The effects of lesions to the rat hippocampus or rhinal cortex on olfactory and spatial memory: retrograde and anterograde findings

The role of the hippocampal system in retrograde and anterograde amnesia was investigated by using a novel olfactory-guided paradigm and a traditional test of spatial learning. In the retrograde study, rats were trained on a sequence of two-choice olfactory discriminations in the weeks prior to receiving neurotoxic lesions of the hippocampus or aspiration lesions of the perirhinal-entorhinal cortex. Memory tests for preoperatively learned discriminations revealed no statistical impairment for subjects with damage to the hippocampus on a problem learned remote in time from surgery (i.e., 4 weeks +) or on the two recently learned discriminations (i.e., 1–3 weeks prior to surgery). The performance of subjects with perirhinal-entorhinal damage provided an important comparison for subjects with specific hippocampal lesions. Despite showing intact memory for the remotely learned problem, perirhinalentorhinal damage resulted in numerically (although not significantly) weaker performance on postoperative tests of retention for the discriminations learned in the 3 weeks prior to surgery. In the anterograde portion of the study, long-term memory for newly acquired discriminations was spared in subjects with damage to the hippocampus, whereas subjects in the perirhinal-entorhinal lesion group again showed the weakest memory performance on these tests of 5-day retention. Postoperative water maze learning was uniformly impaired in subjects with damage to the hippocampus and perirhinalentorhinal cortex, thus confirming the effect of these lesions and supporting the involvement of these brain areas in spatial processes. These findings further dissociate the specific involvement of the hippocampus in tasks of a spatial-relational nature versus nonrelational tasks, such as discrimination learning and recognition memory (e.g., Duva et al., 1997; Eichenbaum, 1997; Eichenbaum, Schoenbaum, Young, & Bunsey, 1996). Moreover, the results suggest that damage to the hippocampus itself does not contribute to retrograde or anterograde memory impairments for all types of information, whereas the data suggest a more important role for the perirhinal-entorhinal cortex in recognition memory, irrespective of modality.     

Hypothermia-induced anterograde amnesia: is memory loss attributable to impaired acquisition?

The present investigation examined whether the poor test performance observed in studies of anterograde amnesia reflects a memory deficit or is a by-product of weaker initial learning resulting from impaired sensory, motivational, or associative processes. Two experiments were performed which utilized latent extinction (Experiment 1) and delay of punishment (Experiment 2) manipulations in order to assess the nature of original learning in rats trained under either hypothermic (29 degrees C) or normothermic conditions. Results from both experiments provided evidence that hypothermia treatment administered prior to training had relatively little influence on the animal's ability to acquire a passive avoidance response. Therefore, the rapid forgetting observed in hypothermia-induced anterograde amnesia is most likely due to memory deficits rather than an artifact of poorer acquisition.     

Growth points in research on memory and hippocampus.

We present an overview of two of our on-going projects relating processes in the hippocampus to memory. We are trying to understand why retrograde amnesia occurs after damage to the hippocampus. Our experiments establish the generality of several new retrograde amnesia phenomena that are at odds with the consensus view of the role of the hippocampus in memory. We show in many memory tasks that complete damage to the hippocampus produces retrograde amnesia that is equivalent for recent and remote memories. Retrograde amnesia affects a much wider range of memory tasks than anterograde amnesia. Normal hippocampal processes can interfere with retention of a long-term memory stored outside the hippocampus. We conclude that the hippocampus competes with nonhippocampal systems during memory encoding and retrieval. Finally, we outline a project to understand and manipulate adult hippocampal neurogenesis in order to repair damaged hippocampal circuitry to recover lost cognitive functions.     

Functional amnesia: clinical description and neuropsychological profile of 10 cases

We carried out the first neuropsychological study of a series of patients with functional amnesia. We evaluated 10 patients, first with a neurological examination and then with three tests of anterograde amnesia and four tests of retrograde amnesia. Excluding one patient who later admitted to malingering, all patients had a significant premorbid psychiatric history and one or more possible precipitating factors for their amnesia. Eight of the 10 patients still had persistent retrograde amnesia at our last contact with them (median = 14 mo after the onset of amnesia). On tests of anterograde amnesia, the patients performed normally as a group, though some patients scored poorly on tests of verbal memory. On tests of retrograde amnesia, all patients had difficulty re-collecting well-formed autobiographical memories of specific events from their past. In contrast, patients performed as well as controls at distinguishing the names of cities from fictitious city names. On remote memory tests for past public events and famous faces, different patients exhibited different but internally consistent patterns of impaired and spared performance. The variability in the clinical and neuropsychological findings among our patients may be understood by supposing that memory performance is poor in proportion to how directly a test appears to assess a patient's common sense concept of memory. The presentation of patients with functional amnesia is as variable as humankind's concept of what memory is and how it works.     

Retrograde amnesia and memory reactivation in rats with ibotenate lesions to the hippocampus or subiculum

The retrograde effects of hippocampal lesions on spatial memory were studied. Rats were given a series of 48 place-navigation trials in an open-field water-maze followed, either 3 days or 14 weeks later, by ibotenic acid lesions of the hippocampus (HPC) or subiculum (SUB), or by sham-surgery (SHAM). Two weeks after surgery they were given a retention test without a hidden escape platform. There was a significant decline in performance with time in the SHAM group, but with the 14-week SHAM group performing significantly better than chance levels, whereas both lesioned groups performed at chance at both retention intervals. All rats were then retrained for 24 trials. SHAM rats escaped rapidly within 2 trials, suggesting a reactivation of memory rather than relearning. The HPC groups were severely impaired during retraining, with a developing trend towards better performance in the 3-day group. After 24 trials of training with the escape platform placed in the opposite quadrant of the pool, this new location was learned successfully by SHAM and SUB rats, but not by HPC rats. These results indicate that selective hippocampal formation lesions can cause deficits in retrieval but do not reveal a time-dependent gradient of memory consolidation.     

Acquisition and extended retention of a conditioned taste aversion in preweanling rats

The time course of memory decay for infant rats may shed light on the processes responsible for infantile amnesia. A taste aversion conditioning procedure appropriate for both neonatal and adult rats was employed in four experiments to investigate the ontogeny of extended retention. In Experiment 1, rats trained at 1, 10, 20, or 60 days of age were tested for retention of the taste aversion 25 days later. At testing, only those rats conditioned when 20 or 60 days old demonstrated significant taste aversions. Experiments 2 and 3 established that rats 14-15 days old and older were able to retain significant taste aversions following a 25-day retention interval. Younger rats did, however, acquire and retain the aversion for several days and showed a gradual retention loss over progressively longer retention intervals (Experiment 4). These findings suggest that preweanling rats demonstrate initial consolidation, storage, and retrieval of conditioned taste aversions. It is only after this initial period that retention deficits become evident.     

Object recognition memory and the rodent hippocampus

In rodents, the novel object recognition task (NOR) has become a benchmark task for assessing recognition memory. Yet, despite its widespread use, a consensus has not developed about which brain structures are important for task performance. We assessed both the anterograde and retrograde effects of hippocampal lesions on performance in the NOR task. Rats received 12 5-min exposures to two identical objects and then received either bilateral lesions of the hippocampus or sham surgery 1 d, 4 wk, or 8 wk after the final exposure. On a retention test 2 wk after surgery, the 1-d and 4-wk hippocampal lesion groups exhibited impaired object recognition memory. In contrast, the 8-wk hippocampal lesion group performed similarly to controls, and both groups exhibited a preference for the novel object. These same rats were then given four postoperative tests using unique object pairs and a 3-h delay between the exposure phase and the test phase. Hippocampal lesions produced moderate and reliable memory impairment. The results suggest that the hippocampus is important for object recognition memory.Recognition memory refers to the ability to judge a previously encountered item as familiar and depends on the integrity of the medial temporal lobe (Squire et al. 2007). Tasks that assess recognition memory (and object recognition memory in particular) have become increasingly useful tools for basic and preclinical research investigating the neural basis of memory (Winters et al. 2008). Perhaps the best known of these tasks is the novel object recognition task (NOR) (also known as the visual paired-comparison task in studies with humans and monkeys).Studies of the NOR task in humans with hippocampal damage (McKee and Squire 1993; Pascalis et al. 2004) and in monkeys with selective damage to the hippocampus (Pascalis and Bachevalier 1999; Zola et al. 2000; Nemanic et al. 2004) have resulted in clear and consistent findings. Damage limited to the hippocampus is sufficient to produce impaired recognition memory (Squire et al. 2007, Box 1). In rats and mice, the NOR task has become particularly popular and is currently a benchmark task for assessing recognition memory. Yet despite its widespread use in rodents, the findings are rather mixed. For example, in the rat, although there is agreement that the perirhinal cortex is critically important for normal NOR performance, there is less agreement about the hippocampus (for review, see Winters et al. 2008). Although some of the discrepancies between studies may be attributed to differences in lesion size and in the length of the retention delay (Broadbent et al. 2004), these factors cannot account for all the findings (Squire et al. 2007).Whereas most studies have investigated the effects of hippocampal lesions on postoperative NOR performance, there is also interest in the effects of hippocampal lesions on memory for previously encountered objects. For a number of tasks, hippocampal lesions produce temporally graded retrograde amnesia, such that memory acquired recently is impaired and memory acquired more remotely is spared (for review, see Squire et al. 2004; Frankland and Bontempi 2005). In the case of the single study of retrograde memory that has involved the NOR task, recognition memory was impaired when a 5-wk interval intervened between training and hippocampal surgery (Gaskin et al. 2003). It remains possible that memory might be spared if a longer delay was imposed between training and surgery.The aim of the present study was to assess both the anterograde and retrograde effects of hippocampal lesions on recognition memory using the NOR task. To thoroughly assess the effects of hippocampal lesions we used (1) large groups of animals, (2) multiple tests of NOR memory, (3) a scoring method that allowed object preference to be determined on a second-by-second basis during the recognition tests, and (4) a novel training protocol that permitted the evaluation of recognition memory even after a retention interval as long as 10 wk.     

Studies on retrograde and anterograde amnesia of olfactory memory after denervation of the hippocampus by entorhinal cortex lesions

The effect of hippocampal denervation on olfactory memory in rats was tested after interrupting the lateral olfactory tract projections at the level of the entorhinal cortex. When lesioned animals were trained to learn new odors, they showed no evidence of retention 3 h after acquisition. These results confirm earlier data on rapid forgetting in rats after hippocampal deafferentation and are in parallel to the anterograde amnesia typically found in humans with hippocampal damage. On the other hand, preoperatively learned information was minimally impaired after hippocampal deafferentation even if it was acquired within less than 1 h before the lesion. This finding differs from reports on humans as well as monkeys with hippocampal damage where memories formed during a critical time span of months or even years before the lesion are found to be impaired. This may suggest that the consolidation process in humans and rodents has different time scales or that the roles of the human and the rat hippocampal structure in memory formation are somewhat different.     

逆行性遗忘、额叶与远期记忆的组织

通过对一例严重记忆障碍合并额叶损伤病人的逆行性遗忘的分析,对远期记忆的组织特点进行了探讨。被试的额叶功能受损较为明显。除顺行性遗忘外,患者的逆行性遗忘也较为严重。对病人进行的逆行性遗忘检测包括：著名人物测验、著名事件、一般知识测验和自传性记忆测验等。被试对著名人物、著名事件的回忆和再认成绩、以及有关个人的情节和语义记忆成绩均较低,但没有典型的随时间下降的趋势,而是呈平直斜率;患者儿童期的自传性记忆和公众事件记忆也受损。这两个特点均与内侧颞叶一间脑系统损伤的特点不同,提示额叶参与了远期记忆的提取等过程。     

Footshock/ECS induced state dependent learning in rats parametric evaluation of ECS intensity and time of testing

Rats were given a footshock followed by ECS of either low or high intensity. Controls received neither footshock nor ECS. Twenty-four hours later all subjects acquired a simple position habit in a water maze. Then, independent subgroups were reversal trained at 24-hr intervals up to 144 hr post-treatment. Compared to controls, rats given footshock, and ECS showed memory for training at the initial test followed by amnesia, memory recovery, and finally amnesia at subsequent tests. The alternating pattern of retention appeared to be a function of ECS intensity. In a second experiment, rats were first maze trained then given footshock and ECS 24 hr later. Like the results of the first experiment, ensuing tests indicated an alternating retention function in experimental animals again influenced by ECS intensity. Several possible explanations of these results were discussed, and it was suggested that the altering retention function observed in the experimental animals resulted from a footshock and ECS induced state dependency effect that subsided and recurred spontaneously up to 144 hr post-treatment.     

Reconsolidation after remembering an odor-reward association requires NMDA receptors

A rapidly learned odor discrimination task based on spontaneous foraging behavior of the rat was used to evaluate the role of N-methyl-D-aspartate (NMDA) receptors (NMDARs) in ongoing memory consolidation. Rats were trained in a single session to discriminate among three odors, one of which was associated with palatable food reward. Previous experiments showed that the NMDAR antagonist DL-APV induced amnesia for this task when injected immediately after training. In the present study, memory was reactivated 24 h after training by exposure to the rewarded odor within the experimental context after which rats received an intracerebroventricular injection of APV. Combined reactivation-drug treatment induced profound amnesia when tested 48 h later. Animals receiving drug alone, in absence of reactivation, showed perfect retention. It is concluded that NMDARs support a consolidation process taking place after memory reactivation.     

Strength of scopolamine-induced amnesia as a function of time between training and testing

Variations in the strength of scopolamine-induced amnesia as a function of age of the habit were studied in Swiss Webster mice. Animals were trained in an active avoidance task to a criterion of 9/10 avoidances and immediately following training injected with scopolamine hydrochloride (1.0 mg/kg) or saline. Retention of the avoidance learning was evaluated by testing different groups of animals 1, 3, 7, 10, 14, and 28 days following training. The retention test consisted of five trials in which the CS but not the UCS was presented. Results indicated that saline-treated mice exhibited near-perfect retention up to 14 days post-training with forgetting beginning to be apparent at 28 days. Scopolamine treatment produced strong amnesia in animals tested 1 and 3 days post-training but normal retention in animals tested 7 and 10 days after learning. The amnesia abruptly reappeared at 14 days after which time it remained stable. The marked similarity of the scopolamine retention curve to changes in the strength of memory of discrimination learning in undertrained rats reported by Deutsch suggested that scopolamine resulted in the storage of a weak memory of the avoidance response. To explore this idea further we trained mice to a criterion (4/5) which would result in a weak avoidance response and tested different groups 1, 3, 10, 14, and 28 days following learning. Results showed that strength of the memory of avoidance learning increased up to 10 days and then decreased abruptly at 14 days thus replicating the general shape of the retention curve produced by injecting scopolamine following strong training. These data suggest that scopolamine disrupts processes essential for the formation of durable memories.     

Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.     

Retrograde facilitation under midazolam: The role of general and specific interference

In a double-blind, placebo-controlled experiment that usedmidazolam, a benzodiazepine that creates temporary amnesia, we compared acquisition and retention of paired associates of different types. Some word pairs were studied before the injection of saline or midazolam, and two lists of word pairs were studied after the injection. Critical comparisons involved retention of pairs that were practiced on all three lists, pairs studied on only one list, and pairs that involved recombining cue and response terms from one list to the next, as a function of drug condition. Previous research with benzodiazepines had found retrograde facilitation for material acquired prior to injection, compared with the control condition. One explanation for this facilitation is that the anterograde amnesia produced by the benzodiazepine frees up the hippocampus to better consolidate previously learned material (Wixted, 2004, 2005). We accounted for a rich data set using a simple computational model that incorporated interference effects (cue overload) at retrieval for both general (experimental context) interference and specific (stimulus term) interference without the need to postulate a role for consolidation. The computational model as an Excel spreadsheet may be downloaded from www.psychonomic.org/archive.     

Short-term and long-term memory deficit following intracarotid Amytal injection: Further support for the memory consolidation hypothesis

To test the three main hypotheses of the human amnesic syndrome (encoding, consolidation, retrieval), we designed an original protocol for memory assessment under Amytal that included, in addition to a retrograde memory measure, both short-term and long-term anterograde memory measures. Twenty epileptic patients with SEEG-confirmed unilateral temporal lobe foci were given right and left injections on successive days. Only the long-term memory measure for material presented under Amytal was significantly related to the presence of a temporal contralateral epileptogenic focus, even if it was assessed when the hemisphere had completely recovered from the effect of Amytal. Short-term memory deficits were observed equally often after injections ipsilateral and contralateral to the epileptogenic focus, and no retrograde amnesia was observed. These results are consistent with the consolidation hypothesis.     

Making context memories independent of the hippocampus

We present evidence that certain learning parameters can make a memory, even a very recent one, become independent of the hippocampus. We confirm earlier findings that damage to the hippocampus causes severe retrograde amnesia for context memories, but we show that repeated learning sessions create a context memory that is not vulnerable to the damage. The findings demonstrate that memories normally dependent on the hippocampus are incrementally strengthened in other memory networks with additional learning. The latter provides a new account for patterns of hippocampal retrograde amnesia and how memories may become independent of the hippocampus.Contextual fear conditioning can be supported by two neural systems, one that contains the hippocampus (HPC), and one that does not. Evidence for this assertion comes from studies in which the HPC, in rats, is damaged either before or after the contextual fear conditioning. Extensive damage to the HPC before conditioning has little effect on contextual fear conditioning (Maren et al. 1997; Frankland et al. 1998; Wiltgen et al. 2006). This result can only mean that there is a non-HPC memory system that can support fear of context. In contrast, there is unequivocal evidence that moderate to extensive damage to the HPC soon after learning severely impairs the ability of the conditioning context to evoke fear, suggesting that the HPC normally makes a major contribution to this type of memory (Kim and Fanselow 1992; Maren et al. 1997; Frankland et al. 1998; Anagnostaras et al. 1999; Debiec et al. 2002; Lehmann et al. 2007b; Sutherland et al. 2008; Wang et al. 2009).The dissociable effects of pre- and post-training HPC damage on contextual fear conditioning have been interpreted as suggesting that: (1) When the HPC is intact during learning it interferes with other systems and prevents them from acquiring an independent contextual fear conditioning memory, and (2) when the HPC is absent, these other systems are released from this interference and are able to rapidly acquire an independent memory (Maren et al. 1997; Frankland et al. 1998; Fanselow and Poulos 2004; Driscoll et al. 2005; Lehmann et al. 2006; Sutherland et al. 2006). The latter interference from the HPC on the other memory systems has been termed overshadowing. Supplemental Figure S1 depicts data from our laboratory demonstrating the overshadowing phenomenon and the dissociable effects of HPC damage induced before and after contextual fear conditioning.Very little, however, is known about the parameters determining the extent to which the HPC system interferes with the non-HPC system for control over contextual fear. The purpose of the current study is to provide some insight into this issue. Typically, contextual fear conditioning in rats is conducted in a single conditioning session in which a configuration of static background cues is paired with several footshocks. When returned to the conditioning context, rats display several species-specific defensive responses including freezing (i.e., absence of movement except for breathing). Several theorists have proposed that non-HPC systems are more likely to be recruited when there are multiple experiences with similar events, which, in turn, would mitigate the necessity of the HPC for memory expression (O''Keefe and Nadel 1978; Sherry and Schacter 1987; McClelland et al. 1995; O''Reilly and Rudy 2001; White and McDonald 2002). Accordingly, we hypothesized that repeated contextual fear conditioning sessions separated by hours and days would overcome the HPC interference or overshadowing effect. In other words, with repeated learning sessions, enough information would be incrementally captured by the non-HPC system to support a contextual fear memory that would survive complete damage to the HPC.Adult male rats received 11 fear-conditioning sessions across 6 d. In each session, they were placed in a context and received mild footshocks (Shock Context). Concurrently, the rats were exposed 10 times to another context in which they never received shock (No-Shock Context). The No-Shock Context served as a control condition to measure whether the rats simply showed generalized fear or could show context-specific memory. Within 72 h following the last conditioning session, rats either received sham surgery or complete lesions of the HPC using the neurotoxin N-methyl-d-aspartic acid (NMDA) (Lehmann et al. 2007a). Rats were then tested for retention in both the Shock and No-Shock Contexts in a counterbalanced order. In addition, in a single learning episode, another group of rats received a matching number of shocks (i.e., 12 shocks) and context exposure (i.e., 17 min), and then received surgery 7–10 d after conditioning. The latter interval is identical to the interval between the initial conditioning session and surgery in the repeated learning condition. Figure 1 illustrates and describes the design of the experiments.Open in a separate windowFigure 1.Illustration of the experimental design used in (A) the single conditioning session and (B) repeated conditioning session experiments. In A the rats were initially placed in the conditioning chamber for 17 min and received the first of 12 footshocks (1 mA/2 sec) at the 300-sec mark, and then one every following 58 sec after shock offset. Seven to 10 d later, the rats either received sham or HPC damage (Sx). Approximately 10 d after, the rats were returned to the chamber to assess freezing over a 5-min retention test. In B the rats were placed initially in the conditioning chamber for 1 min and received a shock at the 45-sec mark (Shock Context). Approximately 45 min later, the rats were placed in a different chamber for 1 min and did not receive shock (No-Shock Context). The procedure was repeated twice daily for five consecutive days, and the Shock and No-Shock chamber order was counterbalanced according to the principles of a Latin Square design. The rats then received sham or HPC damage 1–3 d later. The rats'' retention was assessed in both contexts ∼10 d after surgery in both the Shock and No-Shock Context in a counterbalanced order with a 24-h span between tests. Importantly, the number of shocks, context exposure time, and interval between initial learning and surgery were matched between both experiments.When all shocks were delivered in a single session, HPC damage caused profound retrograde amnesia. As illustrated in Figure 2A, the HPC rats displayed significantly less freezing than control rats during the retention test (t₍₈₎ = 23.895, P < 0.001). This result replicates all previous studies in which the HPC was damaged days after a single contextual fear conditioning training session (Kim and Fanselow 1992; Maren et al. 1997; Frankland et al. 1998; Anagnostaras et al. 1999; Debiec et al. 2002; Lehmann et al. 2007b; Sutherland et al. 2008).Open in a separate windowFigure 2.Mean (± SEM) percent time freezing by Sham and HPC rats during the retention test of the (A) single conditioning (12 shocks) experiment and (B) repeated conditioning session experiment. In A the HPC rats showed significantly less freezing (P < 0.001) than the Sham rats, suggesting that the damage caused profound retrograde amnesia for contextual fear conditioning learned in a single session 7–10 d before surgery. In B the performance of the HPC rats did not significantly differ from the Sham rats, and they exhibited significantly more freezing in the Shock Context than the No-Shock Context (P < 0.001). Consequently, repeated conditioning sessions prevented the retrograde amnesic effects normally observed in contextual fear conditioning following HPC damage, suggesting that other neural networks were now able to support the memory.In striking contrast, memory for contextual fear conditioning was spared when the HPC was damaged after repeated conditioning sessions. Figure 2B shows the percent time spent freezing during the retention test in the Shock and No-Shock Contexts. An ANOVA with between-group factor (Lesion: Sham and HPC) and within-group factor (Context: Shock and No-Shock) revealed a significant main effect of Context (F_(1,14) = 84.731, P < 0.001), indicating that the rats displayed higher levels of freezing in the Shock than in the No-Shock Context. The effect of Lesion (F_(1,14) = 4.280, P = 0.058) was not significant, nor was the Lesion × Context interaction (F_(1,14) = 0.877, P = 0.369), suggesting that extensive HPC damage did not impair memory. The tendency for an effect of Lesion is due to the HPC rats freezing less than the Sham rats in the No-Shock Context (P = 0.06) rather than freezing less in the Shock Context (P = 0.457).The repeated conditioning sessions clearly enabled a contextual fear representation to be established in non-HPC memory systems. However, it is surprising that the HPC damage did not impair the ability to discriminate between the Shock and No-Shock Context, because evidence suggests that context discrimination is dependent on the HPC (see Moscovitch et al. 2006). Indeed, studies of rats with HPC damage induced before learning have shown that contextual fear conditioning is acquired quickly by non-HPC systems in a single session, but the ability to discriminate between the training context and a new context is lost (Frankland et al. 1998; Antoniadis and McDonald 2000; Winocur et al. 2007). Hence, it is significant in the present study that the HPC damage did not impair context discrimination abilities in the rats that received repeated learning episodes. The latter appear to have established a context representation, outside of the HPC, that was not bereft of details. Yet, one should consider that the rats in the repeated sessions experiment received experience in both the Shock and No-Shock Contexts prior to surgery, and this discrimination training procedure may have established two different non-HPC representations. It remains possible that HPC damage would impair the ability to discriminate the Shock Context from a new context, which is what is found in anterograde amnesia studies (Frankland et al. 1998; Antoniadis and McDonald 2000; Winocur et al. 2007). To address this possibility, a new experiment examined whether HPC-damaged rats could discriminate the Shock Context from a Novel Context. Rats were trained with the same repeated learning protocol as described earlier, with the exception that the rats were never placed in the No-Shock Context prior to surgery. One to 3 d following learning, the rats either received Sham or complete HPC damage. They were then tested for retention in the Shock and the Novel (i.e., No-Shock) Context in a counterbalanced order. Figure 3 shows the percent time spent freezing during the retention test in the Shock and Novel Contexts. An ANOVA with between-group factor (Lesion: Sham and HPC) and within-group factor (Context: Shock and Novel) revealed that the rats froze significantly more in the Shock than the Novel Context (F_(1,10) = 57.393, P < 0.001). However, no significant difference was found between the HPC and Sham groups (F_(1,10) = 0.597, P = 0.458) and the Lesion × Context interaction did not reach significance (F_(1,10) = 0.123, P = 0.733). Thus, as in the previous repeated sessions experiment, the HPC damage did not cause retrograde amnesia for contextual fear conditioning and, more importantly, the HPC damage did not impair the ability to discriminate between the original context and new context.Open in a separate windowFigure 3.Mean (± SEM) percent time freezing by Sham and HPC rats in the Shock and Novel Contexts during the retention tests of the discrimination experiment. The rats exhibited significantly more freezing in the Shock than the Novel Context (P < 0.001), and the HPC rats did not significantly differ from the Sham rats, suggesting that the HPC-damaged rats remembered the specific meaning of the Shock Context as well as control rats. Hence, repeated conditioning sessions established a context-rich representation in non-HPC systems, which supports successful context discriminations.The absence of amnesia for contextual fear conditioning in the current study is not due to insufficient damage to the HPC. We calculated (see Lehmann et al. 2007b) that an average of 83% of the HPC was damaged across rats (smallest: 64%; largest: 90%) in the repeated learning experiments (see Supplemental material for more histological details). The amount of HPC damage is substantially more than that found in most studies reporting impairments for contextual fear conditioning following HPC damage (Kim and Fanselow 1992; Maren et al. 1997; Frankland et al. 1998; Anagnostaras et al. 1999; Debiec et al. 2002) and more than for the single-session experiment (average 76%) in which we currently report amnesia. Therefore, the amount of HPC damage inflicted in the rats in this study is certainly sufficient to disrupt HPC-dependent memories.Like others (Kim and Fanselow 1992; Maren et al. 1997; Frankland et al. 1998; Anagnostaras et al. 1999; Debiec et al. 2002; Lehmann et al. 2007b; Sutherland et al. 2008), we found that damage to the HPC after a single contextual fear-conditioning session involving multiple shocks produces profound retrograde amnesia for contextual fear conditioning. However, in two separate experiments, distributing shock across multiple conditioning sessions prevented this amnesia. In one case, the rats experienced Context–Shock pairings in one context and no shock in another context. Following this training, rats with damage to the HPC did not differ from control rats in the absolute amount of freezing in the training context nor in their ability to discriminate between the two contexts. In the second case, rats only received the multiple Context–Shock sessions. Rats with damage to the HPC could not be distinguished from control rats during the test in the training context or in their responses to a novel context. These findings provide new support for the general idea that contextual fear conditioning can be supported by both HPC and non-HPC systems. This conclusion is supported by (1) the finding that damage to the HPC following a single conditioning session virtually eliminates freezing during the test, implying the importance of the HPC system, and (2) that following multiple conditioning sessions, damage to the HPC has no effect on either contextual fear displayed in the training context or their ability to discriminate the training context from other contexts, suggesting the existence of non-HPC systems that can support contextual fear. The findings also reveal that the overshadowing or interference by the HPC over the non-HPC memory systems for control over contextual fear is not absolute. Following a single conditioning session, removal of the HPC produced a devastating retrograde amnesia, illustrating substantial overshadowing. However, distributing conditioning across several sessions completely attenuated the effects of damage to the HPC, revealing that non-HPC systems can support contextual fear conditioning despite the HPC, and revealed the importance of multiple sessions for this to occur.The overshadowing by the HPC is based on the familiar idea in associative learning at the behavioral level, where through a competitive process some of the cues that redundantly predict a reinforcer acquire the ability to generate strong conditioned responding, while other equally predictive, but less salient cues do not (Stout et al. 2003). Conditioning to the less potent cues proceeds more effectively if the more potent competitors are absent. Following the same principle, if the HPC representation is active, then learning in the non-HPC systems suffers strong interference. In contrast, in the absence of the HPC representation, learning in non-HPC systems is released from this interfering effect of the HPC. Thus, the learning rate in non-HPC networks is potently lowered by the activity of the HPC. However, with repeated learning, other structures, which are overshadowed by the HPC, may cumulatively build a representation that achieves HPC independence. The current findings clearly support this hypothesis, whereby repeated learning episodes incrementally established a contextual fear-conditioning representation outside of the HPC that mitigated the usual retrograde amnesic effects of HPC damage.One important question is where does the HPC interference occur? Biedenkapp and Rudy (2009) recently reported that the HPC competes with the basolateral region of the amygdala during fear conditioning. Previously, Guarraci et al. (1999) found that the amount of conditioned fear produced by training could be increased if the dopamine D1 receptor agonist {"type":"entrez-protein","attrs":{"text":"SKF82958","term_id":"1156217255","term_text":"SKF82958"}}SKF82958 was injected into the basolateral region. Biedenkapp and Rudy (2009) reasoned that if this is the area where the HPC interferes with non-HPC systems for the association with shock, then a local infusion of {"type":"entrez-protein","attrs":{"text":"SKF82958","term_id":"1156217255","term_text":"SKF82958"}}SKF82958 before a single session of contextual fear conditioning should attenuate the interference and allow the non-HPC system to gain more control over contextual fear. Their data supported this hypothesis, which leads to the possibility that with multiple conditioning sessions, the non-HPC system gradually gains association with these fear-supporting neurons in this region of the brain.Patients with bilateral damage to the HPC often exhibit temporally graded retrograde amnesia, such that recently acquired memories are lost, whereas remote memories, especially those acquired years before the damage, are more likely to be spared (Scoville and Milner 1957; Rempel-Clower et al. 1996). This pattern of amnesia is taken as evidence for temporally based systems consolidation, whereby over time the essential support for memories is “switched” from dependence on the HPC to neocortical networks (McClelland et al. 1995; Squire and Alvarez 1995; Anagnostaras et al. 2001; Meeter and Murre 2004; Squire et al. 2004; Wiltgen et al. 2004; Frankland and Bontempi 2005). Our research, however, points to another process for becoming independent of the HPC, a change in the strength of the representation in non-HPC systems during learning rather than a consolidation process linked to the passage of time since the learning episode. A study of a former London taxi driver with bilateral HPC damage alludes to this possibility (Maguire et al. 2006). This amnesic patient showed greater retrograde amnesia for roads that he used less commonly than the major arteries that he used regularly. Hence, greater exposure to the major arteries established memories in non-HPC systems, whereas roads with less exposure remained dependent on the HPC regardless of the age of the memory. Our findings add support to this view, because studies examining the effects of complete HPC damage after a single conditioning episode suggest that the HPC is permanently involved in contextual fear conditioning (Lehmann et al. 2007b; Sutherland et al. 2008); yet, with repeated learning episodes we clearly demonstrated that the memory rapidly becomes independent of the HPC. The latter is important because the process for memories becoming independent of the HPC need not require systems consolidation.In conclusion, this is the first example of intact contextual fear memories following complete HPC damage induced soon after learning. Importantly, repetition of the learning episode underlies the change in memory from HPC dependent to HPC independent. We argue that each learning episode incrementally establishes a representation in non-HPC memory systems—a representation that ultimately becomes sufficiently strong to support memory expression without the HPC. The current findings also demonstrate the critical need to consider learning parameters when discussing patterns of retrograde amnesia and the role of the HPC in memory.     

Glucose effects on memory: behavioral and pharmacological characteristics

Recent findings indicate that post-training glucose injections can modulate memory storage for inhibitory (passive) avoidance training. Experiment I extended these findings to determine whether glucose, like other memory modulating treatments, enhances memory storage when administered after training with low footshock and impairs memory storage after high footshock training. In Experiment I, male Sprague-Dawley rats were trained in a one-trial inhibitory avoidance task using either a brief footshock (0.5 mA, 0.7 s) or slightly more intense footshock kept on until escape (0.7 mA, mean escape latency = 3.4 s). Immediately after training, each rat received a subcutaneous injection of glucose (100 mg/kg). When tested for retention performance 24 h later, the glucose-injected animals exhibited enhanced retention performance for low footshock training and impaired retention for high footshock training. Experiment II determined whether pretreatment with adrenergic antagonists blocked the effects of glucose on memory. Pretreatment with the alpha- or beta-adrenergic receptor antagonists, phenoxybenzamine, or propranolol, respectively, had no effect on acquisition or retention in animals trained with the brief footshock and did not affect glucose facilitation of that memory. In animals trained to escape footshock, phenoxybenzamine did not attenuate the amnesia produced by glucose. Propranolol-pretreated animals had impaired retention whether or not they received post-training amnestic injections of glucose; glucose had no effect on retention in these amnestic animals. These findings add further support to the view that glucose release after training and treatment may represent a physiological response subsequent to epinephrine release in modulating memory storage processing.     

Context Memory in Korsakoff’s Syndrome

Memory for contextual information and target-context integration are crucial for successful episodic memory formation and are impaired in patients with Korsakoff's syndrome. In this paper we review the evidence for the notion that a context memory deficit makes an important contribution to the amnesia in these patients. First, we focus on anterograde memory for contextual (spatial and temporal) information. Next, the use of contextual cues in memory retrieval is examined and their role in retrograde amnesia and confabulation. Evidence on the role of contextual cues and associations in working memory is discussed in relation to the underlying neurocognitive mechanisms and their dissociation from long-term encoding. Finally, we focus on implicit learning of contextual information in Korsakoff patients. It can be concluded that Korsakoff patients are impaired in the explicit processing of contextual information and in target-context binding, both in long-term (retrograde and anterograde) memory and in working memory. These results extend the context memory deficit hypothesis. In contrast, implicit contextual learning is relatively preserved in these patients. These findings are discussed in relation to evidence of dysfunction of the extended diencephalic-hippocampal memory circuit in Korsakoff's syndrome.     

Anterograde amnesia for Pavlovian fear conditioning and the role of one-trial overshadowing: effects of preconditioning exposures to morphine in the rat

Four experiments studied anterograde deficits in Pavlovian fear conditioning following prolonged exposure to the mu-opioid receptor agonist morphine. Injections of morphine produced temporally graded anterograde amnesia characterized by deficits in contextual and conditioned-stimulus (CS) conditioning 1 or 7 days and selective impairment in CS conditioning 21 days after last injection. This anterograde deficit in conditioning did not recover across a retention interval, was absent when rats were tested immediately after conditioning, and required the presence of an auditory CS. These results suggest that anterograde deficits in Pavlovian fear conditioning emerged from differences in susceptibility to 1-trial overshadowing of context by CS.     

Time-dependent changes in inaccessible memory

The present experiment examined whether forgetting of contextual attributes—the loss of discriminability of background stimulus features over time—also occurs when a memory remains inaccessible (amnestic) during the retention interval. To examine this issue, rats received an acute hypothermia treatment that caused reversible anterograde amnesia for a passive-avoidance task and were tested 1 or 7 days later in either the same or a different context. At the short retention interval, the subjects discriminated between the contexts, as evidenced by the finding that reversal of amnesia occurred only in the training context. However, at the 7-day interval, recovery of the avoidance response was induced in either context, reflecting the forgetting of differentiating characteristics. These findings indicate that inaccessible memory remains susceptible to processes of modification and distortion that typically influence intact memories.