Hippocampal lesions enhance configural learning by reducing proactive interference

Rats were trained on an operant conditional discrimination in which an ambiguous stimulus (X) indicated both the occasions on which responding in the presence of a second cue (A) would be reinforced and the occasions on which responding in the presence of a third cue (B) would not be reinforced (X → A+, A−, X → B−, B+). Both rats with neurotoxic lesions of the hippocampus and control rats learned this discrimination more rapidly when the training trials were widely spaced (mean intertrial interval of 8 min) than when they were massed (mean intertrial interval of 1 min). With spaced practice, lesioned and control rats learned this discrimination equally well. But when the training trials were massed, lesioned rats learned more rapidly than controls. At the end of training, performance of all rats was tested at three different intertrial intervals, 0.5 min, 1 min, and 8 min. The control rats trained with 8-min intertrial intervals showed deficits in discrimination performance when the test intertrial interval was 0.5 min or 1 min. An analysis of sequential effects indicated that a major source of this performance deficit was the control rats' failure to withhold responding on nonreinforced trials when those trials were immediately preceded by reinforced trials within 0.5 min or 1 min. In contrast, performance of lesioned rats was not affected by either the test intertrial interval or by the nature of preceding trials. Thus, with short intertrial intervals, hippocampal lesions may have improved learning or performance on a given trial by reducing proactive interference from the previous trial. Hippocampus 1998;8:138–146. © 1998 Wiley-Liss, Inc.     

Neonatal hippocampal damage in rats: Long-term spatial memory deficits and associations with magnitude of hippocampal damage

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20–25, PN50–55, or PN90–95, separate groups of rats were tested in a Morris water maze on a visible “cue” condition (visible platform in a fixed location of the maze), a spatial “place” condition (submerged platform in a fixed location), or a no-contingency “random” condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20–25) or as adults (PN50–55 and PN90–95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm. Hippocampus 7:403–415, 1997. © 1997 Wiley-Liss, Inc.     

Evidence for extrahippocampal involvement in place learning and hippocampal involvement in path integration

Although there is a good deal of evidence that animals require the hippocampus for learning place responses, animals with damage to the afferent and efferent fibers coursing through the fimbria-fornix have been shown to acquire a place response. This finding suggests either that the cells of the hippocampus proper (CA1–4 and dentate gyrus), via their connections to the temporal lobe, can mediate place learning or that some extrahippocampal structure is sufficient. We examined this question using rats with ibotenic acid lesions of the cells of the hippocampus. Rats were pretrained to swim to a visible platform and then given probe trials on which the visible platform was removed. Video and kinematic analyses showed that the hippocampal rats expected to find the platform at its previous location because they swam directly to that location and paused and turned at that location after the platform was removed. Additional tests confirmed that they had learned a place response. There were, however, abnormalities in their swimming patterns, and despite having acquired one place response, they did not then acquire new place responses when only the hidden platform training procedure was used. These results demonstrate that place learning can be acquired by rats in which the hippocampus proper is removed. Contrasts between conditions in which hippocampal rats acquire a place response and conditions in which they fail suggests that the hippocampus may serve as an on line system for monitoring movement and integrating movement paths. © 1996 Wiley-Liss, Inc.     

Perseveration on place reversals in spatial swimming pool tasks: Further evidence for place learning in hippocampal rats

Animals with damage to the fimbria–fornix (FF) or cells of the hippocampus (HIP) can learn a place problem but cannot learn matching-to-place problems, which feature a series of place “reversals.” The two experiments described in the present report were designed to examine the causes of impairment on reversal learning. In experiment 1, control, HIP, and FF groups were trained to asymptote on a place problem, and then the location of the platform was moved. Control rats learned the reversal response more quickly than the initial response; the HIP rats learned both problems at the same rate. Swim analysis showed that the impairment in the lesion group on the reversal response was aggravated by perseverative returns to the first learned place. In experiment 2, control and FF groups were trained on a task in which the platform was visible on three daily trials and hidden on one daily trial. After 10 days, the platforms were moved. In the reversal response, the FF group showed enhanced performance on the cue trials and severely impaired performance on the place trials relative to initial learning and control performance. Swim analysis showed that FF rats perseverated on the initial place response in place trials. These experiments provide further evidence for place learning in hippocampal rats and show that perseverative responses contribute to impairments in new learning. The results are discussed in relation to the idea that the hippocampus mediates spatial mapping and/or uses self-movement cues to solve spatial problems. Hippocampus 7:361–370, 1997. © 1997 Wiley-Liss, Inc.     

Similarities vs. differences in place learning and circadian activity in rats after fimbria-fornix section or ibotenate removal of hippocampal cells

Damage to either the fimbria-fornix or to the hippocampus can produce a deficit in spatial behavior and change in locomotor activity but the extent to which the two kinds of damage are comparable is not known. Here we contrasted the effects of cathodal sections of the fimbria-fornix with ibotenic acid lesions of the cells of the hippocampus (Ammon's horn and the dentate gyrus) on place learning in a swimming pool and on circadian activity. Rats in both ablation groups were impaired relative to control rats in learning a single place response but they did acquire the response as measured by swim latencies, errors, and by enhanced searching on probe trials. They were also more active than the control group on the test of activity. Nevertheless, the fimbria-fornix group was initially more impaired on learning and was more active than the hippocampal group. Analysis of the strategies used in learning indicated that the lesion groups were very similar to each other but different from the control group especially in that at asymptotic performance, rats in both lesion groups made rather tight loops as they swam toward the platform. This strategy likely contributed to the greater proportion of time they spent swimming in the correct quadrant on the subsequent probe trial. These findings confirm that rats with fimbria-fornix or hippocampal damage display impairments in place learning and are hyperactive but also show that there are lesion differences. The results are discussed with respect to the relative effectiveness of the lesions and the possibility that fibers in the fimbria-fornix may mediate some functions that are not attributable to the hippocampus. © 1995 Wiley-Liss, Inc.     

Amphetamine-induced c-fos mRNA expression is altered in rats with neonatal ventral hippocampal damage

To further characterize the mechanisms underlying enhanced dopamine-related behaviors expressed during adulthood in rats with neonatal excitotoxic ventral hippocampal (VH) damage, we studied the expression of c-fos mRNA in these rats after a single saline or amphetamine (AMPH) (10 mg/kg, i.p.) injection using in situ hybridization. The VH of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). At the age of 90 days, rats were challenged with AMPH or saline, and the expression of c-fos mRNA using an oligonucleotide probe was assessed 30, 90, and 180 min later. AMPH significantly increased c-fos mRNA expression in medial prefrontal cortex, piriform cortex, cingulate cortex, septal region, and dorsolateral and ventromedial striatum in control and lesioned rats. However, this response to AMPH was attenuated 30 min after AMPH injection in all of these regions in the lesioned as compared to the sham-operated rats. No significant changes were seen at other time points. These results indicate that the neonatal VH lesion alters time-dependent intracellular signal transduction mechanisms measured by AMPH-induced c-fos mRNA expression in cortical and subcortical brain regions. Changes in c-fos mRNA expression in this putative animal model of schizophrenia may have implications for long-term alterations in cellular pheno type because of altered regulation of certain target genes. (This article is a US Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.     

Selective importance of the rat anterior thalamic nuclei for configural learning involving distal spatial cues

To test potential parallels between hippocampal and anterior thalamic function, rats with anterior thalamic lesions were trained on a series of biconditional learning tasks. The anterior thalamic lesions did not disrupt learning two biconditional associations in operant chambers where a specific auditory stimulus (tone or click) had a differential outcome depending on whether it was paired with a particular visual context (spot or checkered wall‐paper) or a particular thermal context (warm or cool). Likewise, rats with anterior thalamic lesions successfully learnt a biconditional task when they were reinforced for digging in one of two distinct cups (containing either beads or shredded paper), depending on the particular appearance of the local context on which the cup was placed (one of two textured floors). In contrast, the same rats were severely impaired at learning the biconditional rule to select a specific cup when in a particular location within the test room. Place learning was then tested with a series of go/no‐go discriminations. Rats with anterior thalamic nuclei lesions could learn to discriminate between two locations when they were approached from a constant direction. They could not, however, use this acquired location information to solve a subsequent spatial biconditional task where those same places dictated the correct choice of digging cup. Anterior thalamic lesions produced a selective, but severe, biconditional learning deficit when the task incorporated distal spatial cues. This deficit mirrors that seen in rats with hippocampal lesions, so extending potential interdependencies between the two sites.     

Impaired spatial and non-spatial configural learning in patients with hippocampal pathology

The hippocampus has been proposed to play a critical role in memory through its unique ability to bind together the disparate elements of an experience. This hypothesis has been widely examined in rodents using a class of tasks known as "configural" or "non-linear", where outcomes are determined by specific combinations of elements, rather than any single element alone. On the basis of equivocal evidence that hippocampal lesions impair performance on non-spatial configural tasks, it has been proposed that the hippocampus may only be critical for spatial configural learning. Surprisingly few studies in humans have examined the role of the hippocampus in solving configural problems. In particular, no previous study has directly assessed the human hippocampal contribution to non-spatial and spatial configural learning, the focus of the current study. Our results show that patients with primary damage to the hippocampus bilaterally were similarly impaired at configural learning within both spatial and non-spatial domains. Our data also provide evidence that residual configural learning can occur in the presence of significant hippocampal dysfunction. Moreover, evidence obtained from a post-experimental debriefing session suggested that patients acquired declarative knowledge of the underlying task contingencies that corresponded to the best-fit strategy identified by our strategy analysis. In summary, our findings support the notion that the hippocampus plays an important role in both spatial and non-spatial configural learning, and provide insights into the role of the medial temporal lobe (MTL) more generally in incremental reinforcement-driven learning.     

Baclofen infused in rat hippocampal formation impairs spatial learning

Recent studies show that baclofen, a selective GABA_B agonist, impairs different kinds of learning. In the present study we investigated the effect of microinfused baclofen into the hippocampus of male Wistar rats, on the performance in the Morris water maze. Rats of 8–10 weeks of age were implanted with cannulae aimed bilaterally at the hippocampal formation. Baclofen (1 μl of 0.2 mM, 2.0 mM, and 20.0 mM) or sterilized saline was microinfused 1 h before each daily session (3 trials/session, 1 session/day) for 4 days. On the fifth day, the animals did not receive drug or saline injections and the retention of the location of the escape platform was tested in a 30 s free swim trial. Results from the free swim trial indicate that the doses of baclofen used during training affected the ability of the rats to swim to the target quadrant. Although no significant difference compared with the saline group was observed, the experimental rats showed a more generalized swim trajectory in the area of the target and both adjacent quadrants. Moreover, 1μl of 20.0 mM baclofen also impaired the acquisition. We suggest that baclofen has an impairing action on spatial learning, although more studies should be conducted to reach a more precise conclusion. Hippocampus 1998;8:109–113. © 1998 Wiley-Liss, Inc.     

The effects of ibotenic hippocampal lesions on discriminative fear conditioning to context in mice: impairment or facilitation depending on the associative value of a phasic explicit cue

To what extent the hippocampus is required for contextual conditioning remains a matter of debate. The present experiments examined the effects of ibotenate hippocampal lesions on discriminative fear conditioning to context in mice using measures of freezing in two conditioning paradigms. In both paradigms animals received foot shock as the unconditional stimulus (US) when placed in the (conditioning) context and no foot-shock when placed in the other (neutral) context. In both contexts, animals were presented with a tone as the conditioned stimulus (CS). In the conditioning context there was either no interval (delay condition) or a 30-s interval (trace condition) between tone CS end and shock US onset. These two paradigms were used because theory predicts that in the trace condition animals would learn more about contextual cues as predictors, or not, of shock US occurrence than in the delay condition. In agreement with this, we observed that sham-operated mice learned the context discrimination faster in the trace than in the delay condition. Lesions of the hippocampus significantly retarded, but did not prevent, the acquisition of the context discrimination in the trace condition. In contrast, lesions produced an opposite (facilitatory) effect in the delay condition, which was mainly observed during tone CS presentation. The data suggest that mice used two distinct competing strategies in solving this discrimination task: (i) a strategy relying on the processing of background contextual stimuli allowing direct establishment of context-US associations of different strengths, and (ii) a conditional cue (tone)-based strategy. Hence, hippocampal lesions may impair the use of the former strategy while exacerbating (unmasking) the use of the latter.     

Borna disease virus-induced hippocampal dentate gyrus damage is associated with spatial learning and memory deficits

In neonatally inoculated rats, Borna disease virus (BDV) leads to a persistent infection of the brain in the absence of an inflammatory response and is associated with neuroanatomic, developmental, physiologic, and behavioral abnormalities. One of the most dramatic sites of BDV-associated damage in the neonatal rat brain is the dentate gyrus, a neuroanatomic region believed to play a major role in spatial learning and memory. The absence of a generalized inflammatory response to neonatal BDV infection permits direct effects of viral damage to the dentate gyrus to be examined. In this report, neonatally BDV-infected rats at various stages of dentate gyrus degeneration were evaluated in the Morris water maze, a swimming test that assesses the rats' capacity to navigate by visual cues. Our data demonstrate progressive spatial learning and memory deficits in BDV-infected rats that coincided with a gradual decline in the estimated hippocampal dentate gyrus neuron density.     

Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats

Substantial information is available concerning the influence of global hippocampal lesions on spatial learning and memory, however the contributions of discrete subregions within the hippocampus to these functions is less well understood. The present investigation utilized kainic acid to bilaterally lesion specific areas of the rat hippocampus. These animals were subsequently tested on a spatial orientation task using a circular water maze, and on an associative/contextual task using passive avoidance conditioning. The results indicate that both the dorsal CA1 and the ventral CA3 subregions play important roles in learning. Specifically, CA1 lesions produced a deficit in the acquisition of the water maze task and a significant memory impairment on the passive avoidance task. CA3 lesions also caused learning deficits in the acquisition of the water maze task, and produced even greater impairments in performance on the passive avoidance task. We conclude that CA1 and CA3 hippocampal subregions each play significant roles in the overall integration of information concerning spatial and associative learning.     

Dorsal hippocampal kindling selectively impairs spatial learning/short-term memory.

Kindling with electrical stimulation of the dorsal hippocampus has been shown to disrupt spatial task performance in rats. The present study investigated the specificity of this effect in terms of the possible contribution of nonmnemonic effects, the presence of a more general mnemonic deficit, and the involvement of learning/short-term memory and/or long-term memory processes. Rats were fully kindled with stimulation of the dorsal hippocampus and subsequently tested for acquisition, 7-day retention, and 28-day retention of a hidden platform (HP) location in the Morris water maze and an object discrimination problem in a modified water maze. To control for nonmnemonic behavioral impairments, testing on both tasks was preceded by training on visible platform control tasks. Kindling impaired acquisition of the HP location but spared performance on all other aspects of testing, indicating a specific impairment of spatial learning/short-term memory. These results suggest that epileptogenesis induced by hippocampal stimulation is indeed associated with a selective disruption of the mechanisms mediating spatial learning/short-term memory.     

Neonatal ketamine exposure-induced hippocampal neuroapoptosis in the developing brain impairs adult spatial learning ability

Ketamine exposure can lead to selective neuroapoptosis in the developing brain.p66ShcA,the cellular adapter protein expressed selectively in immature neurons,is a known pro-apoptotic molecule that triggers neuroapoptosis when activated.Sprague-Dawley rats at postnatal day 7 were subcutaneously injected in the neck with ketamine 20 mg/kg,six times at 2-hour intervals.At 0,1,3,and 6 hours after final injection,western blot assay was used to detect the expression of cleaved caspase-3,p66ShcA,and phosphorylated p66ShcA.We found that the expression of activated p66ShcA and caspase-3 increased after ketamine exposure and peaked at 3 hours.The same procedure was performed on a different group of rats.At the age of 4 weeks,spatial learning and memory abilities were tested with the Morris water maze.Latency to find the hidden platform for these rats was longer than it was for control rats,although the residence time in the target quadrant was similar.These findings indicate that ketamine exposure resulted in p66ShcA being activated in the course of an apoptotic cascade during the neonatal period.This may have contributed to the deficit in spatial learning and memory that persisted into adulthood.The experimental protocol was approved by the Institutional Animal Care and Use Committee at the University of Texas at Arlington,USA (approval No.A13.008) on January 22,2013.     

Impairments in visual discrimination learning and recognition memory produced by neurotoxic lesions of rhinal cortex in rhesus monkeys

Much work on the cognitive functions of the primate rhinal (i.e. entorhinal plus perirhinal) cortex has been based on aspiration lesions of this structure, which might disrupt fibres passing nearby and through the rhinal cortex in addition to removing the cell bodies of the rhinal cortex itself. To determine whether damage limited to the cell bodies of the rhinal cortex is sufficient to impair visual learning and memory, four rhesus monkeys (Macaca mulatta) were preoperatively trained on a battery of visual learning and memory tasks, including single-pair discrimination learning for primary reinforcement, single-pair discrimination reversals, concurrent discrimination learning and reversal, and delayed matching-to-sample. Following acquisition of these tasks and a preoperative performance test, ibotenic acid was injected bilaterally into the rhinal cortex, and the monkeys were retested. Consistent with the results of studies using aspiration lesions, the monkeys were impaired on single-pair discrimination learning as well as recognition memory performance postoperatively, although reliable reversal learning impairments were not observed. The magnitude of postoperative impairment in discrimination learning was not correlated with the magnitude of postoperative impairment in recognition memory, suggesting a possible dissociation between these functions within the rhinal cortex. The correspondence of behavioural deficits following aspiration and neurotoxic lesions of the rhinal cortex validates the attribution of various cognitive functions to this structure, based on the results of studies with aspiration lesions.     

Music intervention improves spatial learning and memory and alters serum proteomics profiling in rats

Music has a long history of healing or mitigating physical and mental illness in the clinical setting. We aimed to test changes in behavioral cognition and serum proteomics in rats undergoing music intervention (MI). The Morris water maze (MWM) was used to evaluate spatial learning and memory in rats. Serum protein expression profiling was examined using magnetic bead‐based matrix‐assisted laser desorption/ionization time‐of‐flight (MALDI‐TOF‐MS). MI improved spatial learning and memory in both male and female rats. Peak 1708.61 (m/z values) was significantly increased in MI females vs. female controls. Peak 3925.09 (m/z values) was significantly reduced in MI males versus male controls. The two differential serum peptide peaks (m/z values: 1708.61, 3925.09) were further sequence identified as regions of proteins Desmin and Acsm1. Western blot and immunofluorescence testing of Desmin expression showed consistent results on proteomics analysis. MI plays an important role in behavioral cognition and protein expression in rats. This study provides a foundation in proteomics that suggests that MI might improve spatial learning and memory ability.     

Selective effects of hippocampal and frontal cortex lesions on a spatial learning problem in two inbred strains of mice

The effects of dorsal hippocampal and medial frontal lesions of the cortex on a spatial learning problem were studied in two inbred strains of mice (C57BL/6 and DBA/2) which present both neuroanatomical differences of such structures and various patterns of spontaneous exploration. The results showed that hippocampal lesions produced impairments of the learning performance in each strain of mouse, but the temporal distribution of the errors over the experiment was found to be strain dependent. On the other hand, medial frontal cortex lesions selectively affected the learning performances since the acquisition process of only the C57BL/6 lesioned mice differed significantly from the other groups. The effects of these lesions are discussed in terms of genetically associated differences of brain structures and functions. It is suggested that investigations of such differences can provide an experimental model for the study of functional and structural recovery.     

Bilateral vestibular deafferentation impairs performance in a spatial forced alternation task in rats

Converging behavioral, electrophysiological, and neurochemical data suggest that lesions to the peripheral vestibular system result in impairment of the hippocampus. Nonetheless, relatively few studies have examined the hippocampus or behavior related to it, over a long period of time following the lesion, to determine if any recovery takes place. Here we used the spatial forced alternation task in a T maze, which is sensitive to the integrity of the hippocampus, to evaluate learning and memory in rats at 3 weeks, 3 months, and 5 months following bilateral vestibular deafferentation (BVD) or sham surgery. BVD rats made significantly fewer correct choices at all time points when compared with the sham controls. However, the percentage correct choice for BVD rats was at chance level at 3 weeks postop, and was significantly above chance at 5 months postop. These results add to the evidence that BVD causes a long-term impairment of hippocampal function and spatial learning and memory, but suggest that some recovery of function might take place over the long term.