Impaired memory consolidation in rats produced with beta-adrenergic blockade

Despite abundant evidence that systemic administration of adrenergic drugs and hormones can produce retrograde memory enhancement, the literature contains no clear demonstration that postlearning systemic administration of adrenergic antagonists produces retrograde amnesia. Here we demonstrate retrograde amnesia for a stressful learning task (a spatial water maze) with systemic administration of the beta-adrenergic antagonist propranolol (5 mg/kg). The amnesic effect of the drug depended on the degree of learning in the subjects: Propranolol caused a robust retrograde amnesia in "good learners," but did not significantly affect memory in "poor learners." The findings provide critical additional support for the hypothesis that postlearning adrenergic activation modulates memory consolidation processes after emotionally stressful events and help explain previous failures to detect memory impairment after systemic administration of adrenergic blocking drugs.     

Differential Effects of Ketaset/Rompun Anesthesia on Hypothermia-Induced Retrograde Amnesia and Its Recovery

A nonbarbiturate anesthetic consisting of ketamine HCl (Ketaset) and xlyazine (Rompun) was administered to assess the effects of anesthesia on hypothermia-induced retrograde amnesia in Long Evans hooded and Sprague–Dawley albino rats. Results from Experiment 1a indicate that this anesthetic does not attenuate retrograde amnesia, and the findings from Experiment 1b suggest that awakening from Ketaset/Rompun anesthesia at normal body temperature (following administration of deep body cooling) does not attenuate the resulting hypothermia-induced retrograde amnesia. Experiment 2 demonstrated that various delays between training and hypothermia resulted in a temporal gradient that was the same for animals cooled while either conscious or under anesthesia. The results of Experiment 3 showed that rats made amnesic while under anesthesia did not recover the target memory if given a recooling treatment, but rats that were made amnesic while conscious did recover the memory with the same reminder treatment. These findings indicate that the conscious processing of stimuli associated with hypothermia treatment is not necessary in inducing hypothermia-induced retrograde amnesia, but that conscious processing is an important factor if the amnesia is to be recovered with a recooling treatment.     

Reconsolidation Reconsidered

Some of the considerations that led to a consolidation interpretation of retrograde amnesia (RA), which states that RA results from the disruption of memory processing and storage when neural activity is interrupted by a brain insult, are reviewed here. The time-dependent gradient of memory loss (i.e., new memories are more vulnerable to amnesia than old memories) that characterizes RA seemed to fit nicely with the notion of a cascade of cellular events occurring during the immediate post-acquisition period that would transform a labile representation into a more stable form (i.e., consolidate the memory). However, a variety of observations came to challenge the storage-disruption model, and among these was the finding of amnesia for old but reactivated memories. A recent study by Nader, Schafe, and LeDoux (2000) provides an important analytic extension of the work on "reconsolidation" by showing that inhibition of protein synthesis in the lateral and basal nuclei of the amygdala immediately following the reactivation of old memory will induce retrograde amnesia. We offer a retrieval-oriented conceptualization to account for the temporal gradient and the "reconsolidation" phenomena.     

Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala

When administered near the time of training, protein synthesis inhibitors such as anisomycin impair later memory. A common interpretation of these findings is that memory consolidation requires new protein synthesis initiated by training. However, recent findings support an alternative interpretation that abnormally large increases in neurotransmitter release after injections of anisomycin may be responsible for producing amnesia. In the present study, a local anesthetic was administered prior to anisomycin injections in an attempt to mitigate neurotransmitter actions and thereby attenuate the resulting amnesia. Rats received lidocaine and anisomycin injections into the amygdala 130 and 120 min, respectively, prior to inhibitory avoidance training. Memory tests 48 h later revealed that lidocaine attenuated anisomycin-induced amnesia. In other rats, in vivo microdialysis was performed at the site of amygdala infusion of lidocaine and anisomycin. As seen previously, anisomycin injections produced large increases in release of norepinephrine in the amygdala. Lidocaine attenuated the anisomycin-induced increase in release of norepinephrine but did not reverse anisomycin inhibition of protein synthesis, as assessed by c-Fos immunohistochemistry. These findings are consistent with past evidence suggesting that anisomycin causes amnesia by initiating abnormal release of neurotransmitters in response to the inhibition of protein synthesis.     

The many faces of amnesia

Results from studies of retrograde amnesia provide much of the evidence for theories of memory consolidation. Retrograde amnesia gradients are often interpreted as revealing the time needed for the formation of long-term memories. The rapid forgetting observed after many amnestic treatments, including protein synthesis inhibitors, and the parallel decay seen in long-term potentiation experiments are presumed to reveal the duration of short-term memory processing. However, there is clear and consistent evidence that the time courses obtained in these amnesia experiments are highly variable within and across experiments and treatments. The evidence is inconsistent with identification of basic temporal properties of memory consolidation. Alternative views include modulation of memory and emphasize the roles that hormones and neurotransmitters have in regulating memory formation. Of related interest, converging lines of evidence suggest that inhibitors of protein synthesis and of other biochemical processes act on modulators of memory formation rather than on mechanisms of memory formation. Based on these findings, memory consolidation and reconsolidation studies might better be identified as memory modulation and "remodulation" studies. Beyond a missing and perhaps unattainable time constant of memory consolidation, some current views of memory consolidation assume that memories, once formed, are generally unmodifiable. It is this perspective that appears to have led to the recent interest in memory reconsolidation. But the view adopted here is that memories are continually malleable, being updated by new experiences and, at the same time, altering the memories of later experiences. Studies of memory remodulation offer promise of understanding the neurobiological bases by which new memories are altered by prior experiences and by which old memories are altered by new experiences.     

Impaired Memory Consolidation in Rats Produced with β-Adrenergic Blockade

Despite abundant evidence that systemic administration of adrenergic drugs and hormones can produce retrograde memory enhancement, the literature contains no clear demonstration that postlearning systemic administration of adrenergic antagonists produces retrograde amnesia. Here we demonstrate retrograde amnesia for a stressful learning task (a spatial water maze) with systemic administration of the β-adrenergic antagonist propranolol (5 mg/kg). The amnesic effect of the drug depended on the degree of learning in the subjects: Propranolol caused a robust retrograde amnesia in “good learners,” but did not significantly affect memory in “poor learners.” The findings provide critical additional support for the hypothesis that postlearning adrenergic activation modulates memory consolidation processes after emotionally stressful events and help explain previous failures to detect memory impairment after systemic administration of adrenergic blocking drugs.     

Reconsolidation reconsidered

Some of the considerations that led to a consolidation interpretation of retrograde amnesia (RA), which states that RA results from the disruption of memory processing and storage when neural activity is interrupted by a brain insult, are reviewed here. The time-dependent gradient of memory loss (i.e., new memories are more vulnerable to amnesia than old memories) that characterizes RA seemed to fit nicely with the notion of a cascade of cellular events occurring during the immediate post-acquisition period that would transform a labile representation into a more stable form (i.e., consolidate the memory). However, a variety of observations came to challenge the storage-disruption model, and among these was the finding of amnesia for old but reactivated memories. A recent study by Nader, Schafe, and LeDoux (2000) provides an important analytic extension of the work on “reconsolidation” by showing that inhibition of protein synthesis in the lateral and basal nuclei of the amygdala immediately following the reactivation of old memory will induce retrograde amnesia. We offer a retrieval-oriented conceptualization to account for the temporal gradient and the “reconsolidation” phenomena.     

A neuropsychological study of fact memory and source amnesia

We investigated the ability of amnesic patients to learn new facts (e.g., Angel Falls is located in Venezuela) and also to remember where and when the facts were learned (i.e., source memory). To assess the susceptibility of fact and source memory to retrograde amnesia, patients prescribed electroconvulsive therapy were presented facts prior to the first treatment and were tested after their second treatment. All amnesic patients exhibited marked fact memory impairment. In addition, some amnesic patients exhibited source amnesia (i.e., they recalled a few facts but then could not remember where or when those facts had been learned). Source amnesia was unrelated to the severity of the memory deficit itself, because patients who exhibited source amnesia recalled as many facts as the patients who did not. These results show that the deficit in amnesia includes an impairment in acquiring and retaining new facts. Source amnesia can also occur, but it is dissociable from impaired recall and recognition and appears to reflect difficulty in remembering the specific context in which information is acquired. The findings are discussed in terms of their significance for how memory is organized.     

Memory and metamemory: a study of the feeling-of-knowing phenomenon in amnesic patients

Accuracy of the feeling of knowing was tested in patients with Korsakoff's syndrome, patients prescribed electroconvulsive therapy, four other cases of amnesia, and control subjects. In Experiment 1, we tested feeling-of-knowing accuracy for the answers to general information questions that could not be recalled. Subjects were asked to rank nonrecalled questions in terms of how likely they thought they would be able to recognize the answers and were then given a recognition test for these items. Only patients with Korsakoff's syndrome were impaired in making feeling-of-knowing predictions. The other amnesic patients were as accurate as control subjects in their feeling-of-knowing predictions. In Experiment 2, we replicated these findings in a sentence memory paradigm that tested newly learned information. The results showed that impaired metamemory is not an obligatory feature of amnesia, because amnesia can occur without detectable metamemory deficits. The impaired metamemory exhibited by patients with Korsakoff's syndrome reflects a cognitive impairment that is not typically observed in other forms of amnesia.     

Fading in

Patient H.M. can form new memories and maintain them for a few seconds before they fade away. From a neurobiological perspective, this amnesia is usually attributed to the absence of memory consolidation, that is, memory storage. An alternative view holds that this impairment reflects that the memory is present but cannot be retrieved. This debate has been unresolved for decades. Here, we will consider some of the arguments that make it so difficult to resolve this issue. In addition, some recent work will be discussed that has gone beyond the shortcomings of previous experimental approaches to strongly suggest that amnesia can be due to a retrieval impairment that can be overcome with a reminder--an example of memories fading in. Finally, this review will suggest some strategies for resolving this debate.     

Prolonged inactivation of the hippocampus reveals temporally graded retrograde amnesia for unreinforced spatial learning in rats

We investigated whether systems consolidation of spatial memory could be detected in a non-navigational, spatial-learning test that takes advantage of rats’ natural propensity to preferentially investigate an object that was displaced relative to spatial cues more than an object that remained stationary. Previous studies using navigational spatial-learning tests have generally failed to reveal temporally-graded retrograde amnesia, possibly because the hippocampus needs to be intact for the retrieval and/or processing of navigational information during the test. In the present study, the hippocampus of rats was kept inactivated, at two sites along its septo-temporal axis (dorsal and intermediate), for four consecutive days, beginning either 3 h or 5 days after familiarization to two identical objects in an open field. Rats that had their hippocampus inactivated beginning 5 days but not 3 h after familiarization showed evidence that they remembered the previous location of the displaced object. The results suggest that systems consolidation of spatial memories can be detected using a non-navigational test of spatial memory.     

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.     

Memory Without Consolidation: Temporal Distinctiveness Explains Retroactive Interference

Is consolidation needed to account for retroactive interference in free recall? Interfering mental activity during the retention interval of a memory task impairs performance, in particular if the interference occurs in temporal proximity to the encoding of the to‐be‐remembered (TBR) information. There are at least two rival theoretical accounts of this temporal gradient of retroactive interference. The cognitive neuroscience literature has suggested neural consolidation is a pivotal factor determining item recall. According to this account, interfering activity interrupts consolidation processes that would otherwise stabilize the memory representations of TBR items post‐encoding. Temporal distinctiveness theory, by contrast, proposes that the retrievability of items depends on their isolation in psychological time. According to this theory, information processed after the encoding of TBR material will reduce the temporal distinctiveness of the TBR information. To test between these accounts, implementations of consolidation were added to the SIMPLE model of memory and learning. We report data from two experiments utilizing a two‐list free recall paradigm. Modeling results imply that SIMPLE was able to model the data and did not benefit from the addition of consolidation. It is concluded that the temporal gradient of retroactive interference cannot be taken as evidence for memory consolidation.     

Defining the boundary of childhood amnesia

When adults are asked to recall their earliest autobiographical memories most can recall nothing about their infancy and early childhood, a phenomenon commonly referred to as childhood amnesia. There is general consensus regarding the existence of childhood amnesia, but there remains considerable debate over its boundary. Most researchers have argued that the boundary of childhood amnesia occurs between the ages of 3 and 4 years, but in 1993 Usher and Neisser published a highly influential paper, which has subsequently been used to argue that the boundary may be as low as 2 years. In the present experiment we examined how changes in scoring criteria influence our estimates of the age of adults' earliest memories. We conclude that some coding criteria are more valid than others and that the best estimates of childhood amnesia will include measures of free recall in addition to the specific questions that have dominated prior research in this area.     

Defining the boundary of childhood amnesia

When adults are asked to recall their earliest autobiographical memories most can recall nothing about their infancy and early childhood, a phenomenon commonly referred to as childhood amnesia. There is general consensus regarding the existence of childhood amnesia, but there remains considerable debate over its boundary. Most researchers have argued that the boundary of childhood amnesia occurs between the ages of 3 and 4 years, but in 1993 Usher and Neisser published a highly influential paper, which has subsequently been used to argue that the boundary may be as low as 2 years. In the present experiment we examined how changes in scoring criteria influence our estimates of the age of adults’ earliest memories. We conclude that some coding criteria are more valid than others and that the best estimates of childhood amnesia will include measures of free recall in addition to the specific questions that have dominated prior research in this area.     

Retrieval failure versus memory loss in experimental amnesia: definitions and processes

For at least 40 years, there has been a recurring argument concerning the nature of experimental amnesia, with one side arguing that amnesic treatments interfere with the formation of enduring memories and the other side arguing that these treatments interfere with the expression of memories that were effectively encoded. The argument appears to stem from a combination of (1) unclear definitions and (2) real differences in the theoretical vantages that underlie the interpretation of relevant data. Here we speak to how the field might avoid arguments that are definitional in nature and how various hypotheses fare in light of published data. Existing but often overlooked data favor very rapid (milliseconds) synaptic consolidation, with experimental amnesia reflecting, at least in part, deficits in retrieval rather than in the initial storage of information.     

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.     

Infantile amnesia: A neurogenic hypothesis

In the late 19th Century, Sigmund Freud described the phenomenon in which people are unable to recall events from early childhood as infantile amnesia. Although universally observed, infantile amnesia is a paradox; adults have surprisingly few memories of early childhood despite the seemingly exuberant learning capacity of young children. How can these findings be reconciled? The mechanisms underlying this form of amnesia are the subject of much debate. Psychological/cognitive theories assert that the ability to maintain detailed, declarative-like memories in the long term correlates with the development of language, theory of mind, and/or sense of "self." However, the finding that experimental animals also show infantile amnesia suggests that this phenomenon cannot be explained fully in purely human terms. Biological explanations of infantile amnesia suggest that protracted postnatal development of key brain regions important for memory interferes with stable long-term memory storage, yet they do not clearly specify which particular aspects of brain maturation are causally related to infantile amnesia. Here, we propose a hypothesis of infantile amnesia that focuses on one specific aspect of postnatal brain development-the continued addition of new neurons to the hippocampus. Infants (humans, nonhuman primates, and rodents) exhibit high levels of hippocampal neurogenesis and an inability to form lasting memories. Interestingly, the decline of postnatal neurogenesis levels corresponds to the emergence of the ability to form stable long-term memory. We propose that high neurogenesis levels negatively regulate the ability to form enduring memories, most likely by replacing synaptic connections in preexisting hippocampal memory circuits.     

Preserved ability to recognize keywords related to remote events in the absence of retrieval of relevant knowledge: a case of postencephalitic amnesia

We describe a case of severe anterograde and retrograde amnesia resulting from herpes simplex encephalitis. Magnetic resonance imaging revealed pathological changes in the bilateral hippocampi, parahippocampal gyri, fusiform gyri, medial temporal poles, posterior part of the cingulate gyri, and insula. The patient showed severe amnesia for autobiographical episodic memory in relation to events that had occurred throughout her life, but temporally graded amnesia for autobiographical semantic memory, and severe amnesia without a temporal gradient for public events and famous people. However, using a multiple-choice method, she showed a high level of accuracy when choosing keywords related to public or personal events, although this did not prompt her recollection of the events. An important indication of these results is that, even with severe retrograde amnesia, memories of past events are not completely lost. We propose that an event may be stored in a fragmented form, consisting of many components, and that normal recall of an event may require recombination or reconstruction of these components.