented for 1 minute. When lights were presented, OS showed marked response suppression but SE and CNT showed little one. When screams were presented, SE revealed strong suppression although CNT and OS showed weak one. These results indicate that aversion to screams was determined by Pavlovian conditioning.

[Effects of hippocampal lesions on punishment training in rats (author's transl)].

The present experiment was designed to determine the effect of hippocampal lesions on punishment training and to evaluate the spatial cognition hypothesis. Hippocampectomized and operated control rats were each divided into runway and goal box punishment groups. Food motivated animals were tested in the elevated straight alley on 10 acquisition days and 1 punishment day. Start box latency, runway running time, goal box entry time and goal box time were measured. The controls spent longer time in all measures on the postashock trial. The hippocampals showed no hesitation in the start box latency on the postshock trial, but they spent longer time in other measures. The location of punishment had significant effects only on the start box latency of the controls. These results support the spatial cognition hypothesis.

[The influence of conspecific distress responses on the lever choice behavior in the rat].

We examined whether distress responses of rats would be a negative reinforcer or not. In Experiment 1, two rats were placed in adjacent compartments. One rat was reinforced by a food pellet for pressing either of two levers. One of the levers produced food while the other produced food plus electric shock (0.5-2.0 mA) to the other rat. All rats preferred the former lever. In addition, this tendency was more prominent in rats that had experienced shock previously than those without experience. In Experiment 2, one lever produced food while the other produced food plus auditory stimuli, a recorded distress scream (65 dB) or a pure tone (3 kHz, 65 dB). Rats that chose between food and food plus another rat's scream avoided being exposed to the scream. Rats that chose between food and food plus the pure tone chose the two levers equally. These results suggest that negative emotional responses of the conspecifics could be a negative reinforcer.

[Effects of fimbria-fornix lesion on the temporal discrimination revealed by peak interval procedure in rats].

When temporal discrimination is examined by a peak interval (PI) procedure in rats, a shortening of peak time is induced by the fimbria-fornix (FF) lesion. The aim of this research is to investigate the extent of peak time shortening induced by FF lesion and the acquisition process of temporal discrimination. In FF lesioned rats, the peak time was very short (about 13 sec) in earlier phase, then became longer as the training progressed and reached a steady level, which was approximately 20% shorter than control rats. These results suggest that the "non-timing process" is involved in addition to the "timing process" in FF lesioned rats.

[Effects of lesions in the central nucleus and lateral nucleus of the amygdala on fear conditioning with a visual conditioned stimulus in rats].

Lesions in the central nucleus or lateral nucleus of the amygdala have been known to interfere with the acquisition of fear conditioning when a sound is used as a conditioned stimulus (CS). The present study examined whether or not a similar interference would occur with a visual CS. Seven rats with lesions in the central nucleus (AMY-C group), 8 with lesions in the lateral nucleus (AMY-L group), and 16 unoperated control rats were trained using a visual CS (25 W light, 3.7 s duration) paired with footshock (1.0 mA, 0.5 s). The behavioral index of fear conditioning was a potentiation of startle reflex in the presence of CS. All control rats and AMY-L group showed the potentiation, but AMY-C group did not. These results suggest that the lateral nucleus of the amygdala may not be involved in fear conditioning to a visual CS. It is possible that each modality of CS has a specific pathway to the central nucleus of the amygdala to mediate fear conditioning.

[Learning strategies of hippocampectomized rats on an elevated maze].

Hippocampectomized (N = 19) and control (N = 18) rats were trained on an elevated T-maze in which place, cue and response strategies employed could be separated from one another. For nine hippocampals and nine controls, a place task was followed by a cue task (place-cue condition) while the order was reversed for the remaining subjects (cue-place condition). The effects of hippocampal lesions on acquisition and transfer of place and cue learning were assessed in terms of correct responses and strategies used by the rats. In both training conditions, performance of hippocampals was significantly impaired for the place task but not for the cue task. Hippocampals used a cue strategy in the cue task but employed a response strategy in the place task. Controls, on the other hand, used a place strategy in the place task and a cue strategy in the cue task. These results suggest that rats with hippocampal lesions are imparied in their ability to employ a place strategy with the result that other strategies are adopted in a place task situation.

Effects of fimbria-fornix lesions on door discrimination and route choice in a lattice maze by rats.

The present experiment discusses (1) the use of "cognitive maps" in rats by showing that they can orient themselves and their direction of movement at a given place in a maze and (2) the role of the hippocampus in spatial cognition by examining the effects of hippocampal lesions on rats performing maze tasks. The apparatus employed was a lattice maze consisting of eight alleys which cross orthogonally. The alleys were partitioned by a total of 24 apparently identical doors; 8 doors were locked and the others were unlocked. Fimbria-fornix-lesioned (FF) (n = 16) and control (n = 18) male Wistar rats were trained to run from one of four start boxes to the goal with a salient visual cue under open and closed conditions. Rats in the OPEN-Cont group successfully discriminated between locked and unlocked doors and were able to choose detour routes as well as the shortest route. This was regarded as evidence of their ability to form a cognitive map. Rats in the CLOSED-Cont group did not have intra- or extramaze cues but were also able to learn the task. It is proposed that they used proprioceptive cues to form cognitive maps, which enabled them to solve the problem. Rats in the FF group could not avoid locked doors because they were not able to form cognitive maps. However, they utilized the goal stimulus as a cue to solve the problem.

Effects of dorsal-striatum lesions and fimbria-fornix lesions on the problem-solving strategies of rats in a shallow water maze.

In solving a spatial problem, animals can use a place, cue, or response strategy. The present research was designed to evaluate the role of dorsal striatum (DS) in spatial problem solving and to compare it with that of fimbria fornix (FF). Rats were trained with a place + cue task in a shallow pool, then were divided into three groups (DS, FF, control), and lesions were made in the corresponding areas. After retraining, four probe tests were given: Test 1 (start position moved), Test 2 (goal and start positions moved), Test 3 (invisible goal), and Test 4 (curtain test). The test results suggest that the DS and Control groups performed the original task by using the place strategy, whereas the FF group used the cue strategy, which strongly implies that the DS group was impaired in the use of the cue strategy. This research also provides evidence supporting the usefulness of a shallow pool in evaluating animal behavior.

Effects of glucose on scopolamine-induced learning deficits in rats performing the Morris water maze task.

In order to assess the effects of glucose on drug-induced spatial learning deficits, three experiments were conducted using the Morris water maze. Scopolamine and glucose were injected ip at various stages of training. Rats of Wistar strain served as subjects. In Experiment 1, scopolamine (0.4 mg/kg) and 10, 100, or 500 mg/kg of glucose were administered every day from the start of training, and the effect on acquisition was evaluated. In Experiment 2, scopolamine and 100 or 500 mg/kg of glucose were administered after 6 days of training, and the effect on performance was assessed. In Experiment 3, scopolamine and 500 mg/kg of glucose were injected after 2 days of training, and the effect on the following trial was tested. In all experiments, scopolamine impaired acquisition/performance of the task. Glucose at 500 mg/kg showed a significant enhancing effect on acquisition regardless of scopolamine injection only when injected daily from the start of training (Experiment 1). Glucose injected after the performance has reached asymptote (Experiment 2) did not affect performance, and glucose in the middle of training showed a slight but insignificant enhancing effect (Experiment 3). These results may suggest that the effect of glucose changes as a function of the degree of learning of the spatial learning task. The possibility of task specificity of the glucose effect was also discussed in relation to the cholinergic systems and local cerebral glucose utilization.