Memory Consolidation

Stages of Memory Consolidation

Most experimental research on memory consolidation has focused on a time window of several hours after learning. However, evidence that memory consolidation may continue for weeks, months, and perhaps even years in humans, suggests that there are different stages of memory consolidation.

Evidence that different stages of consolidation rely on different cellular mechanisms and brain systems has been provided by human and animal studies showing that lesions of the hippocampus generally impair memory of recently learned information (i.e., within days or weeks prior to the lesion), whereas the ability to recall older memories is preserved.

Thus, although the hippocampus and related structures are crucially involved in mediating the consolidation of several types of memory, other brain areas appear to play a more prominent role as loci of consolidation and storage at later stages.

The time-limited role of the hippocampus for the storage of some types of memory has led to the widely accepted view of systems consolidation, in which neural alterations associated with memory consolidation and storage occur first in the hippocampus followed by the gradual consolidation of a more distributed memory trace in neocortical areas.

This view is supported by findings from animal studies where the effects of pharmacological manipulations of different brain areas on memory consolidation depend on the time interval between training and intervention.

Thus, memory consolidation and storage would involve the sequential activity of the hippocampus followed by cortical areas such as the entorhinal and posterior parietal cortices.

More recently, evidence suggesting that the memory-related engagement of cellular mechanisms involved in synaptic plasticity occurs in the hippocampus and cortical areas with a similar time course has indicated the need for a more complex model in which long-term consolidation in humans depends on a complex and integrated interplay between the hippocampus and cortical areas rather than on a simple sequential activation of brain structures.

Multiple Memory Systems

An important aspect of memory formation is the evidence that different types of memory are mediated by relatively independent brain systems.

Considerable evidence indicates that the early consolidation of cognitive or declarative memories relies mostly upon the medial temporal lobe (e.g., hippocampus), whereas the formation of procedural and habit memories depends on the basal ganglia (e.g., caudate putamen and striatum).

Converging evidence from animal and human studies suggest that multiple memory systems can be activated simultaneously and in parallel by learning, and interact and compete with each other in influencing the behavioral responses after learning.

For instance, a rat trained to find a reward (such as food) in the right arm of a maze might simultaneously learn two types of memory: where to go to find food (a memory based on spatial location) and what behavioral response to make (i.e., turn right to get into the arm where the food is).

Experimental evidence using different amounts of training and functional inactivation of the hippocampus and caudate nucleus prior to testing indicates that formation of the place memory relies primarily on the hippocampus and the response memory involves the caudate nucleus.

In addition, evidence indicates that both hippocampus – and basal-ganglia-based types of memory receive neuromodulatory influence from the amygala.

Interaction of Brain Systems in Modulating Memory Consolidation

1. Amygdala

The amygdala is a nuclear complex in the dorsomedial portion of the temporal lobe that forms part of the limbic system. It comprises several functionally and anatomically distinct nuclei: the central nucleus, the medial nucleus, the cortical portions, and the basolateral complex or basolateral amygdala (BLA; basal, lateral, and accessory basal nuclei). The amygdala has many connections to and from subcortical and cortical brain areas.

2. Basolateral amygdala (BLA)

The BLA comprises the basal, lateral, and accessory basal nuclei of the amygdala. Extensive evidence indicates that the BLA is the portion of the amygdala which is critical in mediating modulatory influences on memory consolidation.

3. Calcium-calmodulin-dependent protein kinase II (CaMKII)

A protein kinase activated by calcium. In neurons, CaMKII activation in response to increases in cellular calcium is a key biochemical event downstream of glutamine receptor activation associated with synaptic plasticity.

4. Caudate nucleus

A major component of the basal ganglia, together with the putamen and globus pallidus. The caudate nucleus has been shown to play a crucial role in formation of some types of memory, such as response memories.

5. Corticosterone

The main glucocorticoid hormone in rodents. Glucocorticoids are secreted by the adrenal cortex and regulate several aspects of the brain function, including consolidation of emotional memory.

6. Cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)

A protein activated by cAMP that increases gene transcription by binding to specific regions of DNA. CREB has been shown to play a major role in stimulating gene transcription associated with synaptic plasticity and memory consolidation.

7. Entorhinal cortex (EC)

Cortical area located in the anterior part of the parahippocampal gyrus. The EC provides inputs to both the hippocampus and the amygdala and is importantly involved in memory consolidation. The EC is one of the first areas to be affected in patients with Alzheimer’s disease Opens in new window.

8. Epinephrine

Usually referred to as adrenaline, epinephrine is a catecholamine hormone released by the adrenal medulla. Epinephrine modulates memory consolidation, probably by activating vagal afferents to the brain.

9. Extracellular signal-regulated protein kinase (ERK)

ERKs are a subset of the mitrogen-activated protein kinase (MAPK) family of protein kinase (MAPK) family of protein kinases involved in intracellular signaling. ERK-mediated signaling downstream of receptor activation in neurons plays a major role in synaptic plasticity and memory formation.

10. Hebbian synapse

A concept describing memory formation at the synaptic level.

In his book published in 1949, the psychologist DO Hebb proposed a hypothesis of memory based on the assumption that when two neural cells are activated simultaneously, structural or metabolic changes would increase the efficiency of communication between the cells. Such a mechanism would be the cellular basis for the consolidation and storage of long-term memory.

11. Hippocampus

The hippocampus is part of the limbic system, located in the medial temporal lobe. It plays an important role in the formation of new memories, particularly declarative memory involving spatial or contextual information.

12. Norepinephrine

Norepinephrine or noradrenaline is a catecholamine that acts as a neurotransmitter in both the brain and peripheral nervous system upon release by noradrenergic neurons.

Norepinephrine in brain areas, including the amygdala, has been shown to mediate modulatory influences on consolidation of emotional memory.

13. Nucleus accumbens (NAcc)

This is a brain structure that is part of the basal ganglia. The NAcc is connected to the BLA and plays a role in modulating memory consolidation.

Consolidation and Reconsolidation

The traditional consolidation theory has been challenged in recent years by evidence that reactivations of a previously consolidated memory during retrieval might again render this memory susceptible to disruption by amnesic treatments, a process generally referred to as reconsolidation.

The concept of memory reconsolidation was initially proposed in the 1960s, yet it was only in 2000 that a new wave of studies showing that administration of drugs to animals after retrieval could impair memory assessed at subsequent retention tests sparked considerable interest in reconsolidation.

Although reconsolidation has been defined by experiments using intra-cerebral infusions of protein synthesis inhibitors, several studies have extended the candidate mechanisms involved in reconsolidation-like processes to a number of neuronal receptors and signal transduction pathways.

Thus, experiments using systemic or intra-cerebral injections in rodents have shown that memory for emotionally motivated tasks can be impaired by postretrieval administration of a variety of pharmacological agents, including

• benzodiazepines,
• antagonists of glumatergic,
• noradrenergic and glucocorticoid receptors, and
• inhibitors of protein kinases such as PKA and ERK/MAPK.

These studies argue in favor of the so-called ‘reconsolidation hypothesis’ based on findings of amnesia produced by postretrieval interventions. As with consolidation and extinction, brain areas mediating the effects of postretrieval amnesic treatments include the dorsal hippocampus and basolateral amygdala.

Other studies, however, have provided evidence against reconsolidation, showing negative results (i.e., lack of the effect of postretrieval treatments) or opposite effects related to memory extinction.

Another major caveat for the reconsolidation hypothesis is that many of the findings interpreted as possible reconsolidation impairments have been shown to be transient or reversible.

The recovery of the deficits induced by postretrieval interventions can be either spontaneous or triggered by reminders. This has led to the interpretation of many findings as temporary retrieval deficits rather than reconsolidation blockades.

Other studies, however, have provided evidence for reconsolidation by showing long-lasting memory impairment after postretrieval administration of amnesic treatments, with no detectable recovery. Evidence has been also provided suggesting that, as with consolidation, memories can undergo reconsolidation at both the cellular and systems level.

Taken together, the evidence suggests that the occurrence of reconsolidation-like processes in animals in an experimental setting depends on several factors including duration of exposure to the original context, absence of significant extinction, time interval between learning and retrieval, and encoding of new information at the time of retrieval.

At this point, it seems clear that under specific conditions, either temporary or long-lasting labialization of recently learned memory traces can occur.

It may be possible to reconcile the apparent discrepant findings regarding the reconsolidation phenomenon by viewing consolidation and reconsolidation as different but integrated components of the long-term processes underlying memory storage.