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La dystrophie musculaire de Duchenne (DMD) est un syndrome neuromusculaire dû à des mutations dans le gène dmd qui conduisent à la perte d’expression des dystrophines, protéines normalement exprimée dans différents tissus y compris le cerveau. Le profil cognitif des patients est hétérogène et la présence d’une déficience intellectuelle dépend de la position des mutations dans le gène. Cette variabilité s’explique par la complexité du gène dmd qui comprend plusieurs promoteurs internes permettant l’expression cérébrale de plusieurs dystrophines de tailles différentes. Dans ce travail de thèse, nous nous sommes intéressés à deux dystrophines : la dystrophine complète (Dp427), normalement exprimée dans le muscle et le cerveau et absente chez tous les patients DMD, et la forme la plus courte de dystrophine, la Dp71, produit cérébral majeur du gène dmd absente dans un sous-groupe de patients. Ces deux dystrophines ont des fonctions cellulaires différentes : La Dp427, normalement exprimée dans les synapses inhibitrices en interaction avec les récepteurs du GABA, joue un rôle dans la plasticité synaptique, l’apprentissage et la mémoire. Sa perte conduit à des déficits cognitifs modérés. La Dp71, majoritairement exprimée dans les astrocytes périvasculaires, contribue à l’ancrage de canaux ioniques impliqués dans l’homéostasie cérébrale et joue aussi un rôle dans la synapse glutamatergique. La perte de Dp71 aggrave fortement les déficits associés à la perte de Dp427 chez les patients et conduit à une déficience intellectuelle sévère. Les relations génotypes-phénotypes restent à préciser et on suppose qu’au-delà de la sévérité des déficits, la nature même des altérations cognitives, ainsi que que la présence de troubles sensoriels, cognitifs, exécutifs et neuropsychiatriques, dépendent des formes de dystrophines touchées. Pour étudier le rôle de ces deux dystrophines, nous avons utilisé deux modèles murins : la souris mdx uniquement déficiente en Dp427, et la souris Dp71-null uniquement déficiente en Dp71. Une étude comportementale à large spectre nous a permis de mieux caractériser le phénotype associé à la perte de Dp427 et de Dp71, en précisant l’intégrité de la perception et du traitement des stimuli sensoriels auditifs, des réponses émotionnelles et de la réactivité au stress, des performances d’apprentissage, ainsi que de certaines composantes des fonctions exécutives, comme la mémoire de travail spatiale et la flexibilité comportementale. Ce travail a été complété par des études collaboratives visant à caractériser le rôle de la Dp71 dans la plasticité corticale et à développer une approche de thérapie génique pour restaurer la fonction de la Dp427 chez la souris mdx. Nous montrons que la perte de Dp427 perturbe les fonctions GABAergiques, les réponses émotionnelles induites par un stress ainsi que la mémoire émotionnelle et la mémoire à long terme, sans altération majeure des fonctions sensorielles et exécutives. Nous montrons aussi qu’une thérapie génique basée sur des injections systémiques d’oligonucléotides antisens, porteurs de chimies spécifiques et passant la barrière hémato-encéphalique, est capable de restaurer une Dp427 fonctionnelle par la technique du saut d’exon et de compenser les altérations émotionnelles des souris mdx. La perte de Dp71 a un impact différent : Elle altère la balance excitation/inhibition et la plasticité synaptique corticale et perturbe l’apprentissage, la flexibilité comportementale et la mémoire de travail dans des tâches d’apprentissage spatial. Notre étude de ces modèles murins a donc permis de clarifier les relations génotype-phénotype et les bases neurobiologiques de cette maladie, et d’identifier des phénotypes utiles pour valider l’efficacité de traitements ciblant le cerveau dans des études précliniques. / Duchenne muscular dystrophy (DMD) is a neuromuscular syndrome caused by mutations in the dmd gene, leading to the loss of dystrophin proteins, which are normally expressed in various tissues including the brain. Patients exhibit heterogenous cognitive profiles and the presence of intellectual disability depends on the location of the mutation within the gene. This variability can be explained by the complexity of the dmd gene, which includes several internal promoters leading to the cerebral expression of several dystrophins of different sizes. In this thesis work, we focused on two dystrophins : the full-length dystrophin (Dp427) normally expressed in muscle and brain and lost by all DMD patients, and the shortest dystrophin, Dp71, major cerebral product of the dmd gene that is absent in a subgroup of patients. These two dystrophins have distinct cellular functions : Dp427, normally interacting with GABA receptors in inhibitory synapses, plays a role in synaptic plasticity, learning and memory. Its loss leads to mild cognitive deficits. Dp71, mostly expressed in perivascular astrocytes, contributes to the anchoring of ionic channels involved in brain homeostasis and also plays a role in glutamatergic synapses. Dp71 loss strongly aggravate the deficits associated with the loss of Dp427 in patients and lead to severe intellectual disability. Genotype-phenotype relationships need be further specified and it is assumed that beyond deficits severity, the actual nature of cognitive alterations, as well as the presence of sensorial, cognitive, executive and neuropsychiatric disturbances, depend on the specific forms of dystrophin affected by mutations. To study the role of these two dystrophins, we used two mouse models : the mdx mouse that only lacks Dp427, and the Dp71-null mouse that only lacks Dp71. A extensive behavioral study allowed us to better characterize the phenotype associated with the loss of Dp427 and Dp71, detailing integrity of perception and processing of auditory sensory stimuli, of emotional responses and stress reactivity, of learning performance, and of components of executive functions, such like spatial working memory and behavioral flexibility. The work has been completed by collaborative studies aimed at characterizing the role of Dp71 in cortical plasticity and at developing gene therapy approaches to rescue Dp427 function in the mdx mouse. We demonstrate that Dp427 loss perturbs GABAergic functions, stress-induced emotional responses, as well as emotional and long-term memories, without major alterations of sensory and executive functions. We also show that a gene therapy based on systemic injections of antisens oligonucleotides holding specific chemistries and crossing the blood-brain barrier enables Dp427 functional rescue by exon-skipping strategy and alleviates emotional disturbances in mdx mice. The loss of Dp71 has a distinct impact : It alters cortical excitation/inhibition balance and plasticity and disrupt learning, behavioral flexibility and working memory in spatial learning tasks. Our study of these mouse models therefore enabled to clarify the genotype-phenotype relationships and neurobiological bases of this disease, and identified valuable phenotypes to validate treatment efficacy in future brain-targeting preclinical studies.

This thesis aims to investigate how well associative learning can account for human sequence learning under incidental conditions. It seems that we can learn complex sequential information about events in our environment, for example language or music, incidentally, without being aware of it. Awareness is, however, a complex issue with arguments for (Dienes, 2012) and against (Shanks, 2005) the existence of implicit learning processes. A dual process account proposes that there exist two different learning systems, one based on conscious, controlled reasoning and rules, and the other based on automatic association formation, which can take place outside of awareness (McLaren, Green, & Mackintosh, 1994). This thesis attempts to use the predictions of an associative account in conjunction with a suitable method for investigating implicit learning: sequence learning (Destrebecqz & Cleeremans, 2003). The research involves a collection of serial reaction time (SRT) tasks whereby participants respond to on-screen stimuli that follow a sequence that they were (intentional learning) or were not (incidental learning) informed of. Following on from the experimental design of Jones and McLaren (2009) this thesis provides evidence that humans differ in their ability to learn different sequential contingencies. After training sequences of trials where the current trial location was twice as likely to be either: the same as (Same rule); or different to (Different rule) the location two trials before this, participants were far better at learning the latter rule. I found that this result was not adequately simulated by the benchmark associative model of sequence learning, the Augmented SRN (Cleeremans & McClelland, 1991), and present a revised model. This model, amongst other attributes, represents all the stimuli experienced by participants and can therefore learn stimulus-response contingencies. These seem to block learning (to some extent) about the Same rule thus providing an associative explanation of the advantage for acquisition of the Different rule. Further predictions regarding the role of additional stimuli alongside sequence learning were then derived from this associative account and tested on human participants. The first of these was that additional stimuli within the task will interact with sequence learning. I found that human participants show increased Same rule learning when additional, concurrently presented stimuli follow the previous element in the sequence. I demonstrate that when participants perform an SRT task where responses are predicted by the colour of a cue, they are able to learn about this relationship in the absence of awareness. Using this cue-response learning I further investigate cue-competition between sequences and colours under incidental conditions and find evidence that suggests between cue associations may alter the influence of cue competition. These results altogether suggest that stimuli – both simple and sequential – can be learned under incidental conditions. This thesis further proposes that learning about simple and more complex relationships between stimuli interacts according to the predictions of an associative account and provides evidence that contributes to a dual process understanding of human learning.

The conversion of a memory from an initially fragile state to an enduring representation requires cellular, molecular, and systems-level brain network changes. This reorganization is hypothesized to involve time-dependent neuroanatomical changes that may differentially support some types of remote versus recent memory, and may also influence the latency to decide and complete responses during retrieval. To quantify the timecourse of learning and retrieval after different retention durations, a paradigm is developed to measure in humans and monkeys the retrieval speed of visuomotor associations, which require an intact hippocampus for initial acquisition but not for retrieval after days or weeks. Two components of retrieval speed, a decision time to initiate movement and a velocity-dependent movement completion time to complete a motor response, are shown to change differently relative to a pre-retention baseline. Movement completion times decrease across repetitions within single learning session, and continue to decrease from the level reached at the end of learning following retention. Decision times also decrease within the learning session, but increase on the first post-retention retrieval attempt as a function of retention interval duration. Extensive practice is required for decision times to reach a level below that obtained at the end of learning, and the transition from a long- to short-latency decision depends on the number and spacing of practice trials. The findings are discussed in a framework in which post-retention processing time is influenced by the speed of visual identification, the time to retrieve the associative relationship from long-term memory, and the time to plan and execute a motor response. The creation of sparser, long-lasting visual form representations and strengthened cortico-striatal connections predict behavioral efficiency gains in visual identification and motor responses after learning. Decision times could be fast and automatic following extensive practice when the neural representation may become stored permanently in cortico-cortical and cortico-striatal linkages, or could increase after retention because of several cognitive and neural factors, including interference and frontal inhibition of the hippocampal system to prevent new learning before choice feedback. The experimental results are discussed in the context of the existing literature on memory consolidation.

This thesis explores the behaviour of participants taking an associative approach to a task-cueing paradigm. Task-cueing is usually intended to explore controlled processing of task-sets. But small stimulus sets plausibly afford associative learning via simple and conditional discriminations. In six experiments participants were presented with typical task-cueing trials: a cue (coloured shape) followed by a digit (or in Experiment 5 a symbol) requiring one of two responses. In the standard Tasks condition (Monsell Experiment and Experiments 1-3), the participant was instructed to perform either an odd/even or a high/low task dependent on the cue. The second condition was intended to induce associative learning of cue + stimulus-response mappings. In general, the Tasks condition showed a large switch cost that reduced with preparation time, a small, constant congruency effect and a small perturbation when new stimuli were introduced. By contrast the CSR condition showed a small, reliable switch cost that did not reduce with preparation time, a large congruency effect that changed over time and a large perturbation when new stimuli were introduced. These differences may indicate automatic associative processing in the CSR condition and rule-based classification in the Tasks condition. Furthermore, an associative model based on the APECS learning algorithm (McLaren, 1993) provided an account of the CSR data. Experiment 3 showed that participants were able to deliberately change their approach to the experiment from using CSR instructions to using Tasks instructions, and to some extent vice versa. Experiments 4 & 5 explored the cause of the small switch cost in the CSR condition. Consideration of the aspects of the paradigm that produced the switch cost in the APECS model produced predictions, which were tested against behavioural data. Experiment 4 found that the resulting manipulation made participants more likely to induce task-sets. Experiment 5 used random symbols instead of numbers, removing the underlying task-sets. The results of this experiment broadly agreed with the predictions made using APECS. Chapter 6 considers an initial attempt to create a real-time version of APECS. It also finds that an associative model of a different class (AMAN, Harris & Livesey, 2010) can provide an account of some, but not all, of the phenomena found in the CSR condition. This thesis concludes that performance in the Tasks condition is suggestive of the use of cognitive control processes, whilst associatively based responding is available as a basis for performance in the CSR condition.

Social learning plays a valuable role in the lives of many animal taxa, sometimes allowing individuals to bypass the costs of personal exploration. The ubiquity of this behaviour may arise from the fact that learning from others is often underpinned by simple learning processes that also enable individuals to learn asocially. Insects have proven to be particularly valuable models for investigating parsimonious hypotheses with regards to social learning processes, due to their small brain sizes and the prevalence of social information use in their life histories. In this thesis, I use social insects to further investigate the mechanisms underlying more complex social learning behaviours and explore the circumstances under which social information use manifests. In the first chapter, I investigate the proximate mechanisms underlying social learning and demonstrate that even seemingly complex social learning behaviours can arise through simple associative learning processes. In Chapter two, I investigate whether bees are more predisposed to learning from conspecific cues and discover that social information is learnt to a greater extent than information originating from non-social sources. In Chapter four, I demonstrate that classical conditioning also underpins learning from evolved social signals in honeybees. Finally, I investigate whether social information is used adaptively by bumblebees: Chapter three demonstrates that joining behaviour in free-flying bees is contingent upon whether flowers are familiar or not, and in Chapter six, I show that when social information is costly to acquire, bees are more likely to rely on social information to make foraging decisions. Taken as a whole, my findings suggest that bees may be specially adapted for receiving social information, but the ability to learn from others arises through general associative learning mechanisms.

Since the introduction of the American Academy of Pediatrics Back to Sleep Campaign infants have not met the recommendation to “incorporate supervised, awake “prone play” in their infant’s daily routine to support motor development and minimize the risk of plagiocephaly”. Interventions are needed to increase infants’ tolerance for prone position and prone playtime to reduce the risk of plagiocephaly and motor delays. Associative learning is the ability to understand causal relationship between events. Operant conditioning is a form of associative learning that occurs by associating a behavior with positive or negative consequences. Operant conditions has been utilized to encourage behaviors such as kicking, reaching and sucking in infants by associating these behaviors with positive reinforcement. This dissertation is a compilation of three papers that each represent a study used to investigate a potential play based interventions to encourage prone motor skills in infants. The first paper describes a series of experiment used to develop the Prone Play Activity Center (PPAC) and experimental protocols used in the other studies. The purpose of the second study was to determine the feasibility of a clinical trial comparing usual care (low tech) to a high-tech intervention based on the principles of operant conditioning to increase tolerance for prone and improve prone motor skills. Ten infants participated in the study where parents of infants in the high tech intervention group (n=5) used the PPAC for 3 weeks to practice prone play. Findings from this study suggested the proposed intervention is feasible with some modifications for a future large-scale clinical trial. The purpose of the third study evaluated the ability of 3-6 months old infants to demonstrate AL in prone and remember the association learned a day later. Findings from this study suggested that a majority of infants demonstrated AL in prone with poor retention of the association, 24 hours later. Taken together these 3 papers provide preliminary evidence that a clinical trial of an intervention is feasible and that associative learning could be used to reinforce specific prone motor behaviors in the majority of infants.

The association of olfactory information with a resource is broadly known as olfactory-based associative learning. From an ecological perspective, associative learning can reduce search time for resources and fine tune responses to changing biotic and abiotic factors in a variable environment, which in mosquitoes has implications for pathogen transmission and vector control strategies. The purpose of this dissertation was to examine the ability for olfactory-based associative learning across the major life history domains of mosquitoes. Six different experiments comprise this dissertation. The first was to evaluate the response of mosquitoes following conditioning to 5, 10 or 50% sucrose concentrations with individual level mosquito conditioning and testing and introduction of statistical analysis with binary logistic regression. Mosquitoes did not respond in a dose dependent manner with respect to positive response to target odors following conditioning. This effect appears to be related to the mosquitoes' prior exposure to sugar as those exposed to 10% sucrose before conditioning did not prefer 50% sucrose but significantly fewer chose 5% sucrose. In an evaluation of host associated odors and second blood meal choice by females using a dual-choice olfactometer no significant effects were observed. The lack of significance may have been due to insufficient sample sizes, problems with odor collection or physiological state of mosquitoes. Effects of predatory mosquitofish on larval development and female oviposition choice were evaluated by rearing in separated habitats under three different treatments followed by an oviposition choice assay. Females did not prefer their natal habitat or avoid predators but chose substrate that had contained mosquitofish fed conspecific larvae. Mosquitofish affected larval development with acceleration in treatments with mosquitofish fed Tetramin® and delayed pupation in treatments with mosquitofish fed conspecific larvae. Mosquito memory length was evaluated by conditioning and testing at six time intervals from colony and field populations at two ages. Younger mosquitoes showed higher levels of positive response after conditioning at all time intervals except the longest (24h). Finally the olfactory-based associative learning ability of Anopheles cracens was evaluated. Significant evidence for learning was observed in males but not females at a memory length interval of 24h.

<p>In the present study, we examined the predictions of an attentional-associative model (Schmajuk, Lam, & Gray Journal of Experimental Psychology: Animal Behavior Processes, 22, 321-349, 1996) regarding the effect of attentional manipulations on both discrete and contextual conditioned inhibitors.</p><p>The SLG model assumes that non-reinforced presentations of an inhibitory conditioned stimulus (CS) do not decrease its inhibitory associations. However, the model predicts that extended presentations will decrease attention to the inhibitor, thereby, decreasing both the expression of its inhibitory power in a summation test and the rate of acquisition in a retardation test. The model also predicts that subsequent presentations of the inhibitory CS with a novel CS will increase both its inhibitory power in a summation test and the rate of acquisition in a retardation test. Using a predictive learning design in humans, Experiment 1 examined the predictions involving the summation tests, whereas Experiments 2 and 3 examined the predictions involving the retardation tests. Experimental results were in agreement with the predictions of the model. </p><p>The SLG model also predicts that a salient extinction context (CX) becomes inhibitory and prevents extinction of the excitatory CS-unconditioned stimulus (US) association. Although some data seem to contradict that prediction (e.g., Bouton and King, 1983, Bouton and Swartzentruber, 1986, 1989), Larrauri and Schmajuk (2008) indicated that the CX might not appear inhibitory in a summation test because attention to the CX decreases with many but not few extinction trials. In a human predictive learning experiment, we confirmed the model's predictions that the inhibitory power of the extinction CX can be detected after a few extinction trials when attention to the CX is still high, but not after many extinction trials once attention to the CX has decreased (Experiment 4), and even after many extinction trials by presenting novel CSs to increase attention to the unattended CX (Experiment 5). Furthermore, using an eye-tracker, we confirmed the model's explanation of Experiment 4 results by showing decreased overt attention to the CX after many but not after few extinction trials (Experiment 6).</p><p> Importantly, the view that the extinction CX becomes inhibitory allows the model to explain spontaneous recovery (because attention to the excitatory CS increases before attention to the inhibitory CX), renewal (because the inhibition provided by the extinction CX disappears), and reinstatement (the inhibitory CX becomes neutral or excitatory), as well as a very large number of other experimental results related to extinction. Based on the prediction of the SLG, model the implications of our results for the treatments of anxiety disorders were discussed.</p> / Dissertation

Retrospective revaluation— learning about implied but unpresented cues— poses one of the greatest challenges to classical learning theories. Whereas theorists have revised their models to accommodate revaluation, the empirical reliability of the phenomenon remains contentious. I present two sets of experiments that examine revaluative learning under different but analogous experimental protocols. Results provided mixed empirical evidence that is difficult to interpret in isolation. To address the issue, I apply two computational models to the experiments. An instance-based model of associative learning (Jamieson et al., 2012) predicts retrospective revaluation and anticipates participant behaviour in one set of experiments. An updated classical learning model (Ghirlanda, 2005) fails to predict retrospective revaluation, but anticipates participant behaviour in the other set of experiments. I argue that retrospective revaluation emerges as a corollary of basic memorial processes and discuss the empirical and theoretical implications.