Retrograde amnesia for visual memories after hippocampal damage in rats

It is generally believed that the hippocampus is not required for simple discrimination learning. However, a small number of studies have shown that hippocampus damage impairs retention of a previously learned visual discrimination task. We propose that, although simple discrimination learning may proceed in the absence of the hippocampus, it plays an important role in this type of learning when it is intact. In order to test the role of the hippocampus in simple discrimination learning, we performed a series of experiments utilizing a two-choice picture discrimination task. Our experiments confirm that rats readily learn simple two-choice picture discriminations after hippocampus damage. However, if such discriminations are first learned while the hippocampus is intact, subsequent hippocampus damage causes severe retrograde amnesia for the discriminations. Furthermore, retrograde amnesia for simple picture discriminations was equally severe when the interval between training and damage was 1 d or 60 d; remote picture memories are not spared. Similarly, the rule or schema underlying a recently or remotely acquired picture discrimination learning set was lost after hippocampus damage. The severity of retrograde amnesia for simple picture discriminations is negatively correlated with the volume of spared hippocampus tissue. Thus, the hippocampus plays an essential role in long-term memories supporting simple picture discriminations.     

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.     

Retrograde amnesia in patients with hippocampal, medial temporal, temporal lobe, or frontal pathology

There is considerable controversy concerning the theoretical basis of retrograde amnesia (R.A.). In the present paper, we compare medial temporal, medial plus lateral temporal, and frontal lesion patients on a new autobiographical memory task and measures of the more semantic aspects of memory (famous faces and news events). Only those patients with damage extending beyond the medial temporal cortex into the lateral temporal regions showed severe impairment on free recall remote memory tasks, and this held for both the autobiographical and the more semantic memory tests. However, on t-test analysis, the medial temporal group was impaired in retrieving recent autobiographical memories. Within the medial temporal group, those patients who had combined hippocampal and parahippocampal atrophy (H+) on quantified MRI performed somewhat worse on the semantic tasks than those with atrophy confined to the hippocampi (H-), but scores were very similar on autobiographical episodic recall. Correlational analyses with regional MRI volumes showed that lateral temporal volume was correlated significantly with performance on all three retrograde amnesia tests. The findings are discussed in terms of consolidation, reconsolidation, and multiple trace theory: We suggest that a widely distributed network of regions underlies the retrieval of past memories, and that the extent of lateral temporal damage appears to be critical to the emergence of a severe remote memory impairment.     

Opioid mechanisms are involved in the disruption of arcaine-induced amnesia by context pre-exposure

Previous exposure to the training context disrupts glutamatergic N-methyl-d-aspartate receptor (NMDAr) antagonist-induced amnesia, indicating that novelty is necessary for such an amnestic effect. While there are reports that novelty-related release of opioids cause amnesia, no study has addressed whether the amnestic effect of NMDAr antagonists involve opioid mechanisms. In this study we investigated whether pharmacological manipulation of the opioid system immediately after context pre-exposure alters the amnestic effect of arcaine, a NMDAr antagonist. Adult male Wistar rats were habituated (pre-exposed) to a fear conditioning training apparatus or to a different context (open field). Immediately after pre-exposure, animals were injected with saline or naloxone (0.5 mg/kg, i.p.) or anti-beta-endorphin antibody (1:500, i.c.v.). Forty eight hours after pre-exposure session, all animals were subjected to fear conditioning acquisition protocol and saline or arcaine (30 mg/kg, i.p.) was administered immediately after training. Testing was carried out 24 h later, and freezing responses due to re-exposure to the training apparatus were recorded. Pre-exposure to the training apparatus prevented the impairment of memory induced by post-training arcaine. Administration of naloxone or anti-beta-endorphin antibody, immediately after pre-exposure to the training apparatus, reinstated the amnesic effect of post-training arcaine. The results suggest that endogenous opioid mechanisms are involved in the pre-exposure-induced loss of the amnestic effect of arcaine.     

Factors in the modification by isolation of electroconvulsive shock-produced retrograde amnesia in the rat.

It has been demonstrated that placing rats in a sensory-restricted environment during the electronconvulsive shock- (ECS) retention interval following 1-trial appetitive learning will prevent or eliminate ECS-produced retrograde amnesia. The first study replicated this finding with a 1-trial aversive learning task, indicating that this effect is not task specific. The second study attempted to determine whether illumination or the restricted environment was the crucial factor in this penomenon. Rats placed in the light during the ECS-retention interval, whether restricted or in the colony, demonstrated retrograde amnesia after ECS. However, rats left in the dark during this interval demonstrated little, if any, retention deficit particularly if this condition was combined with sensory isolation. These studies further indicate that manipulation of the general environment of the animal after ECS can alter ECS-produced retention losses.     

Decursin from Angelica gigas mitigates amnesia induced by scopolamine in mice

We previously reported that a total methanolic extract of the underground part of Angelica gigas Nakai (Umbelliferae) (here-in-after abbreviated AG) significantly inhibited acetylcholinesterase (AChE) activity. We characterized 12 coumarin derivatives including both decursin and decursinol from extracts of AG. In this study, we evaluated the anti-amnestic activity of decursin, a major coumarin constituent isolated from AG, in vivo using ICR mice with amnesia induced by scopolamine (1 mg/kg body weight, s.c.). Decursin, when administered to mice at 1 and 5 mg/kg body weight i.p., significantly ameliorated scopolamine-induced amnesia as measured in both the passive avoidance test and the Morris water maze test. Moreover, decursin significantly inhibited AChE activity by 34% in the hippocampus of treated mice. These results indicate that decursin may exert anti-amnestic activity in vivo through inhibition of AChE activity in the hippocampus.     

Two time windows of anisomycin-induced amnesia for inhibitory avoidance training in rats: protection from amnesia by pretraining but not pre-exposure to the task apparatus

We have studied the effect of training conditions on hippocampal protein synthesis-dependent processes in consolidation of the inhibitory avoidance task. Adult male Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.4 mA foot shock, 24 hr training–test interval). Fifteen minutes before or 0, 3, or 6 hr after training, animals received a 0.8-μl intrahippocampal infusion of the protein-synthesis inhibitor anisomycin (80 μg) or vehicle (PBS, pH 7.4). The infusion of anisomycin impaired retention test performance in animals injected 15 min before and 3 hr after the training session, but not at 0 or 6 h post-training. Pretraining with a low foot shock intensity (0.2 mA) 24 hr before training, prevented the amnestic effect of anisomycin injected at 15 min before or 3 hr after training. However, simple pre-exposure to the inhibitory avoidance apparatus did not alter the amestic effects of anisomycin. The results suggest that hippocampal protein synthesis is critical in two periods, around the time of, and 3 hr after training. A prior weak training session, however, which does not itself alter step-down latencies, is sufficient to prevent the amnestic effect of anisomycin, suggesting that even if not behaviorally detectable, weak training must be sufficient to produce some lasting cellular expression of the experience.     

Response suppression produced by vestibular stimulation in the rat

Seven rats were trained to stable performance levels on either Fixed Ratio 47, Variable Ratio 47, Variable Interval 1-min, or Fixed Interval 1-min schedules of food reinforcement. Subjects were then tested for sensitivity to vestibular stimulation from rotation, using an ascending method of limits technique with increments in velocity of one revolution per minute every 5 min. Centrifugal forces were minimized by locating the test chamber over the axis of rotation. Response rates decreased in all subjects as a function of increasing rotation speed. In addition, characteristic differences in the patterns of response decrement were found between subjects on ratio and on interval schedules. Repeated tests indicated high intra-subject reliability in sensitivity to rotation. Similarities of these data to "motion sickness" phenomena in other species were noted. It is suggested that this behavioral approach provides a sensitive and quantifiable technique for assessing the effects of vestibular stimulation in animals.     

Variability in the semantic errors produced by brain-injured patients

One of the most common types of errors produced by aphasic patients during oral word production is semantic errors. However, although aphasia semantic errors are often treated as a single homogenous group, there are, in fact, several subtypes defined by the nature of the error-target relationship: paradigmatic, if the two words are category coordinates; syntagmatic, if they are associatively related but from different semantic categories; and superordinate, if the meaning of the error is broader than the meaning of the target. The goal of this study was to investigate whether or not these various subtypes of semantic errors have a similar processing origin. With this objective, we compared the patterns of semantic errors made by a group of Alzheimer patients in a picture-naming task with those made by a group of aphasic patients. We examined the percentages of the different error types, the degree of association between target and error, and the frequency values both of errors and targets. The results suggest that the three subtypes of semantic errors have different origins: the superordinate appear to arise at the semantic level, the syntagmatic at the lexical level, and the paradigmatic at both levels of processing.     

Reactivation-dependent amnesia for appetitive memories is determined by the contingency of stimulus presentation

Previously acquired aversive and appetitive memories are not stable and permanent. The reactivation of such memories by re-exposure to training stimuli renders them vulnerable to disruption by amnestic agents such as the noncompetitive N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo{a,d}cyclohepten-5,10-imine maleate (MK-801). However, relatively little is known about the parameters that influence the reactivation process. Here, we show that the method of stimulus presentation during memory reactivation is of great importance. Male Lister Hooded rats were trained to acquire a lever press response that delivered a sucrose reward paired with a light conditioned stimulus (CS). The CS-sucrose association was then reactivated through re-exposure to the CS, either contingently upon the lever press response, or noncontingently in the absence of instrumental responding. Systemic administration of MK-801 (0.1 mg/kg) at the time of memory reactivation resulted in amnesia, and hence a reduction in subsequent sucrose seeking induced by, and dependent upon, presentation of the CS, only when the memory was reactivated contingently. Therefore, stimuli may have to be presented in the same manner at memory reactivation as during learning in order to render a previously acquired memory vulnerable to disruption. These results have important implications for the potential translational use of glutamatergic treatments in conjunction with targeted memory reactivation.