Hugo Lehmann

Complete or partial hippocampal damage produces equivalent retrograde amnesia for remote contextual fear memories

We examined the effects of partial or complete damage to the hippocampus on long‐term retention of a Pavlovian conditioned fear response to context. Rats received a single contextual fear‐conditioning episode and 1 week, 3 months or 6 months later they received sham, partial (dorsal) or complete NMDA‐induced damage of the hippocampus. During a retention test conducted 2 weeks after surgery, the control rats exhibited high levels of freezing in the context, although their level of freezing was significantly lower with longer retention intervals. Rats with complete hippocampal damage displayed very little freezing in the context at each learning–surgery interval. Partial hippocampal damage caused a smaller but consistent deficit in conditioned responding, especially at longer learning–surgery intervals. Neither group of hippocampus‐damaged rats showed less retrograde amnesia for more remote memories. We found that the severity of retrograde amnesia for contextual fear conditioning following hippocampal damage is related to the extent of the damage and that there is consistent and severe retrograde amnesia for even remote contextual fear memories. These findings support the idea that the hippocampal formation has an essential and long‐lasting, possibly permanent, role in memory for contexts.

Absence of systems consolidation of fear memories after dorsal, ventral, or complete hippocampal damage.

We examined the effects of dorsal, ventral, or complete damage to the hippocampus on long‐term retention of a Pavlovian conditioned fear response to a tone and a context paired with foot shock. Rats received a fear conditioning episode, in which a tone and context or context‐alone were paired with foot shock. Two days or 12 weeks later, they received sham, dorsal, ventral, or complete NMDA‐induced damage of the hippocampus. During a retention test conducted 2 weeks after surgery, the sham control rats exhibited high levels of freezing in the context and in the presence of the tone. Rats with dorsal, ventral, or complete hippocampal damage displayed very little freezing in the context at either learning‐surgery intervals. Partial hippocampal damage tended to cause a smaller but consistent deficit in conditioned responding to context at the shorter (2 day) learning‐surgery interval. Rats with hippocampal damage did not display less severe retrograde amnesia for more remote (12 weeks) memories. A similar pattern of results was observed for freezing to the tone. We find that the severity of retrograde amnesia for fear conditioning is related to the extent of the damage and that there is consistent and severe retrograde amnesia for remote contextual and cued fear memories. These findings support the idea that the hippocampal formation plays an essential and possibly permanent role in fear memories.

Perirhinal cortex damage and anterograde object-recognition in rats after long retention intervals

Damage to the perirhinal cortex (PRh) in rats impairs anterograde object-recognition memory after retention intervals of up to several hours, but there is little direct evidence to link PRh function to object-recognition abilities after substantially longer intervals that span several days or weeks. We assessed the effects of PRh lesions on anterograde object recognition using a novel-object preference test, with retention intervals lasting 24 h and 3 weeks. The rats received multiple exposures to the sample object during the learning phase--5 min per day on 5 consecutive days. Control rats displayed a significant novel-object preference after both retention intervals, indicating recognition of the sample object, whereas the rats with PRh lesions displayed a significant preference after the 24-h interval, but not after the 3-week interval. When the learning phase of the trial was shortened to a single 5-min session, the PRh group was impaired in the 24-h condition. The findings indicate that the disruptive effects of PRh damage on anterograde object recognition persist over very long postlearning intervals. The results indicate further that object recognition impairments following PRh damage are not ubiquitous, and that learning conditions play a significant role in determining the subsequent recognition performance in rats with PRh damage.

Hippocampus and retrograde amnesia in the rat model: A modest proposal for the situation of systems consolidation

The properties of retrograde amnesia after damage to the hippocampus have been explicated with some success using a rat model of human medial temporal lobe amnesia. We review the results of this experimental work with rats focusing on several areas of consensus in this growing literature. We evaluate the theoretically significant hypothesis that hippocampal retrograde amnesia normally exhibits a temporal gradient, affecting recent, but sparing remote memories. Surprisingly, the evidence does not provide much support for the idea that there is a lengthy process of systems consolidation following a learning episode. Instead, recent and remote memories tend to be equally affected. The extent of damage to the hippocampus is a significant factor in this work since it is likely that spared hippocampal tissue can support at least partial memory retrieval. With extensive hippocampal damage gradients are flat or, in the case of memory tasks with flavour/odour retrieval cues, the retrograde amnesia covers a period of about 1-3 days. There is consistent evidence that at the time of learning the hippocampus interferes with or overshadows memory acquisition by other systems. This contributes to the breadth and severity of retrograde amnesia relative to anterograde amnesia in the rat. The fact that multiple, distributed learning episodes can overcome this overshadowing is consistent with a parallel dual-store theory or a Distributed Reinstatement Theory in which each learning episode triggers a short period of memory replay that provides a brief hippocampal-dependent systems consolidation.

Enhanced context-dependency of object recognition in rats with hippocampal lesions.

Object recognition memory was assessed on a novel-object preference (NOP) task in rats with lesions of the hippocampal formation (HPC). The learning and test phases of NOP trials occurred in either the same context or in different contexts. When the learning and test contexts were the same, rats with HPC lesions performed like control rats, displaying a significant tendency to investigate a novel object more than a familiar sample object. When the test occurred in a context that was familiar but different from the learning context, performance was unaffected in control rats, but rats with HPC lesions no longer discriminated between the objects, and therefore showed no evidence of recognizing the sample object. When the test context was unfamiliar, novel-object preference in control rats was attenuated but still above chance levels, whereas rats with HPC lesions did not show a preference. The data suggest that the HPC is not critical for encoding or retrieving conjunctive representations of the context in which incidental learning occurs, whereas it plays an essential role in recognition of objects that are subsequently encountered in different contexts.

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.

Alternative conceptions of memory consolidation and the role of the hippocampus at the systems level in rodents

We discuss very recent experiments with rodents addressing the idea that long-term memories initially depending on the hippocampus, over a prolonged period, become independent of it. No unambiguous recent evidence exists to substantiate that this occurs. Most experiments find that recent and remote memories are equally affected by hippocampus damage. Nearly all experiments that report spared remote memories suffer from two problems: retrieval could be based upon substantial regions of spared hippocampus and recent memory is tested at intervals that are of the same order of magnitude as cellular consolidation. Accordingly, we point the way beyond systems consolidation theories, both the Standard Model of Consolidation and the Multiple Trace Theory, and propose a simpler multiple storage site hypothesis. On this view, with event reiterations, different memory representations are independently established in multiple networks. Many detailed memories always depend on the hippocampus; the others may be established and maintained independently.

Amygdala lesions do not impair shock-probe avoidance retention performance

The present experiment used the shock-probe paradigm, a procedure usually used to assess anxiolytic processes, to assess memory in amygdala-lesioned rats. Rats were placed in a chamber that contained a probe protruding from 1 of 4 walls and were kept there for 15 min after they contacted the probe. For half the rats, the probe was electrified (2 mA). Four days later, sham or neurotoxic amygdala lesions were induced. Retention performance was assessed 8 days later by measuring the latency to contact the probe and the number of contact-induced shocks. The results indicated that, although shock-naive amygdala-lesioned rats were impaired on the 2nd shock-probe test, shock-experienced amygdala-lesioned rats were not. These data indicate that the memory of a shock experience, as indexed with a shock-probe avoidance response, is spared in rats with large amygdala lesions.

Suppression of Neurotoxic Lesion-Induced Seizure Activity: Evidence for a Permanent Role for the Hippocampus in Contextual Memory

Damage to the hippocampus (HPC) using the excitotoxin N-methyl-D-aspartate (NMDA) can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity) during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX), a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours) or remote (5 weeks) time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.

Retrograde amnesia for fear-potentiated startle in rats after complete, but not partial, hippocampal damage

We assessed the involvement of the hippocampus in recall of learned fear of a discrete visual stimulus using a fear-potentiated startle (FPS) procedure. Recall was measured by an increase in acoustic startle in the presence of a light that was paired with footshock. In Experiment 1, rats either received sham, dorsal, ventral, or complete (dorsal and ventral) NMDA-induced damage of the hippocampus following FPS acquisition. During the post-surgery retention test, only the rats with complete hippocampal damage showed a significant FPS deficit. In Experiment 2, we examined whether recent and remote memory for FPS would be differentially affected by complete hippocampal damage. Rats received sham or complete hippocampal damage 1- or 4-wk after FPS acquisition. During the retention test, sham rats exhibited significant FPS, whereas rats with hippocampal damage showed a large FPS deficit that was equivalent for recent and remote memories. In Experiment 3, we found that rats with complete hippocampal damage induced before conditioning showed levels of FPS that did not significantly differ from sham rats. Combined, these findings suggest that extensive damage to the hippocampus causes retrograde amnesia for a memory involving a light-shock association that is not temporally graded. The same damage does not cause anterograde amnesia in the same memory task. Partial damage of the hippocampus, whether of the dorsal or ventral region, was insufficient to cause retrograde amnesia. Thus, the hippocampus normally has a critical and long-lasting role enabling recall of fear conditioning to a discrete visual stimulus. In the absence of the hippocampus other memory systems support new learning.