The effects of vestibular lesions on hippocampal function in rats

Interest in interaction between the vestibular system and the hippocampus was stimulated by evidence that peripheral vestibular lesions could impair performance in learning and memory tasks requiring spatial information processing. By the 1990s, electrophysiological data were emerging that the brainstem vestibular nucleus complex (VNC) and the hippocampus were connected polysynaptically and that hippocampal place cells could respond to vestibular stimulation. The aim of this review is to summarise and critically evaluate research published in the last 5 years that has seen major progress in understanding the effects of vestibular damage on the hippocampus. In addition to new behavioural studies demonstrating that animals with vestibular lesions exhibit impairments in spatial memory tasks, electrophysiological studies have confirmed long-latency, polysynaptic pathways between the VNC and the hippocampus. Peripheral vestibular lesions have been shown to cause long-term changes in place cell function, hippocampal EEG activity and even CA1 field potentials in brain slices maintained in vitro. During the same period, neurochemical investigations have shown that some hippocampal subregions exhibit long-term changes in the expression of neuronal nitric oxide synthase, arginase I and II, and the NR1 and NR2A N-methyl-d-aspartate (NMDA) receptor subunits following peripheral vestibular damage. Despite the progress, a number of important issues remain to be resolved, such as the possible contribution of auditory damage associated with vestibular lesions, to the hippocampal effects observed. Furthermore, although these studies demonstrate that damage to the vestibular system does have a long-term impact on the electrophysiological and neurochemical function of the hippocampus, they do not indicate precisely how vestibular information might be used in hippocampal functions such as developing spatial representations of the environment. Understanding this will require detailed electrical stimulation and lesion studies to elucidate the way in which different kinds of vestibular information are transmitted to various hippocampal subregions.     

Discrimination learning and stimulus generalization in rats with hippocampal lesions

Rats with hippocampal lesions and sham operated control animals were trained on a go-no-go tone discrimination. For half of the animals of each group the tone was the positive stimulus while for the other half the tone was negative. The hippocampal tone negative group took the greatest number of days to learn the task. Tone generalization tests administered the day after the learning criterion was reached did not yield any differences in either excitatory or inhibitory stimulus control between the hippocampal and sham animals.     

Anxiolytic effects of cytotoxic hippocampal lesions in rats

Rats with cytotoxic lesions of the hippocampus were given 3 anxiety tests: social interaction with a novel rat, the elevated zero-maze (a modification of the plus-maze), and hyponeophagia (eating familiar and novel foods in a novel place). Marked anxiolytic effects were seen in the social interaction and hyponeophagia tests, but not on the zero-maze. These results confirm and extend previous experiments that used traditional lesion techniques. The zero-maze result was consistent with other experiments using the plus-maze, in which intrahippocampal administrations of pharmacological agents were not anxiolytic, although variability in ethological tests may also be a factor. As the hyponeophagia test used an elevated apparatus, as in the zero- and plus-mazes, the lack of a lesion effect in the zero-maze was unlikely to have been due to an inability to relieve height-induced anxiety.     

Red ginseng ameliorated place navigation deficits in young rats with hippocampal lesions and aged rats

Effects of hippocampal lesions and aging on spatial learning and memory and ameliorating effects of red ginseng on learning deficits were investigated in the following two experiments: performance of young rats with selective hippocampal lesions with red ginseng by mouth (p.o.; Experiment 1) and aged rats with red ginseng (p.o.; Experiment 2) in the spatial tasks was compared with that of sham-operated or intact young rats. Each rat in these two behavioral experiments was tested with the three types of spatial-learning tasks (distance movement task, DMT; random-reward place search task, RRPST; and place-learning task, PLT) in a circular open field using intracranial self-stimulation as reward. The results in the DMT and RRPST tasks indicated that motivational and motor activity of young rats with hippocampal lesions with and without ginseng were not significantly different from that of sham-operated young rats in Experiment 1. However, young rats with hippocampal lesions displayed significant deficits in the PLT task. Treatment with red ginseng significantly ameliorated place-navigation deficits in young rats with hippocampal lesions on the PLT task. Similarly, red ginseng improved performance of aged rats on the PLT task in Experiment 2. The results, along with previous studies showing significant effects of red ginseng on the central nervous system, suggest that red ginseng ameliorates learning and memory deficits through effects on the central nervous system, partly through effects on the hippocampal formation.     

Selective hippocampal lesions and behavior: effects of kainic acid lesions on performance of place and cue tasks

Kainic acid (KA) lesions were used to study the effects of damage to the CA3 cell field and subiculum on performance of complex place and cue tasks. In Experiment 1, neuroanatomical techniques were employed to determine the selectivity of the lesions. In a within-subjects design, rats in Experiment 2 were trained before the operations to run on an eight-arm radial maze with procedures that involved two kinds of learning (place and cue) and two memory functions (reference memory and working memory). Interrupting the intrahippocampal circuit by damaging the CA3 cell field with KA had minimal effects on performance; injections into subiculum and complete aspiration lesions of hippocampus resulted in impairments on the place but not the cue task. Only intraventricular injections of KA affected performance on both tasks. These results fail to support either the cognitive map or the working memory theory of hippocampal function. The presence of distant damage beyond the immediate area of injection complicates interpretation of the results and may serve to limit the usefulness of KA as a neurotoxin in behavioral investigations.     

Effects of interference on discrimination learning and recall by rats with hippocampal lesions

The performance of rats with hippocampal, cortical, or sham lesions on a visual pattern discrimination task was examined under various interference conditions. In Experiment 1, all groups learned the discrimination within normal limits but the hippocampal group was impaired in a retention test if a high interference task involving similar stimulus material was introduced between original learning and retesting. In Experiment 2, animals with hippocampal lesions were similarly impaired in the initial acquisition of the discrimination habit when the high interference task was introduced prior to the beginning of training. The results were related to similar deficiencies in human amnesics with known or suspected hippocampal damage and were interpreted as reflecting a basic inability to use available cues to dissociate competing experiences.     

Estrogen-induced changes in place and response learning in young adult female rats

Many findings suggest that changes in circulating estrogen levels influence cognition, in some cases impairing performance and in others enhancing performance. One interpretation of these mixed effects is that estrogen biases the strategy used to solve a task. To test this idea, young adult female rats, ovariectomized for 21 days, were trained after acute hormone or control treatment in 2 very similar tasks with different cognitive requirements. One task required place learning and the other response learning. Rats given two 10-microg injections of estradiol 48 and 24 hr before training learned the place task significantly faster than did rats without estradiol. Conversely, rats without estradiol performed better on the response task than did rats with replacement. These data suggest that the cognitive actions of estrogen may be task-specific by modulating the relative contribution of different learning and memory systems.     

Contribution of hippocampal place cell activity to learning and formation of goal-directed navigation in rats

Although extensive behavioral studies have demonstrated that hippocampal lesions impair navigation toward specific places, the role of hippocampal neuronal activity in the development of efficient navigation during place learning remains unknown. The aim of the present study was to investigate how hippocampal neuronal activity changes as rats learn to navigate efficiently to acquire rewards in an open field. Rats were pre-trained in a random reward task where intracranial self-stimulation rewards were provided at random locations. Then, the rats were trained in a novel place task where they were rewarded at two specific locations as they repeatedly shuttled between them. Hippocampal neuronal activity was recorded during the course of learning of the place task. The rats learned reward sites within several sessions, and gradually developed efficient navigation strategies throughout the learning sessions. Some hippocampal neurons gradually changed spatial firing as the learning proceeded, and discharged robustly near the reward sites when efficient navigation was established. Over the learning sessions, the neuronal activity was highly correlated to formation of efficient shuttling trajectories between the reward sites. At the end of the experiment, spatial firing patterns of the hippocampal neurons were re-examined in the random reward task. The specific spatial firing patterns of the neurons were preserved if the rats navigated, as if they expected to find rewards at the previously valid locations. However, those specific spatial firing patterns were not observed in rats pursuing random trajectories.These results suggest that hippocampal neurons have a crucial role in formation of an efficient navigation.     

The comparative effects of frontal, parietal, occipitotemporal, and limbic forebrain lesions in weanling rats on learning

Young rats prepared with discrete bilateral lesions to the cerebral cortex, cingulate cortex, or dorsal hippocampus were required to learn a white-black discrimination, a 3-cul maze, and a nonvisual inclined plane discrimination. Only those rats with parietal lesions were impaired in acquiring all three habits. Those with occipitotemporal, frontocingulate, or posterior cingulate lesions were impaired on two habits, those with dorsal hippocampal lesions were impaired on one habit, and those with frontal (motor) cortical lesions failed to show any impairment. These results coupled with others suggest that the parietal cortex is unsurpassed in the wide range of learning and retention deficits which follows restricted neopallial lesions.     

Effects of additional cues on passive avoidance learning and extinction in rats with hippocampal lesions

Following the acquisition of a water-rewarded approach response in a straight runway, the effects of introducing shock in the goal box (passive avoidance - PA) or withdrawing reinforcement (extinction) were compared in hippocampal, cortical, and operated control groups of rats. Under standard test conditions, hippocampal groups were impaired in PA learning and showed strong resistance to extinction, relative to the control groups. When additional cues were provided such that external stimuli associated with goal box events could be easily detected early in the runway, performance differences between the hippocampal and control groups were eliminated in the PA test and significantly reduced in extinction. The results emphasize the inefficient processing by hippocampally-damaged animals of stimulus cues following a shift in experimental contingencies.     

The effects of hippocampal and fimbria-fornix lesions on prepulse inhibition

The present experiments tested the effects of conventional (dorsal aspiration and electrolytic) and excitotoxic (N-methyl-D-aspartate [NMDA]) hippocampal lesions and fimbria-fornix (FF) transection on prepulse inhibition (PPI) of startle response and on open-field activity. Activity was increased by FF transection and by conventional but not excitotoxic hippocampal lesions; complete NMDA lesion increased amphetamine-induced activity. Whereas dorsal hippocampal aspiration lesion disrupted PPI, the phenomenon was not affected by dorsal hippocampal electrolytic lesion, partial or complete excitotoxic (NMDA) hippocampal lesions, or complete FF transection, which interrupted the cholinergic input to the hippocampus as well as the hippocampal-subicular input to the nucleus accumbens. Systemic apomorphine disrupted PPI in both FF-transected rats and their controls. It is suggested that the hippocampus is essential for PPI disruption rather than for PPI expression.     

Dorsal striatal head direction and hippocampal place representations during spatial navigation

Several theories of basal ganglia function describe a striatal contribution to learning that is independent of hippocampal function. This study examined the question of whether the striatum should be regarded as functioning independently of or acting in concert with limbic structures. Dorsal striatal head direction cells and hippocampal place cells were recorded in parallel while rats performed a hippocampal-dependent radial maze task. Changes in the directional preference of head direction cells and the location of place fields were compared following alterations of the sensory environment. When familiar visual cues were presented in new spatial arrangements, or when new visual cues were placed in a familiar environment, rotations of directional preferences were consistent with the mean place-field response. When familiar visual and nonvisual cues were presented in conflict, or when rats were exposed to novel environments, the responses of the two cell types were inconsistent relative to each other. This pattern suggests that current perceptions and expectations of familiar spatial contexts may dynamically modulate the relationship between hippocampus and dorsal striatum. Electronic Publication     

The effects of nucleus basalis magnocellularis lesions in Long-Evans hooded rats on two learning set formation tasks, delayed matching-to-sample learning, and open-field activity

Rats with quisqualic acid lesions of the nucleus basalis magnocellularis (nBM) and control rats were compared in discrimination reversal learning set (DRLS) and olfactory discrimination learning set (ODLS) tasks, a delayed matching-to-sample task (DMTS), and open-field activity. Evidence of learning set formation was seen in control rats but not in nBM-lesioned rats in both the DRLS and ODLS tasks. Better-than-chance performances were seen for both groups in DMTS, indicating no impairment after nBM lesions. There were no group differences in open-field activity. These findings suggest that the nBM is important for higher cognitive processing such as "learning to learn" and thus is important for a complex form of reference memory. In addition, perseverational, working memory, and attentional deficits could not explain learning set impairment after nBM lesions.     

Cue-induced recall of a passive avoidance response by rats with hippocampal lesions

Two experiments are reported in which a stimulus reminder technique was used in an attempt to compensate for the disruptive effects of hippocampal lesions on passive avoidance (PA) conditioning. Groups of hippocampal, cortical and operated control rats were trained to run down an alley for water reward. When the approach response had stabilized, shock was introduced in the goal-box, resulting in increased running times in the control groups and the characteristic PA impairment in the hippocampal group. A recall test was administered 24 hr later but 2 hr before the test, animals were reminded of the previous treatment by being exposed to: (1) shock and related stimuli, (2) related stimuli only, or (3) neutral stimuli. The PA performance of the hippocampus groups in the recall test improved to the level of controls following conditions 1 or 2; there was no effect of condition on Treatment 3. Performance of control groups was virtually unaffected by any of the reminder conditions. The similarities were noted between these results and those of partial cueing studies involving human amnesics with known or suspected damage to the hippocampal system.     

Aging effects on spatial tuning of hippocampal place cells in mice

One reason the electrophysiological correlates of hippocampal neurons are of interest is the possibility that they reflect their representational properties, presumably spatial/relational ones. Stable spatial representations, based on activity of ensembles of hippocampal place cells, initially develop through a series of short-episodic spatial tunings. Hence these short-episodic spatial tunings are important for understanding the establishment of stable place fields. Studies of age-related changes in place cell activities traditionally focus on place fields. In the present study, we characterized the short-episodic spatial tunings (1-min bins) of hippocampal CA1 place cells of freely moving mice in a familiar cylinder arena, and compared these functions in young and old mice. Spatial tuning was expressed by spatial selectivity, which we found fluctuated across a 16-min recording session in both young and old mice. High spatial selectivity, which is mainly due to the low firing of a place cell out of the place field in young mice, was significantly higher in old mice. The high firing rate out of the place field was the main factor contributing to significantly lower spatial selectivity in old mice. In addition, young mice showed a broad peak in the spatial selectivity between 4 and 10 min. In contrast old mice showed no peak in the spatial selectivity during this time period. The stability of place fields after a 24-h interval was also lower in old mice than in young mice. The low spatial tuning and unstable place fields suggest that a hippocampal-based spatial representation was impaired in the old mice. Furthermore, we speculate that the age-related impairment in hippocampal inhibition system may be involved in the impaired spatial representation of hippocampal CA1 place cells in old mice. Electronic Publication     

Differential effects of amygdaloid lesions on conditioned taste aversion learning by rats

Rats with electrolytic lesions placed in either the basolateral or corticomedial divisions of the amygdala acquired a conditioned taste aversion to sucrose. Comparisons with a surgical control group indicated that damage to the corticomedial amygdala did not alter the animals' performance, while damage in the basolateral nuclei resulted in a small but significant attenuation of the aversion. Furthermore, these amygdaloid lesions did not alter the acceptability of two quinine hydrochloride solutions (0.01% and 0.001%). The daily drinking behavior of the rats with basolateral amygdaloid lesions appeared consistent with the hypothesis that this lesion affected the animals' appreciation of the novelty of the sucrose solution, and hence attenuated the subsequent aversion.     

Classical contingencies in rats with hippocampal lesions

Hippocampal, cortical and sham lesioned rats were trained to discriminate between two odors, in non-contingent, partially contingent, and perfectly contingent schedules. In the non-contingent situation both odors signaled shock with probability of 0.5. In the partially contingent situation one odor signaled shock with probability of 0.5 and the other "no shock" with probability of 1. In the perfectly contingent situation one odor signaled shock and the other "no shock" with probabilities of 1. In the non-contingent schedule none of the three surgical groups evidenced learning, in the partially and perfectly contingent cases the hippocampally lesioned animals performed so as to indicate greater learning of the aversion than did the cortically lesioned or the sham operated animals. It is suggested that the behavior of animals with hippocampal lesions is more sensitive to contingencies than that of normal animals.     

Ameliorative effects of a cognitive enhancer, T-588, on place learning deficits induced by transient forebrain ischemia in rats

In the present study, we investigated the effect of (1R)-1-benzo[b]thiophen-5-yl-2-[2-(diethylamino)ethoxy]ethan-1-ol hydrochloride (T-588), a newly synthesized cognitive enhancer, on place learning deficits in rats with damage selective to the hippocampal CA1 subfield induced by transient forebrain ischemia. Three weeks after the ischemic insult, T-588 was daily administered (0.3 or 3.0 mg/kg/day po). Place learning was tested in a task in which the rat was required to alternatively visit two places located diametrically opposite each other in an open field. The ischemic rats without the treatment of T-588 displayed severe learning impairment in this task; their performance level was significantly inferior to that of the sham-operated rats. The treatment of T-588 improved dose-dependently the task performance in ischemic rats, although no apparent protective effects on ischemic damage were found histologically. These results suggested that T-588 has ameliorative effects on learning deficits induced by brain ischemia, which could be produced through enhancement of residual cognitive functions.     

Y-Chromosomal effects on discrimination learning and hippocampal asymmetry in mice

From a four-way cross between unrelated inbred strains of mice, a random-breeding line was developed that segregated at two coat-color loci and carried Y chromosomes from different sources. Adult males were used for measurements of black-white discrimination learning and 7-day response retention in a water maze, body weight, brain weight, and left- and right-side hippocampus weight. Clear evidence was obtained of Y-linked influences on response acquisition, body weight, right-side hippocampus weight, and hippocampal asymmetry, whereas direct effects of autosome 9 were indicated with regard to right-side hippocampus weight only. However, epistatic interactions of the Y chromosome with autosome 9 were found for response acquisition and body weight and with autosome 4 for hippocampal asymmetry.