Memory--a century of consolidation.

The memory consolidation hypothesis proposed 100 years ago by Müller and Pilzecker continues to guide memory research. The hypothesis that new memories consolidate slowly over time has stimulated studies revealing the hormonal and neural influences regulating memory consolidation, as well as molecular and cellular mechanisms. This review examines the progress made over the century in understanding the time-dependent processes that create our lasting memories.

Time-dependent processes in memory storage.

These observations indicate that the long-lasting trace of an experience is not completely fixed, consolidated, or coded at the time of the experience. Consolidation requires time, and under at least some circumstances the processes of consolidation appear to be susceptible to a variety of influences- both facilitating and impairing- several hours after the experience. There must be, it seems, more than one kind of memory trace process (31). If permanent memory traces consolidate slowly over time, then other processes must provide a temporary basis for memory while consolidation is occurring. The evidence clearly indicates that trial-to-trial improvement, or learning, in animals cannot be based completely on permanent memory storage. Amnesia can be produced by electroshock and drugs even if the animals are given the treatment long after they have demonstrated "learning" of the task. Of particular interest is the finding that retention of the inhibitory avoidance response increases with time. In a sense this should be expected, for it has long been known (and ignored) that, within limits, learning is facilitated by increasing the interval between repeated trials (7, 30). Our result may be the simplest case of such an effect. Since the improvement in retention with time seemed not to be due solely to consolidation (as indicated by electroshock effects), it would seem that the "distribution of practice" effect, as it is typically designated, may be due in part to a time-dependent temporary memory storage process. In our work with animals we have found no analog of human immediate memory such as that required for repeating digits (or finishing sentences). Animals tested immediately on the task described above after a trial typically showed no evidence of memory. It could be that the poor performance is due to excessive fright, but the "distribution of practice effect" is also typically observed in learning experiments in which food reward is used rather than shock avoidance. Since the retention tasks require the animals to change their behavior in some way, it could well be that the growth of retention over the first few minutes after a trial is due to time dependent processes involved in the organization of processes necessary for changing behavior, in addition to those involved in temporary storage and retrieval. It is worth pointing out that there is evidence of an analogous process in human memory (32). A complex picture of memory storage is emerging. There may be three memory trace systems: one for immediate memory (and not studied in our laboratory); one for short-term memory which develops within a few seconds or minutes and lasts for several hours; and one which consolidates slowly and is relatively permanent. The nature of the durability of the longterm memory trace (that is, the nature and basis of forgetting) is a separate but important issue. There is increasing evidence and speculation (20, 21, 33) that memory storage requires a "tritrace" system, and our findings are at least consistent with such a view. If there are, as seems possible, at least three kinds of traces involved in memory storage, how are they related? Is permanent memory produced by activity of temporary traces (31), or are the trace systems relatively independent? Although available findings do not provide an answer to this question, there does seem to be increasing evidence that the systems are independent. Acquisition can occur, as we have seen, without permanent consolidation, and both short-term and long-term memory increase with time. All this evidence suggests (but obviously does not prove) that each experience triggers activity in each memory system. Each repeated training trial may, according to this view, potentiate short-term processes underlying acquisition while simultaneously enhancing independent underlying long-term consolidation. Obviously, acceptance of these conclusions will require additional research. If this view is substantially correct, it seems clear that any search for the engram or the basis of memory is not going to be successful. Recognition of the possibility that several independent processes may be involved at different stages of memory may help to organize the search. A careful examination of the time course of retention and memory trace consolidation, as well as examination of the bases of the effects of memory-impairing and memory-facilitating treatments, may help to guide the search. It is clear that a complete theory of memory storage must eventually provide an understanding of time-dependent processes in memory. In 1930 Lashley wrote (2), "The facts of both psychology and neurology show a degree of plasticity, of organization, and of adaptation and behavior which is far beyond any present possibility of explanation." Although this conclusion is still valid, the current surge of interest in memory storage offers hope that this conclusion may soon need to be modified.

Electroconvulsive shock effects on a reactivated memory trace: further examination.

Rats showed amnesia for conditioned fear training if given an electroconvulsive shock immediately after training. Retention was unimpaired, however, when the electroconvulsive shock treatment was given 1 day after training immediately after the presentation of the stimulus used in the fear conditioning training. These results support the view that electroconvulsive shock disrupts memory trace consolidation but does not disrupt a recently reactivated memory trace.

Retrograde amnesia: electroconvulsive shock effects after termination of rapid eye movement sleep deprivation.

Mice that were deprived of rapid eye movement sleep for 2 days immediately after one-trial training in an inhibitory avoidance task and were given an electroconvulsive shock after deprivation displayed retrograde amnesia on a retention test given 24 hours later. Electroconvulsive shock produced no amnesia in comparable groups of animals that were not deprived of rapid eye movement sleep.

Permanence of retrograde amnesia produced by electroconvulsive shock.

The permanence of retrograde amnesia produced for a single training trial by a single electroconvulsive shock was studied. No recovery from amnesia was found with either single or repeated retention tests. Amnesic effects were found to be permanent with retention intervals as long as 1 month.

Retrograde amnesia gradients: effects of direct cortical stimulation.

Electrical stimulation was delivered bilaterally to either the anterior or posterior cortex in rats from 0.1 second to 4 hours after a single training trial on an inhibitory avoidance task. As indicated by a retention test given 24 hours later, the length of the retrograde amnesia gradients ranged from 5 seconds to 240 minutes, depending on the brain region stimulated and the intensity of the stimulating current. The stimulation intensity that was threshold for amnesia varied directly with the length of the interval between training and treatment.

Effects of Electroshock on Memory: Amnesia without Convulsions.

Mice received a single training trial on an inhibitory avoidance task and a retention trial 24 hours later. Electroshock stimulation, administered 25 seconds after the training trial, produced amnesia even if the convulsion was prevented by ether anesthesia. The amnesia produced by such shock is apparently due to the electric current and not to the convulsion.

Theta rhythm: a temporal correlate of memory storage processes in the rat.

We examined the amount of theta rhythm (4 to 9 hertz) in cortical electroencephalograms of rats for 30 minutes after training in one-trial tasks. Some animals received electroconvulsive shock after training. The amount of theta in the electroencephalogram after training was positively correlated with the degree of subsequent retention of a footshock, whether animals had received electroconvulsive shock or not.

Changes in protein levels in perfusates of freely moving cats: relation to behavioral state.

Perfusates from the brains of freely moving cats, obtained by means of a push-pull cannula, contain high concentrations of proteins. The levels vary in a cyclic fashion and are higher during rapid eye movement sleep than during the waking state. The proteins represent a distinctive class of tissue protein and their changing levels appear to reflect an alteration in the protein content of the extracellular space of brain related to behavioral state.

Electroshock effects on brain protein synthesis: relation to brain seizures and retrograde amnesia.

The effects of electroshock on brain seizure activity and brain protein synthesis were studied in male mice. A significant but short-lasting inhibition of brain protein synthesis and an increase in the amount of free leucine were produced by electroshock at intensities above the brain seizure threshold. Electroshock at intensities below the brain seizure threshold did not affect brain protein synthesis.

Retrograde amnesia and the "reminder effect": an alternative interpretation.

Recent findings suggest that amnesic agents block the retrieval of stored information. "Reminder" treatments, such as noncontingent punishments given after the production of amnesia for avoidance learning, improve the later retention performance of an animal. The data reported suggest that noncontingent treatments provide an additional learning experience which adds to the retention performance of partially amnesic or poorly trained animals.

Memory retrieval impairment induced by hippocampal CA3 lesions is blocked by adrenocortical suppression.

There is evidence that in rats, partial hippocampal lesions or selective ablation of the CA3 subfield can disrupt retrieval of spatial memory and that hippocampal damage disinhibits hypothalamic-pituitary-adrenocortical (HPA)-axis activity, thereby elevating plasma levels of adrenocorticotropin and corticosterone. Here we report evidence that attenuation of CA3 lesion-induced increases in circulating corticosterone levels with the synthesis inhibitor metyrapone, administered shortly before water-maze retention testing, blocks the impairing effects of the lesion on memory retrieval. These findings suggest that elevated adrenocortical activity is critical in mediating memory retrieval deficits induced by hippocampal damage.

Mechanisms of emotional arousal and lasting declarative memory.

Neuroscience is witnessing growing interest in understanding brain mechanisms of memory formation for emotionally arousing events, a development closely related to renewed interest in the concept of memory consolidation. Extensive research in animals implicates stress hormones and the amygdaloid complex as key, interacting modulators of memory consolidation for emotional events. Considerable evidence suggests that the amygdala is not a site of long-term explicit or declarative memory storage, but serves to influence memory-storage processes in other brain regions, such as the hippocampus, striatum and neocortex. Human-subject studies confirm the prediction of animal work that the amygdala is involved with the formation of enhanced declarative memory for emotionally arousing events.

The neurobiology of learning and memory: some reminders to remember.

We have learned much about the neurobiology of learning and memory in the past 100 years. We have also learned much about how we should, and should not, investigate these complex processes. However, with the rapid recent growth in the field and the influx of investigators not familiar with this past, these crucial lessons too often fail to guide the research of today. Here we highlight some major lessons gleaned from this wealth of experience. These include the need to carefully attend to the learning/performance distinction, to rely equally on synthetic as well as reductionistic thinking, and to avoid the seduction of simplicity. Examples in which the lessons of history are, and are not, educating current research are also given.

Modulation of memory storage.

For several decades, the concept of modulation of memory storage has significantly influenced research investigating neurobiological memory mechanisms. New evidence provides additional support for the view that stress hormones released during emotionally arousing situations modulate memory processes. Recent experiments have investigated the role of sympathetic adrenomedullary hormones in emotional memory in humans, as well as the role of adrenocortical hormones, primarily in animal studies. Further, it is becoming increasingly clear that the sympathetic adrenomedullary and the pituitary adrenocortical systems interact to modulate memory storage. Other new evidence emphasizes the role of peripheral influences to the brain on emotional memory, as well as the critical contribution of the amygdaloid complex in modulation of memory by emotional arousal.

Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions.

Extensive evidence from rat and human studies indicates that glucocorticoid hormones influence cognitive performance. Posttraining activation of glucocorticoid-sensitive pathways dose-dependently enhances the consolidation of long-term memory. Glucocorticoid effects on memory consolidation rely on noradrenergic activation of the basolateral amygdala and interactions of the basolateral amygdala with other brain regions. Glucocorticoids interact with the noradrenergic system both at a postsynaptic level, increasing the efficacy of the beta-adrenoceptor-cyclic AMP/protein kinase A system, as well as presynaptically in brainstem noradrenergic cell groups that project to the basolateral amygdala. In contrast, memory retrieval and working memory performance are impaired with high circulating levels of glucocorticoids. Glucocorticoid-induced impairment of these two memory functions also requires the integrity of the basolateral amygdala and the noradrenergic system. Such critical interactions between glucocorticoids and noradrenergic activation of the basolateral amygdala have important consequences for the role of emotional arousal in enabling glucocorticoid effects on these different memory functions.

Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between beta- and alpha1-adrenoceptors.

Extensive evidence indicates that norepinephrine modulates memory storage through an activation of beta-adrenoceptors in the basolateral nucleus of the amygdala (BLA). Recent findings suggest that the effects of beta-adrenergic activation on memory storage are influenced by alpha1-adrenoceptor stimulation. Pharmacological findings indicate that activation of postsynaptic alpha1-adrenoceptors potentiates beta-adrenoceptor-mediated activation of cAMP formation. The present study examined whether inactivation of alpha1-adrenoceptors in the BLA would alter the dose-response effects on memory storage of intra-BLA infusions of a beta-adrenoceptor agonist, as well as that of a synthetic cAMP analog. Male Sprague Dawley rats received bilateral microinfusions into the BLA of either the beta-adrenoceptor agonist clenbuterol (3-3000 pmol in 0.2 microliter) or 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo-cAMP) (0.2-7 nmol in 0.2 microliter) alone or together with the alpha1-adrenoceptor antagonist prazosin (0.2 nmol) immediately after training in an inhibitory avoidance task. Retention was tested 48 hr later. Clenbuterol induced a dose-dependent enhancement of retention, and prazosin attenuated the dose-response effects of clenbuterol. Posttraining intra-BLA infusions of 8-bromo-cAMP also induced a dose-dependent enhancement of retention latencies. However, concurrent infusion of prazosin did not alter the dose-response effects of 8-bromo-cAMP. These findings are consistent with the view that alpha1-adrenoceptors affect memory storage by modulating beta-adrenoceptor activation in the BLA. Moreover, these findings are consistent with those of pharmacological studies indicating that beta-adrenoceptors modulate memory storage by a direct coupling to adenylate cyclase, whereas alpha1-receptors act indirectly by influencing the beta-adrenoceptor-mediated influence on cAMP formation.

Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, c-fos, and zif268.

Neuronal immediate-early gene (IEG) expression is regulated by synaptic activity and plays an important role in the neuroplastic mechanisms critical to memory consolidation. IEGs can be divided into two functional classes: (1) regulatory transcription factors (RTFs), which can broadly influence cell function depending on the "downstream" genes they regulate, and (2) "effector" proteins, which may directly modulate specific cellular functions. The objective of the current study was to determine whether the expression of an effector IEG (Arc) was similar to, or different from, that of two well characterized RTF IEGs (c-fos and zif268) after learning. IEG RNA levels from rats trained in spatial and nonspatial water tasks were determined using RNase protection assays and in situ hybridization. Overall, the regulation of the three IEGs was similar in the hippocampus and the entorhinal and primary visual cortices. Consequently, IEG RNA levels were positively correlated within a structure. By contrast, Arc and zif268 RNA levels were not correlated or only weakly correlated across structures, although c-fos RNA levels were moderately correlated across structures. Arc RNA expression differed from that of zif268 and c-fos in two regards: (1) hippocampal Arc RNA levels were correlated with learning of the hippocampal-dependent spatial, but not hippocampal-independent cued response, water task, and (2) Arc RNA levels in the hippocampus and entorhinal cortex increased after spatial reversal learning relative to an asymptotic performance group. Thus, although the expression of Arc, zif268, and c-fos exhibited many similarities, Arc was most responsive to differences in behavioral task demands.

Basolateral amygdala-nucleus accumbens interactions in mediating glucocorticoid enhancement of memory consolidation.

Systemic or intracerebral administration of glucocorticoids enhances memory consolidation in several tasks. Previously, we reported that these effects depend on an intact basolateral nucleus of the amygdala (BLA) and efferents from the BLA that run through the stria terminalis (ST). The BLA projects directly to the nucleus accumbens (NAc) via this ST pathway. The NAc also receives direct projections from the hippocampus and, therefore, may be a site of convergence of BLA and hippocampal influences in modulating memory consolidation. In support of this view, we found previously that lesions of either the NAc or the ST also block the memory-modulatory effect of systemically administered glucocorticoids. The present experiments examined the effects of lesions of the NAc or the ST on the memory-modulatory effects of intracerebral glucocorticoids on inhibitory avoidance training. Microinfusions of the specific glucocorticoid receptor agonist 11beta,17beta-dihydroxy-6,21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one (RU 28362; 1.0 or 3.0 ng) into either the BLA or the hippocampus of male Sprague Dawley rats administered immediately after training enhanced the 48 hr retention performance in a dose-dependent manner. Bilateral lesions of the NAc or the ST alone did not affect retention performance but blocked the memory enhancement induced by intra-BLA or intrahippocampal glucocorticoid receptor agonist administration. These findings indicate that the BLA-NAc pathway plays an essential role in mediating glucocorticoid effects on memory consolidation and suggest that the BLA interacts with hippocampal effects on memory consolidation via this pathway.

Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory.

It is widely believed that the brain processes information and stores memories by modifying and stabilizing synaptic connections between neurons. In experimental models of synaptic plasticity, such as long-term potentiation (LTP), the stabilization of changes in synaptic strength requires rapid de novo RNA and protein synthesis. Candidate genes, which could underlie activity-dependent plasticity, have been identified on the basis of their rapid induction in brain neurons. Immediate-early genes (IEGs) are induced in hippocampal neurons by high-frequency electrical stimulation that induces LTP and by behavioral training that results in long-term memory (LTM) formation. Here, we investigated the role of the IEG Arc (also termed Arg3.1) in hippocampal plasticity. Arc protein is known to be enriched in dendrites of hippocampal neurons where it associates with cytoskeletal proteins (Lyford et al., 1995). Arc is also notable in that its mRNA and protein accumulate in dendrites at sites of recent synaptic activity (Steward et al., 1998). We used intrahippocampal infusions of antisense oligodeoxynucleotides to inhibit Arc protein expression and examined the effect of this treatment on both LTP and spatial learning. Our studies show that disruption of Arc protein expression impairs the maintenance phase of LTP without affecting its induction and impairs consolidation of LTM for spatial water task training without affecting task acquisition or short-term memory. Thus, Arc appears to play a fundamental role in the stabilization of activity-dependent hippocampal plasticity.