Reconsolidation is the process where consolidated memories return to a malleable state and can be modified. The purpose of this dissertation was to examine factors that influence the reconsolidation of conditioned fear memories using a behavioural method, known as the post-retrieval extinction paradigm, across two separate studies. Fear potentiated startle (FPS) and skin conductance response (SCR) were used as measures of fear for both studies. In Study 1, I investigated how the expectation for learning impacts the reconsolidation of conditioned fear memories. Testing took place over three consecutive days and expectation for learning was manipulated via verbal instructions prior to memory reactivation. On Day 1, participants underwent fear acquisition to two distinct spider images. On Day 2, participants were assigned to one of the following conditions: reactivation with expectation for learning condition (n = 16); a reactivation with no expectation for learning condition (n = 16); or a no reactivation condition (n = 16). All participants underwent extinction, and participants in the reactivation conditions had their memory for the conditioned stimulus (CS+) reactivated either with or without the verbal manipulation for the expectation for learning. On Day 3, fear was reinstated, and participants underwent re-extinction to examine if the manipulation on Day 2 affected the memory. Partially consistent with my predictions, I found limited evidence that the expectation for learning enhanced reconsolidation for FPS but not SCR. In Study 2, I examined how the level of spider fear impacted the reconsolidation of conditioned fear memories. I also examined if the effects of reconsolidation generalized to similar stimuli (i.e., stimulus generalization). On Day 1, participants who were either high (n = 17) or low (n = 17) on spider fear underwent fear acquisition to a spider and a snake image, while a neutral image served as the CS-. On Day 2, participants viewed a single presentation of the spider and the neutral images to reactivate their memories. Participants then underwent extinction. On Day 3, fear was reinstated, and participants underwent re-extinction to examine if the effect of reactivation on memory. Fear generalization was measured via presentation of similar but distinct spider and snake images. These images were presented prior to and post-acquisition (Day 1) and on Day 3 following reinstatement. On the same days (1 and 3), a behavioural approach test (BAT) was used as a second measure of fear generalization to assess approach behaviour to novel spider stimuli. Inconsistent with my predictions, for FPS, participants with high levels of spider fear displayed a return of fear to the non-reactivated snake image, but not to the reactivated spider image. Conversely, I found the opposite effect for the low spider fear group as they displayed a return of fear to the reactivated spider image but not the snake image. For SCR, participants in both groups displayed a return of fear to the reactivated spider image but not the snake image. I did not find any evidence that reconsolidation increased approach behaviour for either group during the BAT. These findings suggest that memories with high levels of distress may undergo reconsolidation when fear is measured with FPS but not SCR. The inconsistent findings between the groups suggest that conditioned and natural memories may undergo reconsolidation differently. The findings from both studies have potential theoretical implications for the understanding of the boundary conditions of reconsolidation and have potential implications for the application of reconsolidation in clinical contexts. Limitations and future directions are also discussed.

Recent animal and human research suggest that a behavioral prime before extinction training lessens the spontaneous recovery of learned fear. These findings would have large ranging implications, if they could be applied to the treatment of specific phobias in which spontaneous recovery is often problematic. The present study examined the effects of a behavioral prime paired with exposure therapy versus exposure therapy alone on snake and spider phobics return of fear at one-month follow-up. The findings did not support the proposed hypothesis that those in the primed group would show a significant lessening in return of fear. The study findings do not support the current research, but there are a number of steps that may be taken in the future to gain more objective measurements that may lead to hypothesis support. / text

Reconsolidation theory states that stabilized memories can be reactivated and altered in some way; the memory must then be made stable once again by a process known as reconsolidation. A substantial number of studies have aimed to examine this process and the conditions under which it can occur in animal models and young adults. However, few studies have examined the impact of aging on memory reconsolidation. It has been established that aging affects episodic memories, as a result of several different changes in aging. Further, associative, source, and context memories have been found to be affected by aging. Additionally, consolidation, the process that occurs prior to reconsolidation, has been linked to age-related memory deficits. Given these changes with age, it is possible that memory reconsolidation could also be affected. This dissertation sought to examine the effects of aging on reconsolidation in an established set-learning paradigm typically utilized in young adults to demonstrate reconsolidation-mediated memory updating. In Experiment 1, older adult participants were taught sets of objects on two different days, with one group receiving a reminder intended to reactivate the first day's memory. On a third day, a recognition memory task was given. We found that reconsolidation processes seem relatively intact in our population of older adults. Further, source confusion was implicated in addition to memory updating as the cause of memory errors in the group that received the reminder. Other measures, such as spatial awareness and sleep, were utilized to help explain the outcome of the experiment. In Experiment 2, young adults performed the same procedure as in Experiment 1 to determine the role of some of the aspects of the procedure in this paradigm. Specifically, we wanted to establish whether an added task, spread across the two days of learning, influenced the outcome of this paradigm. It was concluded that this task likely had an influence, such that even the group that did not receive the reminder showed evidence of memory updating. We also wanted to determine a baseline for the spatial awareness task used in the previous experiment. However, results were inconclusive. In Experiment 3, we investigated the time line of errors made by older adults by testing their memory for the first set of objects shortly after they learned the second set, as opposed to on a third day. However, free recall was used as the memory task, unlike the previous two experiments. Unexpectedly, errors were immediately apparent for the group that did not receive the reminder but not for the group that did. The conclusion of this experiment was that the task used to test memory may play a major role in the outcome of this paradigm when performed by older adults. Further testing will need to be performed to fully understand this result. Overall, memory reconsolidation appears to be intact in older adults, though perhaps not in the form seen in young adults. Reconsolidation seen in older adults could be affected by different modes of reactivation, sleep, and methods of memory testing. However, several of the present results could be open to multiple interpretations, which require future research to untangle.

The malleable nature of human memory has been the focus of considerable research in recent years. Memory is no longer viewed as permanent and non-modifiable. When a consolidated memory is reactivated it becomes labile and modifiable again. Recently, updating of reactivated memory has been demonstrated, manifesting as the addition of new but relevant information. New, similar, information that is acquired in a separate learning episode is embedded within the original memory. We were interested in exploring the effects of psychosocial stress on this episodic memory updating. Individuals were stressed prior to reactivation of the original memory (Experiment 1) or prior to the onset of reconsolidation of the original memory (Experiment 2). Based on prior research, we hypothesized that in both experiments stress would impair memory updating. In Experiment 1, stress reduced memory updating, but this effect did not achieve statistical significance. In Experiment 2, stress impaired the consolidation of an `updated' memory. These findings not only corroborate stress-induced impairments of memory but also shed light on the possible consequences of impaired memory updating. We discuss the relevance of these experimental results in the context of problem solving.

Upon acquisition, memories undergo an initial stabilization, or consolidation, process after which they are generally resistant to interference. There is now an abundance of evidence that reactivation or retrieval of a consolidated memory opens up a window of time during which the memory can be strengthened, disrupted, or updated via a process of "reconsolidation". This dissertation is comprised of three experimental studies in rats aimed at investigating previously unexamined aspects of this dynamic memory process. The first study assessed whether spatial memories learned under positively-motivated conditions could be updated with new information following reactivation. Rats that learned a second spatial task in the same environmental context as a previously learned task intruded items from the second episode during recall of the first. This result suggests that the context reactivated the memory for the first task, triggering reconsolidation and updating of the memory. The second study used the memory updating effect obtained in the first study as a behavioral measure to investigate the effects of aging on reconsolidation. Unlike in the young rats, the context reminder did not lead to intrusions of the second learning episode during recall of the first. Older adult human participants in this study also showed a different pattern of results than what had been seen previously in young participants. Therefore, in humans as well as in rats, it appears that aging may lead to changes in spatial memory reconsolidation. The third study piloted an experiment to examine hippocampal network activity associated with the spatial memory reconsolidation task used in the first two studies. Preliminarily, we found that the context reminder manipulation was associated with more place field stability across some spatial tasks and that stability across certain tasks was positively related to our measure of memory updating. Additionally, we found evidence that the context reminder enhanced neural replay of some learning episodes. While preliminary, these results suggest that both place field stability and replay may play roles in this reconsolidation paradigm.

Prior research shows that a contextual reminder can return a previously consolidated memory to an unstable state similar to initial encoding. New knowledge presented before the trace is reconsolidated can emerge as updating of the first experience with knowledge from the second. Sleep has been implicated in the long-term strengthening and storage of newly acquired episodic memories; thus, the delay-dependent emergence of intrusions may be facilitated by a delay containing sleep. The experiments described here explore this possibility by tracking sleep while participants undergo an episodic reconsolidation paradigm, which involves learning two sets of information and a recall task, all separated by 48 hours. Prior work using this paradigm shows that reminding participants of the first learning experience prior to learning the second renders them more likely to intrude information from the second set in their recall of the first. In the present study, Experiment 1 compares amount of sleep across days in order to tease apart the differential effects on consolidation of the original Set 1 memory and its reconsolidation when it is updated with Set 2. In Experiment 2, the first analysis (Analysis A) identifies events in the sleep EEG, such as spindles, that are associated with certain elements of memory consolidation, and expands on the parameters in which they occur in memory reconsolidation in Analysis B. The overall aim of this project is to use sleep as a means to inform the nature of memory reconsolidation, which paints memory as ever changeable.

Memory updating has been established; however, the mechanism supporting this alteration process is subject to disagreement. Reconsolidation theorists argue that memory updating occurs via an old memory becoming reactivated and returned to a state of susceptibility. In this state, newly presented details can become incorporated into the existing memory. As such, memory updating is an effect of old memory reactivation and new information encoding. In contrast, temporal context theory argues that the temporal context in which the old memory was initially formed is reinstated. Newly presented information becomes tagged to the old context. Therefore, at retrieval, when the old context is reinstated again, the initially bound information and the newer information are simultaneously retrieved. Within this theoretical framework, memory modification is the result of retrieval effects. In contrast, this three-paper dissertation provides evidence that reconsolidation is, at least in part, a combined reactivation and encoding effect. In paper 1, I present neural evidence of both old memory reactivation and new encoding, which demonstrates 1) that strength at reactivation predicts the likelihood that a memory will be modified and 2) that greater brain activation during new encoding predicts the extent of accurate recognition. In paper 2, I show that encoding conditions affect the extent to which new information will be misattributed to the old memory. I demonstrate that learners update explicitly encoded memories but not implicitly coded ones. Lastly, in paper 3, I demonstrate that old memories can be reactivated and altered during sleep. When old-memory reactivation is paired with a forget cue, a subsequent degeneration of the memory and its details ensues. In sum, all three papers provide evidence in support of the reconsolidation theory that memory updating occurs during old-memory reactivation and new encoding.

The successful reduction of fear is the aim of clinicians treating people with anxiety disorders such as post-traumatic stress disorder or phobias. Existing treatments for these conditions, however, require many treatment sessions and are prone to relapse. A new technique, first demonstrated in rats by Monfils, Cowansage, Klann, & LeDoux (2009) and later shown to be effective in humans (Schiller et al., 2010), provides a method of efficiently reducing fear in a manner which is resistant to various known triggers of relapse. This procedure involves a single presentation of the fear-inducing stimulus one hour prior to extinction training. This procedure produces extinction learning that is resistant to the return of fear resulting from a change of context, the passage of time, exposure to the unconditioned stimulus, and even further conditioning of the stimulus with an aversive stimulus. This dissertation focuses on one particular property of this procedure: that a stimulus extinguished using this procedure is resistant to subsequent retraining of the fear association. The first four experiments presented here are aimed at replicating this phenomenon and determining whether prediction error at retrieval is necessary for the effect to occur. Following on from these studies, the next chapter presents three experiments which investigate whether trial spacing effects could explain the enhanced extinction and highlights conditions under which the effect is weakened, or possibly reversed. The next three experiments compare the properties of a stimulus extinguished under these conditions with a stimulus extinguished under normal conditions. These studies focus on explanations involving inhibition, inattention and the disruption of stimulus representations. In the final three experiments, the possibility of reversing the effect is investigated. These studies look at the effect of memory retrieval prior to retraining of the stimulus to determine the conditions under which the stimulus can again come to elicit a fear response.

La neurogenèse hippocampique adulte fait référence à la création de neurones durant la vie adulte dans le gyrus denté de l’hippocampe. Une décennie de recherche a démontré l’importance de cette neurogenèse chez l’adulte dans les processus de mémoire. En particulier, la neurogenèse adulte est nécessaire à l’apprentissage spatial et l’apprentissage spatial lui-même augmente la survie et accélère le développement d’une population de nouveaux neurones immatures. Cependant, l’implication de ces nouveaux neurones « sélectionnés » par l’apprentissage dans le devenir de la mémoire reste incertaine. En conséquence, le travail de cette thèse porte sur l’étude du rôle de ces nouveaux neurones dans les processus de mémoire spatiale à long terme résultants de l’apprentissage d’origine, comme la restitution et la reconsolidation de la mémoire. En effet depuis plus d’un siècle, on sait qu’un apprentissage n’induit pas immédiatement une mémoire stable. Les souvenirs sont tout d’abord fragiles, puis vont au fil du temps devenir stables et insensibles aux perturbations via un processus appelé «consolidation de la mémoire». Cependant ce processus n’est pas immuable ; les souvenirs établis peuvent à nouveau devenir labiles lorsqu'ils sont rappelés ou réactivés lors d’une restitution de la mémoire. Cette déstabilisation d’une mémoire consolidée nécessite alors un nouveau processus de stabilisation appelé « reconsolidation de la mémoire ». Depuis sa découverte, la reconsolidation a vivement intéressé le milieu de la recherche sur la mémoire et un nombre croissant d’études a cherché à comprendre les mécanismes sous-tendant cette reconsolidation, en particulier dans l'hippocampe. Étonnamment, le processus de reconsolidation n’a été que très peu envisagé dans le contexte de la neurogenèse hippocampique adulte.Nous avons tout d’abord mis au point un protocole de reconsolidation de la mémoire spatiale du rat dans le labyrinthe aquatique de Morris. Cela nous a permis de montrer que les néo-neurones nés avant l’apprentissage étaient activés lors de la reconsolidation de la mémoire spatiale, ce qui n’est pas le cas des neurones issus du développement précoce. Afin de pouvoir établir une relation de causalité entre néo-neurones et processus de reconsolidation, nous avons ensuite développé un outil basé sur la technique pharmacogénétique des DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) couplés à un rétrovirus. Cet outil permet de marquer les néo-neurones à leur naissance et de les manipuler (inhiber ou stimuler l’activation) plus tard, lors des processus de mémoire à long terme. Nous avons observé que les néo-neurones immatures modifiés par l’apprentissage étaient non seulement activés par la reconsolidation mais également nécessaire à celle-ci, à l’inverse des néo-neurones matures au moment de l’apprentissage. Nous avons enfin montré que stimuler l’activité des néo-neurones au moment de la restitution de la mémoire améliorait les performances des rats dans le labyrinthe aquatique.Ensemble, ces résultats de thèse soulignent le rôle critique de la neurogenèse hippocampique adulte dans la stabilisation de la mémoire spatiale à long terme. / Adult hippocampal neurogenesis refers to the creation of neurons during adult life in the dentate gyrus of the hippocampus. A decade of research has demonstrated the importance of this adult neurogenesis in memory processes. In particular, adult neurogenesis is necessary for spatial learning and spatial learning itself increases survival and accelerates the development of a population of new immature neurons. However, the involvement of these new modified / promoted / amplified / selected neurons by learning in the fate of memory remains unclear. The work of this thesis focuses on the study of the role of these new neurons in the long-term spatial memory processes resulting from the original learning, such as retrieval and reconsolidation.For more than a century, we know that learning does not immediately induce a stable memory. Memories are fragile at first and then become stable and insensitive to interferences over time, through a process called “memory consolidation". However this process is not immutable; the established memories can become labile again when they are reactivated during memory recall. This destabilization of a consolidated memory requires then a new stabilization process called "memory reconsolidation". Since its discovery, the reconsolidation process has strongly interested the memory research community and a growing number of studies have sought to understand the mechanisms underlying this reconsolidation, particularly in the hippocampus. Surprisingly, the process of reconsolidation has rarely been considered in the context of adult hippocampal neurogenesis.We first developed a protocol for memory reconsolidation of spatial memory in the Morris water maze in rats. This allowed us to show that new neurons born before learning were activated during reconsolidation of spatial memory, which is not the case of the neurons generated during the early development. In order to establish a causal relationship between new neurons and reconsolidation, we developed a tool based on the pharmacogenetic technique of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) coupled with a retrovirus. This tool is used to tag new neurons at their birth and manipulate them (inhibit or stimulate their activation) later during long-term memory processes. We observed that the population of neurons that were immature at the time of learning are not only activated by but also necessary for reconsolidation, unlike new neurons that were mature at the time of learning. We have finally shown that stimulating the activity of new neurons during retrieval improves the performance of rats in the water maze.All together, these thesis results highlight the critical role of adult hippocampal neurogenesis in long-term spatial memory stabilization.

Memory plays an important role in defining how one behaves. The neurobiological mechanisms of memory have been studied extensively in animal models and the NMDA glutamate receptor has been identified to play an important role in the consolidation and reconsolidation of appetitive memories. Certain memories, depending on what was learned, can function differently and can be more difficult to disrupt based on a number of factors. Currently, no study has examined whether or not a reward-predictive stimulus attributed with incentive value is more difficult to disrupt than a stimulus that functions as a general reward-predictor. To determine the role of the NMDA receptor on memory consolidation with different functioning reward-predictive stimuli rats underwent a Pavlovian conditioned approach, where a post-session NMDA receptor antagonist was administered daily. Furthermore, to determine the role of the NMDA receptor on memory reconsolidation, another set of rats were trained on a Pavlovian conditioned approach task, after training was complete rats were presented with a reward-predictive stimuli followed by an administration of a NMDA receptor antagonist and then re-tested.