Post-traumatic stress disorder is a disorder characterized by an inability to extinguish traumatic memories and heightened reactivity to emotional stimuli. Due to the heightened resistance of traumatic memories to extinction, treatment for PTSD has been challenging and is limited to behavioral therapies targeted at reducing responsivity to threatening stimuli. Currently there are no standard pharmacological interventions that are specific to PTSD; rather, drugs used appear to target symptoms of some of the co-morbid conditions, such as anxiety (e.g. benzodiazepines) or depression (antidepressants) - which may also affect fear-memory. In this thesis, we explore the effects of natural health products (NHPs) including naturally occurring peptides and some medical botanicals on fear memory in order to explore the efficacy of natural products as potential pharmacological targets for fear-based disorders. Fear-conditioning has been used effectively in both rodents and humans to study fear-learning. Fear-conditioning is a learning paradigm during which an unconditioned aversive stimulus (such as foot shock) is paired with a neutral stimulus (such as light or tone), such that the neutral stimulus becomes associated with aversion. Fear-learning has several well-characterized stages, including acquisition, consolidation, reconsolidation, expression, and extinction that can be manipulated in order to study the pharmacological action(s) on the attenuation of learned-fear. Blockade of reconsolidation, the state during which formed memories are briefly rendered susceptible to change following recall, may provide a window of opportunity to pharmacologically diminish learned fear. In Chapter 1 of the thesis, we discuss fear-conditioning as a pre-clinical model of PTSD to explore the effects of novel pharmacological treatments on the reconsolidation process in rodents. We ultimately hope to provide a framework for translational work in humans for attenuating conditioned responses to trauma-related stimuli among humans with PTSD. In Chapter 2, we present evidence that systemic administration of gastrin-releasing peptide attenuates the reconsolidation of conditioned fear in rodents. Similarly, in chapter 3, we explore the effects of Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on the reconsolidation of learned-fear, and provide evidence that cannabinoid molecules may similarly prove effective at blocking the reconsolidation of conditioned fear memories. In chapter 4, we present evidence demonstrating that extracts of medical botanical Souroubea sympetala and its components may similarly block reconsolidation of conditioned fear-memory, and also exert more general anxiolytic-like activity in the elevated plus maze paradigm. Finally, in chapter 5 a general discussion considers the relative therapeutic potential for future human clinical trials of each of the three tested groups of compounds.

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La cognition se réfère aux mécanismes par lequel l’animal perçoit, apprend, mémorise et agit selon les informations auquel il est confronte dans son environnement. Les animaux on chacun leur propre monde sensoriel et il est primordial qu’ils s’y adaptent en développant des compétences spécialisées en fonction des informations sensorielles qui lui sont le plus utile. Il en est de même des informations qu’il est utile de stocker afin de pouvoir les utiliser ultérieurement. Les mécanismes sous-jacents à ces processus d’adaptation comportementale sont lies à la plasticité du système. Comment cette plasticité permet la mise en place de modules adaptatif reste actuellement une question sans complète explication. Le thème de cette thèse porte sur la plasticité et la modularité des capacités d’apprentissage et de mémoire olfactive chez Drosophila melanogaster. Dans la nature, la drosophile est confrontée à des environnements sensoriels complexes comprenant plusieurs stimuli sensoriels qu’elle doit associées à des renforcements négatifs ou positifs selon les conditions. En laboratoire il est possible de reproduire ce genre d’événement et j’ai ainsi pu tester le niveau d’adaptation des drosophiles à différent niveaux de traitement de l’information. Je démontre dans ce manuscrit que l’adaptation se produit à différents niveaux que ce soit la perception de l’information, les mécanismes de stockage des informations pertinentes et aussi la mise a jour de mémoires qui ne sont plus utiles. Ces processus ont révèle l’existence de modules cognitifs plus ou moins spécialisés qui permettent a l’animal de s’adapter spécifiquement a son milieu. De plus, la réalisation d’une sélection artificielle sur les compétences à stocker les informations révèle l’implication de l’évolution dans la mise en place de ces modules. / Cognition refers to the mechanisms by which animals acquire, store, process and act on information from the environment and this include perception, learning, memory and decision making. Animals have their own perceptual world and adaptation seems to be crucial in order to survive by developing specialized ability in regard of the relevance of each sensory information. The process of storage is another mechanism important for adaptation because learned information can be retained from one occasion to the next. The underlying mechanisms of behavioral adaptation are based on the learning and phenotypic plasticity. How this plasticity induces the formation of these adaptive specialized modules still remains unsolved. The general aim of this PhD hold on the modularity and plasticity of olfactory learning and memory ability in Drosophila melanogaster. Drosophila is always confronted to complex environments with generally more than one stimulus that need to be associated with positive or negative reinforcements. In laboratory, it is possible to reproduce that kind of behavior in various protocols of associative learning. I tested adaptation processes at different level of information processing. I demonstrate in this manuscript that adaptation occurs at each level: perception of complex stimuli, storage of relevant information and also update of memory trace not relevant anymore. This processes revealed the existence of adaptive modules more or less specialized that allows the animal to adapt to its specific environment. Moreover, artificial selection on specific memory ability demonstrates the implication of evolution in the modularity of animal cognition.

La cognition se réfère aux mécanismes par lequel l'animal perçoit, apprend, mémorise et agit selon les informations auquel il est confronte dans son environnement. Les animaux on chacun leur propre monde sensoriel et il est primordial qu'ils s'y adaptent en développant des compétences spécialisées en fonction des informations sensorielles qui lui sont le plus utile. Il en est de même des informations qu'il est utile de stocker afin de pouvoir les utiliser ultérieurement. Les mécanismes sous-jacents à ces processus d'adaptation comportementale sont lies à la plasticité du système. Comment cette plasticité permet la mise en place de modules adaptatif reste actuellement une question sans complète explication. Le thème de cette thèse porte sur la plasticité et la modularité des capacités d'apprentissage et de mémoire olfactive chez Drosophila melanogaster. Dans la nature, la drosophile est confrontée à des environnements sensoriels complexes comprenant plusieurs stimuli sensoriels qu'elle doit associées à des renforcements négatifs ou positifs selon les conditions. En laboratoire il est possible de reproduire ce genre d'événement et j'ai ainsi pu tester le niveau d'adaptation des drosophiles à différent niveaux de traitement de l'information. Je démontre dans ce manuscrit que l'adaptation se produit à différents niveaux que ce soit la perception de l'information, les mécanismes de stockage des informations pertinentes et aussi la mise a jour de mémoires qui ne sont plus utiles. Ces processus ont révèle l'existence de modules cognitifs plus ou moins spécialisés qui permettent a l'animal de s'adapter spécifiquement a son milieu. De plus, la réalisation d'une sélection artificielle sur les compétences à stocker les informations révèle l'implication de l'évolution dans la mise en place de ces modules.

Evidence suggests that when memories are reactivated they become labile and can be updated or even erased. Reactivation induces plasticity in memory representations, rendering them fragile, much as they were after initial acquisition. When a memory has been reactivated it must be re-stabilized, which requires reconsolidation. A recent set of studies established the phenomenon of memory reconsolidation for episodic memory (Hupbach et al., 2007, 2008, 2011). That reconsolidation effects apply to explicit memory, which requires conscious recollection, has far reaching implications. In the Hupbach et al. studies the ability of subtle reminders to trigger reconsolidation was investigated; these reminders consisted of the same spatial context, the same experimenter and a reminder question. Given we live in a predictable world, episodes are not random occurrences of events in time and space, but instead consist of statistical and semantic regularities. This leaves open the question of whether semantic relations and statistical regularities between episodes can trigger a reactivation of episodic memory. If so, how would this affect the status of the reactivated memory? This dissertation explored the role of semantic relatedness between the elements of different episodes in memory reactivation and subsequent updating. We focused particularly on categorical and contextual aspects of semantic relations. A series of experiments considered different kinds of semantic relations between elements of episodes, providing evidence of memory reactivation and updating as a consequence of basic level category relations between items in two separate episodes. We also tested the predictions of the Temporal Context Model (TCM) (Sederberg et al., 2011) for our experimental paradigm and show that the current TCM model is not able to account for all the effects of semantic relatedness in the reconsolidation paradigm. Finally, we explore an alternative approach that seeks to explain memory reconsolidation as Bayesian Inference. Our results provide support for this Bayesian framework, showing the potential of it for exploring different aspects of memory organization.

The amygdala is crucially involved in the acquisition and retention of fear memories. Experimental research on fear conditioning has shown that memory retrieval shortly followed by pharmacological manipulations or extinction, thereby interfering with memory reconsolidation, decreases later fear expression. Fear memory reconsolidation depends on synaptic plasticity in the amygdala, which has been demonstrated in rodents using both pharmacological manipulations and retrieval-extinction procedures. The retrieval-extinction procedure decreases fear expression also in humans, but the underlying neural mechanism have not been studied. Interfering with reconsolidation is held to alter the original fear memory representation, resulting in long-term reductions in fear responses, and might therefore be used in the treatment of anxiety disorders, but few studies have directly investigated this question. The aim of this thesis was to examine the effects of the retrieval-extinction procedure on amygdala activity and behavioral fear expression in humans. The work presented here also investigated whether findings from studies on recent fear memories, established through fear conditioning, extends to naturally occurring long-term phobic fears. Study I, combining fear conditioning and a retrieval-extinction procedure with functional magnetic resonance imaging (fMRI), demonstrated that memory retrieval shortly followed by extinction reduces later amygdala activity and fear expression in healthy subjects. In Study II, these subjects were re-tested 18 months later. The results showed that the effects on fear expression were still present and that initial amygdala activity predicted long-term fear expression. Using an adapted version of the retrieval-extinction procedure, Study III showed that memory retrieval shortly followed by exposure to spider pictures, attenuates subsequent amygdala activity and increases approach behavior in subjects with life-long fear of spiders. In Study IV, these subjects were re-tested 6 months later, and the results showed that effects on amygdala activity as well as approach behavior were maintained. In summation, retrieval-extinction leads to long-lasting reductions in amygdala activity and fear expression. These findings are consistent with the hypothesis that retrieval-extinction alters an amygdala dependent fear memory. Retrieval-extinction can also attenuate long-term phobic fears, indicating that this manipulation could be used to enhance exposure-based treatments for anxiety disorders.

Consolidated memories can become reactivated in order to permit the integration of new information into the memory trace. Blockade of the resultant process, reconsolidation, with NMDA receptor antagonists or protein synthesis inhibition can lead to a decrease in subsequent memory expression. This may offer a potential tool for the treatment of psychiatric disorders characterised by maladaptive memories, including drug addiction and post-traumatic disorder. Given the importance of instrumental associations in supporting drug addiction experiments in Chapters 3 & 4 aimed to disrupt reconsolidation of these memories. Treatment with an NMDA receptor antagonist prior to retrieval sessions of various durations was not able to consistently prevent reconsolidation of these associations. Drug addiction is characterised by memories that have been formed not over days or weeks, but months or years. Experiments in Chapters 5 & 6 therefore investigated how the extent of training affects the propensity of an appetitive pavlovian memory to reconsolidate. Experiments in Chapter 5 were not able disrupt reconsolidation of these memories after a relatively short period of training. In Chapter 6 attempts to disrupt reconsolidation of a cocaine-seeking memory having undergone extensive training (>1 month, designed to promote the formation of drug-seeking habits) were also unsuccessful. However, when animals were trained in a similar fashion to respond for a food reinforcer treatment with a NMDA receptor antagonist prior to a reactivation session resulted in a decrease in food-seeking behaviour the following day. However, this deficit was only found in the first test session; drug treatment had no effect on responding following reminder of the memory. If data from preclinical studies are to inform future psychiatric treatments the findings from these works must be robust and replicable. Experiments in previous chapters encountered several issues in this regard, namely the repeated inability to prevent reconsolidation with NMDA receptor antagonism. Given that reconsolidation of auditory fear memories is well characterised a final series of experiments in Chapter 7 used this procedure to explore the possible reasons for the fleeting or absent effects of disrupted memory reconsolidation in previous chapters. Despite the use of similar methods as published reports showing decreases in memory expression as a result of blockade of reconsolidation it was not possible to disrupt this process with NMDA receptor antagonism or protein synthesis inhibition. Results suggested that the failure to observe reactivation-dependent amnesia was due to the amnestic agent used not being able to prevent reconsolidation, should it be taking place, and a failure of the given retrieval trial to result in memory reactivation. On numerous occasions throughout this thesis it was not possible to disrupt memory reconsolidation. One difficulty in interpreting null data of this nature is that it is often unclear whether the results are due to insufficient retrieval conditions to result in memory reconsolidation, or an inability of the pharmacological agent to disrupt this process. The final experiments of this thesis raised the possibility both of these issues may have contributed in tandem towards this inability to prevent memory reconsolidation.

Learning allows animals to adapt their behaviour to changes in the environment. In humans and other mammals, memories are stored in the hippocampus and cerebellum, whereas in insects, they are stored inside the mushroom bodies (MB). Here, MB-intrinsic Kenyon cells (KCs) form plastic synapses to MB output neurons (MBONs) that are modulated by the reinforcing action of dopaminergic neurons (DANs). Despite decades of research on the MB, the main neurotransmitter underlying the plastic KC → MBON synapse has remained a mystery. Here, I show that this synapse is cholinergic in the fruit fly Drosophila melanogaster. MBONs show fast excitatory responses to direct acetylcholine (ACh) application. KCs synthesise ACh-related proteins ChAT and VAChT. MBONs express and require nicotinic ACh receptors (nAChRs) to become fully activated by odour presentation. Lastly, artificial activation of KCs leads to MBON calcium responses that are blocked by nicotinic antagonists and genetic reduction of VAChT in KCs. Short neuropeptide F (sNPF) may play a role as a modulatory co-transmitter that can either excite or inhibit specific MBONs and DANs. The retrieval of memories is state-dependent and known to potentially change the original memory. Fruit flies need to be hungry to express appetitive memories. Hunger state depends on insulin signalling that activates the GABAergic MBON MVP2, while appetitive memory retrieval depends on decreased activity in M4/6 MBONs. Here, I show that optogenetic MVP2 activation acutely inhibits M4/6 odour responses, rendering MVP2 an inhibitory MBON interneuron. I also show that other MBONs are functionally connected to DANs, thus linking memory reinforcement and retrieval pathways in a way that enables the updating of the original memory. These findings show that associative memories in Drosophila are initially formed at cholinergic-MBON synapses, and can be retrieved and modified through an intricate KC-MBON-DAN network.

Les deux aspects essentiels de la mémoire sont la formation de la trace et la rétention du souvenir à long terme. Afin de comprendre ces processus, nous avons étudié leur mise en place au cours de l'ontogenèse. Chez le raton, nous avons montré que : 1) ERK1/2 et la synthèse de nouvelles protéines sont nécessaires à la consolidation et reconsolidation dès 3 jours postnatals ; 2) les cinétiques de stabilisation de la mémoire raccourcissent au cours du développement post-natal ; 3) une mémoire précoce peut s'inverser avec l'âge ; 4) la capacité de rétention à très long terme apparaît pendant une période critique (une semaine avant le sevrage). Il semble donc que la mémoire précoce implique des mécanismes moléculaires similaires à ceux observés chez l'adulte, mais sa dynamique évolue au cours du développement post-natal.

Repetition and the passage of time influence the consolidation of long-term episodic memories. The experiments presented here have explored the influence of repetition on recent and remote autobiographical memories both behaviorally with regard to qualitative and quantitative measures of content, and neuroanatomically, focusing on changes within the hippocampus and adjacent structures. The first experiment tested the prediction made by MTT that hippocampal memory traces expand and strengthen as a function of repeated memory retrievals. An fMRI paradigm was used to compare the effect of memory retrieval versus the mere passage of time on hippocampal activation. Participants retrieved remote autobiographical memories that had been previously retrieved either one month earlier, two days earlier, or multiple times during the preceding month. Behavioral analyses revealed that the number and consistency of memory details retrieved increased with multiple retrievals but not with the passage of time. Hippocampal activation did not change as a function of either multiple retrievals or the passage of time. The second behavioral investigation was a follow-up to the first experiment, examining the retrieval of those same memories one year later in order to determine whether the level of detail remained stable or whether the memories returned to their original state. Participants reported even more details than they had recalled at least one year earlier, including new details. This finding was consistent across both multiple and single retrieval conditions. These findings together with those of the first study suggest that both repetition and the passage of time are important factors that may result in an increase in recall. The third and final experiment explored the behavioral and neural influences of repeated reactivation of both recent and remote autobiographical memories. Participants were interviewed a total of five times throughout one month and retrieved 20 significant life event memories, from either within the past several months or more than five years ago. Additionally, two fMRI scan sessions were collected, which enabled a direct comparison of the same 20 memories before and after a series of repetitions. Activation increased with repetition in several brain regions including bilateral posterior cingulate and precuneus. Behaviorally, repetition resulted in increased accessibility as suggested by decreased reaction times between the initial and final retrieval sessions, and a general maintenance of the level of recall resulted with repetition.