Consolidation of Memory Research Paper

These ideas were the precursors of the more formal neurobiological view of memory formation proposed by Donald Hebb (1949). Hebb proposed a dual-trace hypothesis of memory consolidation. According to this hypothesis, a learning experience initiates reverberating activity in neural circuits which serves both as a holding mechanism for short-term memory and as a process integral to changing synaptic connections to establish new circuits for long-term memory. This hypothesis therefore used two memory traces, working in a serial manner, to explain how a memory evident immediately after an experience is transitional to a permanent memory trace. The reverberating circuits, dependent on sustained neurophysiological activity, were labile, resulting in memory that was susceptible to perturbation until relatively permanent and stable circuit modifications were established.

The dual-trace hypothesis was supported by clinical findings that head trauma produced retrograde amnesia, the loss of recent memories prior to injury, and anterograde amnesia, the loss of the ability to form new memories. According to a dual-trace hypothesis, retrograde amnesia is a time-dependent phenomenon resulting from the disruption of the continuing formation of memories not yet consolidated into long-term memory, while anterograde amnesia may be either transient or permanent resulting from disruption of brain mechanisms or systems responsible for initiating the processes that would lead to long-term memory.

The dual-trace model also drew support from clinical findings emerging during the preceding decade from the use of electroconvulsive therapy (ECT) to treat psychiatric disorders. Reports from clinical studies indicating that patients experienced retrograde amnesia for recent events prior to treatment were followed by extensive studies in laboratory animals testing the effects on memory of electroconvulsive shock and other treatments that alter brain functions. Many treatments, generally administered soon after training, induce retrograde amnesia. Retrograde amnesia has been noted in a wide range of species, including mammals and other vertebrates, as well as insects and molluscs, suggesting that memory consolidation is a process conserved in evolution.

2. Temporal Gradients of Retrograde Amnesia

The defining characteristic of retrograde amnesia is that the efficacy of a given treatment decreases with time after learning. For many years, considerable effort attempted to identify the temporal gradient of retrograde amnesia. The importance of this effort is that the temporal properties might reveal the time course of memory consolidation, a time constant of great importance for identifying likely biological candidates for the mechanisms of memory formation. However, under some conditions the temporal gradient was very short, one second or less, and under other conditions the gradient was very long. Thus, the timecourse proved to be quite variable and the gradient was eventually found to depend on many factors. Some, such as task, species, motivation, time of day, might be considered to be intrinsic to memory formation itself. Others such as severity of head trauma in humans, or intensity or dose of a treatment in laboratory animals, are not properties of memory per se. Therefore, it became evident that it is unlikely that a single temporal gradient reveals the time required for memory formation. Rather, the findings indicate that memory gradually becomes less susceptible to modification with time after an experience (Gold and McGaugh 1975).

The time-course for loss of susceptibility spanning several hours, and the multiple temporal gradients observed with different treatments, suggests that memory consolidation may reflect the accrual of biological consequences of an experience, including gene expression and protein synthesis. The role of protein synthesis in consolidation of memory is further supported by extensive findings showing that drugs that interfere with protein synthesis produce retrograde amnesia. However, interpretation of this evidence is complicated by findings that many classes of drugs, including drugs acting to augment or to impair neurotransmitter functions, block the effects of antibiotics on memory without reversing the inhibition of protein synthesis.

Recently, the term-memory consolidation has been used to define a phenomenon with somewhat different properties. Experiments indicate that ECT treatments administered to humans can induce retrograde amnesia for events occurring years prior to the treatments. Also, under some circumstances, surgical removal of the hippocampus produces retrograde amnesia for events that preceded surgery by weeks in rodents and months in nonhuman primates. In one sense, these experiments are analogous to those of other studies of memory consolidation, demonstrating time-dependent retrograde amnesia. However, there are also significant differences. First, the time-course of the amnesia extends well beyond the neurobiological processes likely to underlie the formation of memory. Second, most experiments involve treatments, for example, removal of the hippocampus, that result in a permanently altered brain. Therefore, these long temporal gradients seem more likely to reflect continuing reorganization of the neural substrates of memory storage, perhaps modifying the continual integration of old and new memories.

3. Posttraining Design

Beyond the specific information offered about memory formation, research on memory consolidation has also provided an experimental design that has been extremely important in examining the effects of drugs and other treatments on memory. When drugs are administered chronically or soon before training, any effects observed on learning or on later memory might be attributable to actions on sensory functions, motor functions, or motivational factors at the time of learning. Distinguishing effects such as these from primary effects on memory is very difficult. In contrast, studies of memory consolidation, characterized by retroactive effects of treatments on memory, avoid all of these potential confounds. In these experiments, the treatment is administered after training. Also, memory is typically assessed one day or more later, at a time when the acute effects of the treatment have likely dissipated. Therefore, the experiment subjects are unaffected by the treatment at the times of training and testing. In addition, demonstration of retrograde amnesia gradients offers further support for interpretations based on effects memory. As the delay between training and treatment increases, the efficacy of the treatment diminishes. Such findings strongly support the view that any effects observed at the time of testing reflects actions on memory formation and not an extended proactive effect of the treatment at the time of testing. Because of the clarity of interpretation afforded by posttraining treatment experiments, studies of memory consolidation are used extensively to distinguish effects of treatments on memory from potential influences on performance.

4. Retrograde Enhancement of Memory

In addition to studies demonstrating that memory consolidation can be impaired by many treatments, there is also extensive evidence that memory can be enhanced by treatments administered after training. With findings spanning many species of research animals and many learning tasks, memory for recent information can be enhanced by stimulant drugs and by low-level stimulation of specific brain regions such as the mesencephalic reticular formation and the amygdala. Importantly, the enhancement of memory seen with these treatments, like those of amnestic treatments, is greatest when the treatment is administered soon after training and loses efficacy with time after training. Thus, memory consolidation can be both enhanced or impaired by posttraining treatments.

5. Endogenous Modulation of Memory Consolidation

Depending on the drug dose used and other experimental conditions, many treatments can either enhance and impair memory. The dose-response curve for most treatments follows an inverted-U function, in which low doses are ineffective, intermediate doses enhance memory, and high doses impair memory. Moreover, the peak of the dose-response curve interacts with such factors as arousal or stress induced by the training conditions. Generally, higher trainingrelated arousal results in lower doses to enhance or to impair memory. Thus, physiological responses to training apparently summate with physiological responses to the treatments in modifying memory formation.

5.1 Hormonal Regulation of Memory Formation

These findings support the view that endogenous physiological responses to training, such as neuroendocrine events, may modulate memory formation. Considerable evidence indicates that some hormones, when administered soon after training, modulate later memory. These hormones include epinephrine, norepinephrine, vasopressin, adrenocorticotropin, and glucocorticoids.

The susceptibility of memory consolidation to modulation by hormones appears to reflect an ability of hormonal consequences of an experience to regulate the strength of memory formed for that experience. According to this view, memory consolidation enables the significance of events, reflected in hormonal responses, to control how well the events will be remembered. In this context, the conservation of the phenomenon of memory consolidation across evolution may represent the establishment and maintenance of a mechanism for selecting important memories as those that should be retained (Gold and McGaugh 1975).

5.2 Epinephrine Regulation of Memory Formation

The adrenal medullary hormone epinephrine is one of the best-studied examples of hormonal modulation of learning and memory. Posttraining injections of epinephrine enhance memory for a wide range of tasks in experiments with rats and mice. The enhancement follows an inverted-U dose-response curve, in which high doses can impair memory. Moreover, the effective doses, and interactions with training-related arousal, match well against measurements of circulating epinephrine levels after training. In humans, propranolol, a β-adrenergic antagonist that blocks epinephrine receptors, blocks memory for story elements containing high arousal. Propranolol also blocks enhancement of memory for word lists by experimentally induced arousal.

Because epinephrine does not enter the central nervous system in appreciable extent, it is likely that the hormone enhances memory consolidation by peripheral actions. Two major candidates, which are not mutually exclusive, for peripheral mechanisms mediating epinephrine effects on memory are actions on adrenergic receptors on the ascending vagus nerve, with terminations in the brain in the region of the nucleus of the solitary tract, and classic physiological actions on hepatic receptors to increase blood levels of glucose, a substance that has ready access to the brain. Electrical stimulation of vagal afferents to the central nervous system enhances memory in both rats and humans. Also, inactivation of the nucleus of the solitary tract blocks memory-enhancement induced by posttraining administration of epinephrine.

5.3 Glucose Regulation of Memory Formation

A second mechanism by which epinephrine may act to enhance memory is by liberating glucose from hepatic stores, thereby raising blood glucose levels. Because glucose enters the brain readily via a facilitated transport mechanism, glucose then may be an intermediate step between peripherally acting epinephrine and actions on the brain to modulate memory (Gold 2001).

Administration of glucose enhances memory in rats, mice, and humans. The effects of glucose on memory in these species are characterized by an inverted-U dose-response curve. In humans, glucose enhances memory consolidation in a posttraining design, one rarely used in studies of pharmacology of memory in humans. Also, glucose enhances memory in a wide range of humans, including healthy young and elderly adults, as well as individuals with Down syndrome and Alzheimer’s disease. The parallels in humans and laboratory animals between the effects on memory of glucose, as well as of epinephrine and other treatments noted here, are striking and suggest that transitions from studies of memory consolidation in nonhuman animals may contribute significantly to the development of pharmacological treatments to ameliorate cognitive deficits in a range of human conditions (Korol and Gold 1998).

In rats, glucose enhances memory for some tasks when infused in small volume into specific brain areas, such as the medial septum, hippocampus, and amygdala. Although traditional thought was that the brain had a surplus supply of glucose, except under conditions of severe food deprivation, recent evidence indicates that cognitive activity can deplete extracellular glucose levels in the hippocampus during spatial learning. Administration of glucose at doses that enhance memory blocks that depletion. Thus, enhancement of memory may reflect actions to reverse a natural limitation on the glucose reserves of some brain areas. While the proximal mechanism by which glucose enhances memory is not clear, in many instances the effects of glucose on memory appear to be associated with augmented release of acetylcholine in the hippocampus, an action that may be indirect.

5.4 Amygdala Integration of Modulatory Influences on Memory

Other neurotransmitters also appear to have important roles in modulating memory processes. Considerable evidence indicates that norepinephrine, particularly in the basolateral nucleus of the amygdala (BLA), is important in mediating the effects of many treatments on memory. For example, infusions of βadrenergic agonists into the BLA after training enhance memory. Conversely, lesions of the BLA or infusion of β-adrenergic antagonists into the BLA block both enhancement and impairment of memory consolidation by hormones and other treatments. Also, in contrast to findings with healthy human subjects, emotional arousal does not enhance memory in individuals with lesions of the amygdala. Together, these findings support the view that the BLA may play a key role in memory formation by integrating the effects on memory of a broad range of treatments (McGaugh 2000, Cahill and McGaugh 1996).

6. Neural Systems and Memory Consolidation

There is considerable evidence that different neural systems mediate processing of different forms of memory. When administered systemically, many drugs enhance or impair memory for many kinds of tasks. However, when drugs are administered directly into specific brain regions, they may modulate memory for a more restricted set of tasks. For example, amphetamine infused into the hippocampus enhances memory for spatial learning in a swim task but not for learning to find a platform identified with a salient proximal cue. Amphetamine infused into the striatum enhances the cued but not the spatial version of the task. Amphetamine enhanced memory for both tasks when infused into the amygdala after training, consistent with the view that the amygdala integrates modulation of many types of memory.

Many other tasks involve contributions to learning of more than one neural system at a time. Interactions between different memory systems can determine the manner in which a rat solves a maze, perhaps learning on the basis of extra maze cues (e.g., turn toward the light) or perhaps learning on the basis of making a particular response (e.g., turn right). Recent studies have begun to integrate aspects of memory consolidation with neural system approaches to learning and memory. When viewed in this context, modulation of memory may have an important role in biasing what is learned by boosting or blunting memory processing in different neural systems.

7. Cell and Molecular Biology Bases of Memory Formation

Studies of memory consolidation provide a firm basis for examination of memory storage processing that continues for a considerable time after an experience (McGaugh 2000). With this information, several approaches have been taken to identify the nature of the brain systems and mechanisms involved in these processes. Studies of functional brain activation in humans show changes over a period of several hours in the regions activated by learning, perhaps indicating that memory consolidation involves reorganization of brain representations of memory during the time after an experience. The cellular and molecular events that are initiated by an experience, continue for considerable time after that experience, and are important to memory formation for that experience, are currently a topic of much investigation. By evident analogy with shortand long-term memory, cellular and molecular biology contributions are often sorted into those that affect early or late (protein synthesis-dependent)phase memory. The molecular bases are derived also from an analogy, or mechanism depending on one’s view, between long-term potentiation and memory. The early stage of memory consolidation appears to involve CaMKII (calcium-calmodulin-dependent protein kinase II). Inhibitors of CaMKII injected into either the hippocampus or amygdala shortly after training produce retrograde amnesia. When injected into the hippocampus, inhibitors of PKC (protein kinase C) or PKA (protein kinase A) produce retrograde amnesia even if administered hours after training. Moreover, PKA activity and CREB (cAMP response element-binding protein) immunoreactivity increase in the hippocampus up to hours after training, suggesting that the late phases of memory consolidation may involve cAMP-mediated activation, by PKA phosphorylation, of the CREB transcription factor.

There is evidence that earlyand late-phase memory consolidation can be impaired independently by some treatments. However, there are also conditions in which earlyand late-phases are both impaired by a single treatment. These issues return to some raised by Hebb’s initial dual process hypothesis of memory formation. At the levels of both neural systems and cellular and molecular neurobiology, it now seems quite likely that research findings will eventually reveal some neural systems and biochemical processes that act in series and others that act in parallel.

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