Chapter Thirteen - The Tagging and Capture Hypothesis from Synapse to Memory

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Abstract

The synaptic tagging and capture theory (STC) was postulated by Frey and Morris in 1997 and provided a strong framework to explain how to achieve synaptic specificity and persistence of electrophysiological-induced plasticity changes. Ten years later, the same argument was applied on learning and memory models to explain the formation of long-term memories, resulting in the behavioral tagging hypothesis (BT). These hypotheses are able to explain how a weak event that induces transient changes in the brain can establish long-lasting phenomena through a tagging and capture process. In this framework, it was postulated that the weak event sets a tag that captures plasticity-related proteins/products (PRPs) synthesized by an independent strong event. The tagging and capture processes exhibit symmetry, and therefore, PRPs can be captured if they are synthesized either before or after the setting of the tag. In summary, the hypothesis provides a wide framework that gives a solid explanation of how lasting changes occur and how the interaction between different events leads to promotion, reinforcement, or impairment of such changes.

In this chapter, we will summarize the postulates of STC hypothesis, the common features between synaptic plasticity and memory, as well as a detailed compilation of the findings supporting the existence of BT process. At the end, we pose some questions related to BT mechanism and LTM formation, which probably will be answered in the near future.

Introduction

Lasting changes in synaptic plasticity strength and also in memory storage persistence are not only dependent on the characteristics of the stimuli that induce these changes. Events happening before and after these stimuli can also exert influence on the effects they have, raising an essential question about the mechanism that underlies this late-associativity phenomenon. The answer to this question came by considering that these lasting changes should occur selectively in inputs activated by the stimuli. This leads to the emergence of the synaptic tagging and capture (STC) hypothesis.1 The STC hypothesis proposed a cellular mechanism accounting for why a stimulation that normally leads to early long-term potentiation (early-LTP) could also induce long-lasting form of long-term potentiation (late-LTP) if a separate pathway converging on an overlapping population of neurons was strongly tetanized within a specific time window. The STC hypothesis declares that LTP involves the local tagging of synapses at the moment of induction. Thus, stimuli that induce early-LTP cause the transient activation of a synaptic tag, but only those stimuli that induce late-LTP will, besides from setting a tag, also initiate protein synthesis. Those tags capture plasticity-related proteins/products (PRPs) synthesized in the soma or local dendritic domains because of the strong tetanic stimulation, and the interaction between tag and PRPs is essential for stabilization of potentiation from early-LTP to late-LTP.

In this chapter, we will discuss the involvement of synaptic changes in the long-term memory (LTM) storage processes of the mammalian brain. Similar to those seen in synaptic plasticity assays, late-associative effects were also evidenced in learning and memory experiments in animals. It has been shown that a short-lasting memory induced by a weak training can be consolidated into a LTM if animals experience a strong event in a critical time window around the weak training. This process depends on protein synthesis induced by the strong associated experience and was originally named “behavioral tagging” (BT).2 It has been suggested that the weak training sets a learning tag where the PRPs provided by the strong event would be captured in order to establish a persistent mnemonic trace.

Both STC and BT propose analogue mechanisms by which long-term changes induced through electrophysiological stimulations or learning processes are meant to occur. The tagging and capture dynamics is an elegant theoretical framework that is also capable to explain why the persistence of neuronal potentiation as well as the duration of memory is not only dependent on events occurring at the moment of their induction, but also on other occurring previously or subsequently to the stimulus that modifies the activity of the involved neurons. In summary it provides a wide framework capable to explain in which way lasting changes occur and how the interaction between different events leads to promotions, reinforcements, or impairments of such changes.

In this chapter, we will summarize the postulates of STC hypothesis, the features in common between synaptic plasticity and memory (SPM), as well as a detailed compilation of the findings showing the effects of the interaction between electrophysiological and behavioral stimuli drawing a line between STC and BT processes.

Section snippets

The ABC of Tagging and Capture Mechanisms

The principal idea underlying this process is that proteins and other products related to plasticity (PRPs) are used to originate long-lasting changes when they are captured by specific tags. This hypothesis, initially postulated for synaptic plasticity potentiation,1 was demonstrated by separating the tagging stimulus from the PRPs inducing stimulus, by using a weak stimulus unable to induce PRP-dependent lasting changes and a strong independent event able to induce PRP-dependent lasting

Which Criteria Should Satisfy a Candidate for a Tag?

There are several criteria to be satisfied by a synaptic tag3, 4, 5, 6: a tag can be activated by weak stimulation that induces only early-LTP; the lifetime of a tag is transient lasting less than 2 h; the activation of a tag does not require protein synthesis; a tag is induced in an input-specific manner and is relatively immobile and finally a tag must interact with (and therefore capture) PRPs for late-LTP. Using similar assumptions a learning tag has also been defined, where a weak training

Memory Can Be Thought of as Changes in Synaptic Plasticity

It is widely accepted that neural activity induced by learning triggers changes in the strength of synaptic connections within the brain. The most relevant aspect of a memory trace is that those changes in behavior, occurring as a consequence of a learning experience, persist in time. In this way, a model of synaptic plasticity where brief stimulations of a neural pathway induce long-lasting changes in the synapses could provide plausible clues of the mechanisms underlying the formation of

Synaptic Plasticity Was Improved In Vivo by Structural or Behavioral Reinforcements

The hypothesis of STC was postulated 15 years ago using models of synaptic plasticity in hippocampal slices of rats.1, 27, 34 In addition, it was recently shown that SCT also occurs in behaving animals such that the decaying early-LTP, induced by weak tetanization of the ipsilateral CA3–CA1 projection, can be converted into late-LTP by strong tetanization delivered later to the contralateral pathway.35 Moreover, other work has showed that electrical stimulation of several structures had similar

LTM Formation Was Promoted by Synaptic Plasticity and Behavioral Reinforcers

The hypothesis of SPM predicts that the interventions that affect synaptic plasticity processes should also affect memory systems in a similar fashion. So, the complementary situation where LTM formation is promoted by synaptic plasticity or behavioral reinforcers should take place. Consistent with this prediction, it was recently shown that the induction of LTD with electrical stimulation in the CA1 region of the rat hippocampus facilitated the LTM of an IA task.26 However, a strong (but not

Novelty Promotes LTM Formation in IA and Contextual Fear Tasks

According to the BT hypothesis, a learning task that triggers both the setting of a learning tag and the induction of PRPs synthesis in the same neuronal population will be consolidated into LTM. Therefore, in this kind of training, it was impossible to interfere with either the tag setting or the PRP synthesis without having the same amnestic output in the animal behavior. For that reason, we explored the possibility of splitting these processes by using two different tasks. In that sense, a

Novelty Promotes LTM Formation in Spatial Memories

Spatial memory is one of the most important cognitive functions in daily life. Thanks to it, it is possible to distinguish roads, places, or simply recognize an object in a certain environment.58 In this sense, the hippocampal region that includes the CA fields, DG, and subicular complex is part of a system of anatomically related structures in the medial temporal lobe, which are important for mammalian memory.59 Moreover, the hippocampus may be especially important for tasks that depend on

Novelty Improves LTM Formation in CTA Task

One of the most important survival skills that animals have developed in thousands of years of evolution is taste-recognition memory. If we talk about recognition memory, we could describe it as the ability to assert the familiarity of things previously encountered.65, 66 When an animal encounters a new taste, it hesitates to eat or drink it. This behavioral response evidenced through a reduced initial consumption is known as neophobia. However, if this initial consumption does not lead to

Specific Novelties Are Required to Promote Different Memory Traces

So far, it has been established that weak training induces a tag that has a transient lifetime and that this tag can capture proteins synthesized by novel-associated stimuli to facilitate LTM formation. The methodology used to reveal BT processes requires the integration of at least two different and separate experiences arriving at common neural substrates within a period of few hours (see item the ABC of tagging and capture). Knowing that taste induces mainly the activation of insular cortex

Identification of Transmitter Systems and Learning Tag Molecules

The BT hypothesis implies that to allow the consolidation of LTM both the setting of the learning tag and the synthesis of new proteins have to occur. In consequence, neurotransmitter and second-messenger signaling systems should be involved in these processes. The understanding of what processes are linked to the setting of the learning tag and which ones to the synthesis of PRPs might be helpful to unveil which of them are essential to consolidate a memory and which others could be eventually

Memory Traces Compete Under Regimes of Limited Protein Synthesis

Memories are not static entities that remain unchanged in time. Quite on the contrary, memory formation and persistence are very dynamic processes, sensitive to interventions occurring around the learning event. During our everyday life, we experience several events with multiple characteristics. However, not many of them will be stored in our LTM. Sometimes the information is coded but it is not stored or perhaps it has been effectively stored but it cannot be retrieved.

In the model of BT, one

Evidence of BT in Human

We have previously showed that rodents receiving weak training protocols that only induce STM could consolidate a LTM if the training session took place close to an unrelated novel experience. This process begins with the setting of a learning tag established by the weak training and requires synthesis of PRPs induced by novelty. Thus, an essential question arises: is this BT mechanism also acting in human LTM formation? To answer this question, we studied if a novel or familiar experience

Concluding Remarks

In this chapter, we have compiled findings linking synaptic plasticity with memory processes taking place in behaving animals. We then summarized experiments demonstrating that synaptic plasticity was improved in vivo by structural reinforcement or behavioral interventions and also experiments showing how a behavior could be improved by the induction of synaptic plasticity. Finally, the core of this review was aim to detail memory experiments, demonstrating the BT process in which one

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      This is thought to occur because induction of either short-lasting or long-lasting forms of synaptic plasticity leaves a molecular “tag” at the affected synapses, which allows those synapses to “capture” the plasticity-related proteins created in response to the induction of long-lasting plasticity (Frey and Morris, 1997, Frey and Frey, 2008). This cellular phenomenon was originally described in hippocampal slices (Frey and Morris, 1997), but has also been observed in intact animals (Shires, Da Silva, Hawthorne, Morris, & Martin, 2012), and has potential behavioral correlates, such as the ability to remember otherwise innocuous details better when in the context of a traumatic event (Moncada and Viola, 2007, Reymann and Frey, 2007, Viola, Ballarini, Martínez, & Moncada, 2014). It is clearly important to better understand how an animal’s experiences and environmental and internal conditions influence these processes of metaplasticity.

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