Memory Reconsolidation: Time to Change Your Mind

Abstract

A new study shows that temporal expectations about threats are a key part of fear memories and that changing this temporal expectation is enough to trigger the updating and reconsolidation of a previously learned fear.

When faced with new information there are some instances when old memories get updated, and some in which they do not. What factors specifically trigger this updating process? In this issue of Current Biology, Diaz-Mataix et al. [1] address this important unanswered question about our constantly evolving representation of the world. Imagine making a trip to revisit your childhood home. Your destination is your parents’ house, and driving there feels almost automatic — you put little thought into what turns you must make and when to make them. The memories you have for the route home have been strongly formed and you access them with ease. Consider what would happen if you went to make the next turn only to discover that the street is no longer there. New road work since your last visit has altered the street layout. You must take a new route to get to your parent’s home, and subsequently update your mental map to incorporate the new information so your future trips can follow the most efficient route. Ideally, we should benefit from our experiences — not remaining set in our ways, but rather being capable of flexibly adjusting our memories and representations as we encounter new information. It would be extremely inefficient to treat each experience as entirely unique and have to learn things de novo each time we encounter them.

Being able to form memories is ultimately what allows us to learn from experience and carry information about how the world works forward in time; being able to update memories allows us to continuously adapt to changes in the world, as is the case when road crews alter the street layout in your hometown. About 75 years ago the developmental psychologist Jean Piaget referred to the incorporation of new knowledge into our existing mental structures as assimilation, while the changing of cognitive structure based on new experience was called accommodation [2]. This became an enduring problem in the study of cognition, but it was not until fairly recently that we have begun to understand the neurobiological processes that underlie the formation and updating of memories.

Immediately following the formation of new memories there is a period of time in which the memory exists in a labile state, prone to several types of disruption. As more time passes, however, a process of progressive stabilization occurs — a process known as memory consolidation [3]. At one time it was believed that, once consolidation had occurred, memories were permanently fixed. Although several lines of earlier work suggested that following the reactivation of a previously formed memory it might reenter a labile state (see [4] for a review), little research was done on reconsolidation until Nader et al. [5] showed that reconsolidation is dependent on protein synthesis. These authors found that, if done immediately after reactivation of a fear memory, injection of a protein synthesis inhibitor into the basal lateral amygdala, a region now well established as crucial for Pavlovian threat (fear) conditioning [6], caused apparent erasure of the earlier learning.

Since that seminal study progress has been rapid, in part, because researchers converged on Pavlovian threat conditioning as the paradigm for studying learning, memory and reconsolidation. In this protocol a neutral stimulus, known as a conditioned stimulus (CS), is paired with some aversive stimulus, known as an unconditioned stimulus (US). This procedure commonly uses a tone as the CS and an electric foot shock as the US. What gets learned is a temporal expectation that, in the presence of a particular cue (tone), a specific event (electric foot shock) will happen at a particular time. Recent work focusing on the temporal aspect of the learning has made it evident that time is a core aspect of this learning [7] and may even be the foundation for it to occur at all [8,9]. The work of Diaz-Mataix et al. [1] confirms that time is a fundamental component of memory.

Studying the role of time in learning has led to new understanding of the learning process. One of those insights is that, although the emergence of anticipatory conditioned responses may take many trials, the learning that underlies it may be quite rapid [9]. The work of Diaz-Mataix et al. [1] adds in very important ways to this new understanding. Their method, illustrated in Figure 1, involves initial training of 10 presentations of a tone followed by a shock 30 seconds later. The next day, the tone is presented again to reactivate the fear memory, but now the shock occurs at either the same or a different time in different groups of subjects. Only those subjects that experience the shock at a new time retrieve a memory that is vulnerable to disruption during reconsolidation. Injecting a protein synthesis inhibitor into the basal lateral amygdala following reactivation of the memory leads to disruption of the memory only in the animals that experience the shock at the new time. This result clearly shows that the subjects had encoded the time in the original learning and that a single presentation of the shock at a new time was enough to trigger an updating of the memory. In later experiments, they show that even a single CS–US pairing during initial training is sufficient to establish a temporally specific memory, and that a single experience of the shock at a new time triggers reconsolidation. Time is indeed rapidly learned and updated!

Figure 1. Experimental method for testing the effects of altering the temporal relationship between the US and CS on memory reconsolidation.

(A) On day 1, the initial training exposed a rat to pairings (1, 2, or 10) of a neutral stimulus (tone) for 60 seconds with an aversive stimulus (foot shock lasting one second) occurring 30 seconds into the tone. This leads to Pavlovian fear conditioning. (B) On day 2, a reactivation session consists of a single exposure to the same tone conditioned on the previous day for 60 seconds. Subjects either receive a shock at the same time (30 seconds into the tone) or at a different time (for example, 10 seconds into the tone). Immediately following this reminder subjects received an infusion of either a drug that blocked protein synthesis or a vehicle into the basal lateral amygdala, a brain structure that mediates the acquisition of fear memories. (C) On day 3, the subjects were tested for a long-term memory (LTM) of the fear conditioning by presenting the tone and quantifying levels of freezing behavior. The original fear memory was retained in every case except when the subjects received both the reminder shock at a new time and the infusion of the protein synthesis inhibitor immediately following that session. These animals showed no memory of their previous training.

Another contribution of the Diaz-Mataix et al. [1] study is in helping to delineate when new experiences modify old memories. We know reconsolidation does not occur every single time a memory gets reactivated, but it is still unclear what factors determine whether or not a memory becomes labile. Earlier work suggests memories are subject to reconsolidation after brief but not lengthy training [10]. However, Diaz et al. [1] show that the relationship between amount of training and a memory’s propensity to undergo reconsolidation may not be so simple. In their experiments, even a single pairing of a tone and shock produced a memory that was not vulnerable to disruption following reactivation unless new temporal information was introduced during the reminder. An interesting hypothesis is that memories are only subject to reconsolidation when new information is provided. Perhaps, in the Diaz et al. [1] experiments, learning was maximal after a single pairing so no new information is provided by the re-presentation of the original tone and shock. Perhaps other studies, such as that of Wang et al. [10], found a decreased likelihood of reconsolidation with increased training because in that work it took many trials for the information available in training to be fully learned. Said another way, maybe reconsolidation only occurs when learning is incomplete — whether the incompleteness arises from slow original learning or from the introduction of new information.

The Diaz et al. [1] study tells us that the introduction of new temporal information is sufficient for triggering the updating of old representations. Specifically, the protocols in which the animals experienced shock at a new time were the exclusive cases which led to reconsolidation, and these trials were also the only ones to trigger synaptic plasticity in the basal lateral amygdala. Whether there is something special about temporal information, or if any change in information contained within a previously established memory can trigger the labile memory state underlying reconsolidation, remains to be sorted out by future work.

Memories are what allow us to make appropriate behavioral decisions based on information about the past. Given that environmental variables are in constant flux, there are certain to be times when our memories for past experiences are no longer in synch with our current environment and sometimes our reactions based on those memories can be deeply problematic. Irrational fears and post-traumatic stress disorder would seem to be representative of those situations where old memories evoke responses ill-suited to current circumstances. At a very human level, Diaz et al. [1] challenge us to understand the specific neurobiological mechanisms underlying reconsolidation and memory updating so we can design therapeutic interventions in which we ‘evoke and erase’ memories that underlie maladaptive emotional responses.