Neuropsychiatric disorders severely impact quality of life in millions of patients, contributing more Disease Affected Life Years (DALYs) than cancer or cardiovascular disease. The human brain is a complex system of 100 billion neurons connected by 100 trillion synapses, and human studies of neural disease focus on network-level circuit activity changes, rather than on cellular mechanisms. To probe for neural dynamics on the cellular level, animal models such as the nematode C. elegans have been used to investigate the biochemical and genetic factors contributing to neurological disease. C. elegans are ideal for neurophysiological studies due to their small nervous system, neurochemical homology to humans, and compatibility with non-invasive neural imaging. To better study the cellular mechanisms contributing to neurological disease, we developed automated analysis methods for characterizing the behaviors and associated neural activity during sleep and learning in C. elegans: two neural functions that involve a high degree of behavioral and neural plasticity. We developed two methods to study previously uncharacterized spontaneous adult sleep in C. elegans. A large microfluidic device facilitates population-wide assessment of long-term sleep behavior over 12 hours including effects of fluid flow, oxygen, feeding, odors, and genetic perturbations. Smaller devices allow simultaneous recording of sleep behavior and neuronal activity. Since the onset of adult sleep is stochastically timed, we developed a closed-loop sleep detection system that delivers chemical stimuli to individual animals during sleep and awake states to assess state-dependent changes to neural responses. Sleep increased the arousal threshold to aversive chemical stimulation, yet sensory neuron (ASH) and first-layer interneuron (AIB) responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the AVA premotor interneurons, rather than afferent sensory circuits. Traditionally, the study of learning in C. elegans observes taxis on agar plates which present variable environmental conditions that can lead to a reduction in test-to-test reproducibility. We also translated the butanone enhancement learning assay such that animals can be trained and tested all within the controlled environment of a microfluidic device. Using this system, we demonstrated that C. elegans are capable of associative learning by observing stimulus evoked behavioral responses, rather than taxis. This system allows for more reproducible results and can be used to seamlessly study stimulus-evoked neural plasticity associated with learning. Together, these systems provide platforms for studying the connections between behavioral plasticity and neural circuit modulation in sleep and learning. We can use these systems to further our understanding of the mechanisms underlying neural regulation, function, and disorder using human disease models in C. elegans.

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<p>One of the most central and current debates among those studying human contingency learning (HCL) concerns whether it is best understood as the result of associative learning, a product of higher-order cognitive processes, or some combination thereof. Though the field appears to be moving toward the latter accounts, much of the evidence being generated to evaluate and select among them comes from tasks that typically present only information about the few variables involved in the contingency(s), in the exact same manner on every trial. While effective for examining how the statistical properties of experience affect learning, these procedures do not capture some of the conditions of everyday cognition and are apt to be less effective for engaging non-associative and top-down influences on performance.</p> <p>The current work introduces a task that involves learning contingencies in others' behavior from descriptions that require the learner to determine the focus of learning, and to deal with both variability in manifestation of the objects of learning and extraneous information. Across several experiments, performance reflects phenomena, including ΔP, outcome density and blocking effects, which have been well established in HCL and are consistent with associative accounts. At the same time, the findings also suggest that (a) domain-specific theories affect the weighting of evidence in contingency perception and the discoverability of contingencies, and (b) outcome predictions, a typical measure in HCL, are influenced by specific instance memory in addition to abstract contingency knowledge. These findings are difficult to reconcile with the data-driven nature of associative views, and join a growing number of demonstrations suggesting that a viable account of HCL must involve higher-order cognitive processes or top-down influences on performance.</p> / Thesis / Doctor of Philosophy (PhD)

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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 &amp; 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 &amp; 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.

In this study we investigated whether a musical prime would produce a contextspecificity effect in predictive learning. Participants were divided into six conditions of a spy-radio predictive learning task. The six conditions were comprised of a combination of three primes (i.e. visual, music, or both) and two learning phase groups (i.e. retrieve, default). The primes indicated the type of stimulus used to prime the temporal context for the test cue-outcome association. The learning phase groups indicated which temporal context would be primed. In the retrieve group, learning Phase 1 was primed; in the default group learning Phase 2 was primed. The presence of a temporal contextspecificity effect was indicated by lower test predictive judgments for the test cue X in the retrieve group and higher test predictive judgments for this cue in the default group. We hypothesized that all three types of primes would lead to a significant contextspecificity effect. Furthermore, we hypothesized that the context-specificity effect would be strongest in the both prime condition because, with the presentation of both the visual and musical primes, participants would have more information about the learning phase temporal context to inform their test predictive judgment. The results partially supported the first hypothesis as there was a significant context-specificity effect with the visual prime. However, contrary to our hypotheses, we did not obtain a context-specificity effect with the music prime or both prime. Despite the lack of a context-specificity effect in the music prime condition, a relationship between participant musical expertise and predictive judgment suggested that the music did have an effect on context-specificity in predictive learning.