What is the term for the process of converting memories from short term to long

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. The early stage is very likely to be that suggested by Müller and Pilzecker, and Hebb. 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.

1.27.2.4.2 Reconsolidation of the CSM

CSM retention can be observed 24 h after spaced training when the crabs are exposed to the VDS in the training context. When the crabs are exposed to the training context without the presentation of the VDS, a conditioned response is not elicited (Pedreira et al., 2002). Nevertheless, this exposure to the training context has an impact on subsequent memory retention. Namely, the combination of a 5-min context exposure 24 h after training with an injection of protein synthesis inhibitor leads to the inhibition of CSM memory retention 1 day later (Pedreira et al., 2002) (Figure 14(a)). The reconsolidation phenomenon has been induced accordingly.

Abstract

Memory consolidation involves neural processes through which new information is stabilized to result in the storage of enduring memories. A consistent body of evidence accumulated over several decades, particularly from studies using pharmacological interventions given after learning to rodents, has contributed to the understanding of mechanisms mediating and regulating consolidation. Emotional arousal stimulates endogenous systems including stress hormones, which in turn activate the amygdala. Through anatomical and functional interactions with other brain regions, the basolateral amygdala (BLA) modulates neurobiological processing leading to increased memory strength. This review focuses on our current understanding of memory consolidation and how it is regulated at the brain system and biochemical levels.

5.1.1 Memory consolidation

Memory consolidation is a fundamental process of long-term memory formation, as, in fact, has been described to occur in a multitude of different types of memories, species, and memory systems. It refers to the stabilization process of a newly formed long-term memory. Initially, the memory is in a fragile state and can be disrupted by several types of interference, including behavioral, pharmacological, and electrical. Over time, the memory becomes resilient to these forms of interference through the process known as consolidation (Alberini, Bambah-Mukku, & Chen, 2012; Davis & Squire, 1984; McGaugh, 2000). Memory consolidation involves synaptic and broad cellular events that include transcriptional, translational, and post-translational mechanisms, as well as their feedback and feedforward regulation. These molecular changes start with the initial encoding and evolve with time because memory consolidation seems to occur in stages (Alberini, 2008, 2009; Dudai, 1996, 2012; McGaugh, 2000; Squire & Alvarez, 1995). For example, the consolidation of medial temporal lobe-dependent memories, in addition to the cellular consolidation events just described, also involves a redistribution of the memory trace, such that it transitions from hippocampal-dependent to hippocampal-independent (Squire & Alvarez, 1995; Squire, Clark, & Knowlton, 2001; Squire, Stark, & Clark, 2004). Hence, memory consolidation appears to consist of multiple stages, which can be delineated based on the type of interference to which a memory trace is susceptible over time—for example, those that target molecular versus system mechanisms.

3 The Recent Molecular Biology of Memory

Memory processes are very complex. They can be decomposed into a number of various processes ranging from extremely short-term memory (milliseconds) to short-term memory (hours) and finally to long-term memory (days) or very long-term memory (decades).4

Memory consolidation is known to be a continuous process. Marra et al.2 have studied the susceptibility of memory consolidation during lapses in recall. It is known that memories that can be recalled several hours after learning may paradoxically become non-accessible for brief periods after their formation. This raises major questions about the function of these early memory lapses in the structure of memory consolidation. These questions are difficult to investigate due to the lack of information on the precise timing of lapses. Marra et al.2 have used electrophysiological and behavioral experiments in Lymnaea to solve this problem, which reveal lapses in memory recall at 30 minutes and 2 hours post-conditioning. These authors demonstrate that only during these lapses is consolidation of LTM susceptible to interruption by external disturbance. They show that these shared time points of memory lapse and susceptibility correspond to major transitions between separate phases of memory that have different and specific change in molecular mechanisms only during the early stages of memory formation. So it seems that recall of memory becomes more difficult when there are changes in molecular dependencies indicating that distinct molecular pathways are responsible for the different phases of memory formation.18 Their previous experiments revealed that these essential changes in molecular requirements are initiated following a single training trial during an early stage of memory consolidation.19,20 Subsequent downstream mechanisms cause recall between STM and early ITM (at 30 minutes) and between early and late ITM (at 2 hours) to become inherently weaker and susceptible. Marra et al.2 used the training paradigm leading to uninterrupted memory to test for mechanisms of recall failure at the critical times in their pharmacological blocking experiments. This raised the question whether the two training paradigms result in memories using similar or distinct molecular processes. They demonstrated that both training paradigms induced the same translation but not transcription-dependent ITM at 3 hours and protein and RNA synthesis-dependent LTM at 4 and 24 hours. During the identification of different phases of memory, they demonstrated that2:

the memory at 10 minutes is STM as characterized by the lack of requirement for protein and RNA synthesis;

the memory at 1 hour is ITM as characterized by the requirement for protein synthesis and the lack of requirement for new RNA synthesis;

the 4 hour memory trace is LTM because it requires both protein and RNA synthesis.

They proposed that during periods of molecular transition, memory recall is weakened, allowing novel sensory cues to block the consolidation of LTM.

In a review dedicated to the molecular biology of memory, Kandel21 stated that the contributions to synaptic plasticity and memory have recruited the efforts of many laboratories over the world. There are six key steps in the molecular biological delineation of STM and its conversion to LTM for both implicit (procedural) and explicit (declarative) memory: cAMP (cyclic adenosine monophosphate), PKA (protein kinase A), CRE (cAMP response element), CREB-1 (cAMP response element binding protein-1), CREB-2 (cAMP response element binding protein-2) and CPEB (cytoplasmic polyadenylation element binding protein).

In this major review,21 Kandel recalls the emergence of a molecular biology of memory-related synaptic plasticity and the delineation of cAMP and PKA in STM storage; and that classical conditioning involves both pre- and postsynaptic mechanisms of plasticity. He then developed the molecular biology of learning-related long-term synaptic plasticity. As previously stated, the formation of LTM requires the synthesis of new protein. An increase in the level of cAMP leads to longer lasting forms of synaptic plasticity. This more robust pattern of stimulation causes the catalytic subunit of PKA to recruit p42 MAPK (mitogen activated protein kinase) and both then move to the nucleus where they phosphorylate transcription factors and activate gene expression required for the induction of LTM. Various synaptic protein phosphatases act as inhibitors of memory formation as they locally counteract the activity of PKA, and the equilibrium between kinase and phosphorylase activities can regulate both memory storage and retrieval.22 In this review, Kandel21 explains the activation of nuclear transcription factors, how long-term synaptic changes are governed by both positive and negative regulators, and that the transition from short-term facilitation (STF) to long-term facilitation (LTF) requires the simultaneous removal of transcriptional repressors and activation of transcriptional activators. These transcriptional repressors and activators can interact with each other both physically and functionally.

For Kandel,21 it is likely that the transition is a complex process involving temporally distinct phases of gene activation, repression and regulation of signal transduction. As reported in the literature, the CREB-mediated response to extracellular stimuli can be modulated by kinases (PKA, CaMKII or calcium calmodulin-dependent protein kinases II, MAPK, PKC, etc.) and phosphatases (phosphoprotein phosphatase 1 or PP1 and calcineurin). The CREB regulatory unit may therefore serve to integrate signals from various signal transduction pathways. This ability to integrate signaling, as well as to mediate activation or repression, may explain why CREB is so central to memory storage. Chromatin alteration and epigenetic changes in gene expression have been observed with memory storage: integration of LTM-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure.23 Although, epigenetic mechanisms have been widely known to be involved in the formation and long-term storage of cellular information in response to transient environmental signals, the discovery of their putative relevance in adult brain function is relatively recent.23,24

The epigenetic marking of chromatin, such as histone modification, chromatin remodeling and the activity of retro transposons, may thus have long-term consequences in the transcriptional regulation of specific loci involved for long-term synaptic changes.25 LTM fundamentally differs from the short-term process in involving the growth of new synaptic connections. For Kandel21 the growth of new synapses may represent the final and perhaps most stable phase of LTM storage, raising the possibility that the persistence of the long-term process might be achieved, at least in part, because of the relative stability of synaptic structure. The fundamental difference between the storage of LTM and short-term changes is the requirement for the activation of gene expression. LTF and the associated synaptic changes are synapse specific and require CREB-1. For synaptic capture, there is not only a retrograde signaling from the synapse back to the nucleus, but also anterograde signaling from the nucleus to the synapse. The molecular mechanism of synaptic capture involves many factors such as PKA, CPEB that activates mRNA and CRE.21

Experimental Evidence

Memory consolidation takes probably about 5–10 minutes and consolidation is completed after about 1 hour or so – and it has been shown that if protein synthesis is blocked in animals during the acquisition of LTM then the formation of LTM is prevented (Guyton 2008, p. 726). Furthermore, it is documented that if protein synthesis is blocked after about 4 hours, it shows no effect on learning (Barrett et al. 2012, p. 285) – obviously because consolidation is completed and there is no need for new CAMs. Perhaps these experiments stand as good examples for the role of dendritic pleats in LTM.

3.23.1 Endogenous Modulation of Consolidation

Memory consolidation appears to be a highly adaptive function because, as noted earlier, evidence of consolidation is found in a wide variety of animal species. But, why do our long-term memories and those of other animals consolidate slowly? There seems to be no a priori reason to assume that neurobiological mechanisms are not capable of consolidating memory quickly. Considerable evidence suggests that the slow consolidation of memories may serve a highly important adaptive function by enabling endogenous processes activated by an experience, and thus occurring shortly after the event, to modulate memory strength (McGaugh and Roozendaal, 2009; McGaugh, 2015). In a paper published shortly after those reporting that posttraining drug administration can enhance memory consolidation (e.g., Breen and McGaugh, 1961; McGaugh, 1966), Livingston (1967) suggested that stimulation of the limbic system and brainstem reticular formation might promote the storage of recently activated brain events by initiating a “…neurohormonal influence (favoring) future repetitions of the same neural activities (p. 576).” Kety (1972) subsequently offered the more specific suggestion that adrenergic catecholamines released in emotional states may serve “to reinforce and consolidate new and significant sensory patterns in the neocortex… (p. 73).” Although the specific details of current findings and theoretical interpretations differ in many ways from those early views offered by Livingston and Kety, recent findings are consistent with their general hypotheses.

1.17.2.5.2 Reconsolidation of the Conditioned Stimulus

CSM retention can be observed 24 h after spaced training when the crabs are exposed to the VDS in the training context. When the crabs are exposed to the training context without the presentation of the VDS, a CR is not elicited (Pedreira et al., 2002). Nevertheless, this exposure to the training context has an impact on subsequent memory retention. Namely, the combination of a 5-min context exposure 24 h after training with an injection of protein synthesis inhibitor leads to the inhibition of CSM memory retention 1 day later (Pedreira et al., 2002; Fig. 14A). The reconsolidation phenomenon has been induced accordingly. The reconsolidation phenomenon is only induced when reexposure to the training context endures for less then 40 min. A longer reexposure to the training context leads to a new, context–no signal association, and hence extinction learning. This extinction learning results in an extinction memory that depends on protein synthesis (Pedreira and Maldonado, 2003; Fig. 14B). Thus, in crabs, the duration of the reexposure of the training context is critical for the consolidation process induced by the reminder (Pedreira and Maldonado, 2003; Pedreira et al., 2004): A short reexposure, which does not result in extinction, does lead to reconsolidation.

The offset of the reminder stimulus without the appearance of the VDS is critical for either reconsolidation or consolidation of the extinction memory to occur (Pedreira et al., 2004). Thus both consolidation processes, reconsolidation or the consolidation of an extinction memory, only take place when the nonoccurrence of the reinforcement (here the VDS) is irreversible due to the termination of the reminder (Pedreira et al., 2004). Pedreira et al. (2004) conclude that the mismatch between what is expected and what actually occurs triggers memory reconsolidation or extinction. Memory is not labialized when the reminder, i.e., the learning context exposure, is combined with the presentation of the VDS (Frenkel et al., 2005; Pedreira et al., 2004; Pérez-Cuesta and Maldonado, 2009). Thus, in this paradigm it is possible to differentiate between memory reactivation (by exposing the animals to the learning context) and memory retrieval, i.e., memory expression, by the combined exposure to the learning context and the VDS.

Memory Distinctions

Memory storage and memory retrieval mechanisms are known to differ in fundamental ways according to the type of memory in question. Likewise, memory consolidation proceeds differently for different types of memory.

A long-standing distinction in research on human memory allows for separate mechanisms for short-term storage lasting seconds, perhaps minutes, and long-term storage lasting much longer. Donald Hebb’s seminal proposal stated that reverberating neural circuits can keep an experience in mind for a short time, whereas structural changes in neuronal ensembles underlie storage that persists over longer periods. Mental representations of perceptual and conceptual information can be actively maintained through rehearsal. In this sense, short-term storage cannot be defined by a characteristic time span. Rehearsal can continue for an indefinite amount of time. The term immediate memory aptly draws attention to this aspect of memory and is akin to what William James termed primary memory. In contrast, secondary memory refers to information brought back to mind after earlier leaving one’s awareness, rather than information kept in mind through rehearsal. The length of the retention interval, short term versus long term, is thus not a suitable way by itself to differentiate between types of memory. Immediate memory (also known as working memory) belongs in a class by itself due to its dependence on the rehearsal of information.

Aside from immediate memory, there are several distinct ways in which behavior comes under the influence of past experience. Of central relevance for major territories of human cognition, declarative memory pertains to memory for complex facts and personally experienced events, and can be distinguished from a diverse set of memory phenomena collectively known as nondeclarative memory. Nondeclarative memory includes skill learning, habit learning, simple forms of conditioning, various types of priming that can be measured in implicit memory tests, and nonassociative forms of learning like habituation and sensitization.

Some of the molecular building blocks of memory storage are common across these different types of memory. Elaborate layers of molecular machinery can require some passage of time so as to complete the process of memory formation. In many cases, neural plasticity induced during learning can be modulated by subsequent events. Release of epinephrine and cortisol, for example, can allow emotional significance to regulate memory strength. Selective gene activation and protein synthesis also play key roles in stabilizing synaptic changes.

These aspects of memory fall in a category called synaptic consolidation. Relevant molecular changes can require minutes to hours. On the other hand, the present discussion focuses on neural mechanisms of systems-level consolidation that are specific to declarative memory and that tend to occur over a much longer timescale.

III.B.8 Memory Consolidation and the Cingulate Cortex

Memory consolidation refers to processes whereby memories become less susceptible to interference and disruption with the passage of time. It is commonly held that consolidation is based on rearrangements of the circuitry and neuroanatomical substrates involved in memory storage and retrieval. Thus, for example, it has been proposed that the hippocampus and neocortex are critically involved in the initial encoding of complex memory in humans but as the “age” of a given memory increases its dependence on the hippocampus decreases.

Previously, it was indicated that anterior and posterior cingulate cortex are critically involved respectively in mediating the early and late stages of discriminative avoidance learning of rabbits. Therefore, it might be assumed that the posterior cingulate cortex and related thalamic areas are the final sites of habit storage and retrieval. However, it is now known that neither anterior nor posterior cingulate cortex, or the related areas of the limbic thalamus, are involved in mediating discriminative avoidance learning in animals that are highly overtrained. Cingulothalamic lesions that normally block learning and prevent the expression of the learned behavior in subjects that are trained to asymptotic levels before they receive the lesions do not impair performance when they are induced after rabbits have been given extensive post asymptotic overtraining. Thus, in highly overtrained rabbits the brain processes involved in storage and retrieval of the discriminative avoidance habit occur entirely within noncingulate circuitry. These results are in accord with the findings concerning retrosplenial amnesia, suggesting that posterior cingulate cortex is involved in the mediation of memory for recently established memories but not for long-stored, “remote” memories. Similarly, lesions in the hippocampus, a region that is closely interconnected and highly interactive with posterior cingulate cortex, are associated with loss of recent memory but not of remote memory. The areas that mediate storage and retrieval of these remote memories have not been definitively identified, although it is widely assumed that the neocortex plays an important role.