La polarité cellulaire planaire (PCP) est une voie de signalisation conservée au fil de l’évolution et qui joue un rôle crucial dans l’établissement de la polarité des cellules et tissues en régulant la dynamique du cytosquelette. De nombreuses études ont démontré l’implication de la PCP dans les mécanismes développementaux importants comme la gastrulation ou la neurulation chez les mammifères, et la mutation des gènes centraux qui composent la PCP mène à de sévères malformations de nombreux organes, et par conséquent une mort néonatale. Van Gogh-like 2 (vangl2) est un des gènes centraux de la PCP et code pour une protéine transmembranaire de la voie de la PCP, et sa mutation conduit à une absence de fermeture de la gouttière neurale et la mort à la naissance chez les mammifères, y compris l'homme. Certaines études suggèrent que Vangl2 jouerait un rôle dans le guidage axonal, mais aussi l’arborisation dendritique des neurones de l’hippocampe et le nombre des épines dendritiques.Dans ce travail, je montre que Vangl2 est enrichi dans l’hippocampe adulte de souris, et plus précisément dans le gyrus denté (DG) et le stratum lucidum du CA3. De nombreuses études suggèrent que le réseau formé par ces sous-structures sous-tend des processus cognitifs spécifiques impliqués dans l’encodage et le rappel de la mémoire : le pattern separation et le pattern completion. Le pattern separation est un processus d’encodage d’informations similaires en représentations différentes, permettant la formation de souvenirs distincts malgré les similitudes entre les évènements. Le processus de pattern completion permet, à partir de stimuli partiels, de se remémorer un souvenir dans son intégralité. De récentes études suggèrent que la maturation des nouveaux neurones issus de la neurogenèse adulte dans le DG joue un rôle critique dans le maintien d'une balance qui existerait entre ces deux processus cognitifs. Bien que les mécanismes qui sous-tendent les deux processus soient encore mal compris, la connectivité du DG et du CA3 semble essentielle.J’ai ainsi formulé et testé l'hypothèse selon laquelle l'absence d'expression de Vangl2 affecterait ces processus mnésiques. Pour ceci, j'ai généré plusieurs mutants murins n'exprimant pas le gène vangl2 dans différentes régions du cerveau, que j'ai ensuite testé dans des paradigmes comportementaux requérant l’utilisation des processus de pattern separation et de pattern completion. Mes résultats suggèrent que Vangl2 dans le DG est essentiel dans le maintien d'une balance existante entre les deux processus, en régulant la maturation des neurones du DG. / Planar cell polarity (PCP) signaling is an evolutionary conserved pathway known to play a crucial role in the establishment of tissue polarity via a regulation of cytoskeleton dynamics. PCP signaling is essential during critical developmental stages, such as gastrulation or neurulation, to shape tissues and organs, and disruption of core PCP genes in mammals leads to severe malformations and neonatal death. Van Gogh-like 2 (vangl2) is one of the core PCP genes coding for a transmembrane protein, and its mutation leads to a failure of the neural tube closure in mammals, including humans. It has also been suggested that Vangl2 plays a role in axonal guidance, dendritic arborization of hippocampal neurons and dendritic spines number. I showed that Vangl2 protein is enriched in the hippocampus in the adult stage, precisely in the dentate gyrus (DG) and CA3 stratum lucidum subregions. These subregions have been proposed to sustain two cognitive processes involved in memory functions: pattern separation and pattern completion. Pattern separation allows the encoding of similar or overlapping inputs in distinct neuronal representations, allowing formation of new memory without interference of a previous similar encountered event. Pattern completion is described as the ability to guide the recall of an entire memory using partial sensory cues. Recent studies suggest a critical role for the maturation of adult-born granule neurons of the DG in the balance that may exist between pattern completion and pattern separation. Although the mechanisms of both cognitive processes are still debated, the connectivity between DG and CA3 appears to be essential. I thereby tested the hypothesis that in absence of Vangl2 in the brain, these two processes would be affected. I generated several conditional mutant mice in order to excise vangl2 gene in specific areas of the hippocampus, and tested them in behavioral paradigms requiring pattern separation or pattern completion processes. My data support my hypothesis that Vangl2 in the DG is essential for a balance between pattern separation and pattern completion, through the regulation of the maturation of DG neurons.

While people sleep, the brain replays the same neural firings that resulted from waking activities that day. This results in greater memory strength following a sleeping delay than a waking delay. The current project built upon this fact in a series of three experiments. Experiment 1. Although previous research has demonstrated a benefit of sleep to memory strength, the literature has not established the impact of sleep on memory specificity. Computational models of medial temporal lobe function posit that discrimination and generalization across similar memories are accomplished through processes known as pattern separation and pattern completion, respectively. To discover whether sleep predisposes people toward pattern separation or pattern completion, participants studied pictures of common objects. After a 12-hour delay, during which participants either slept or stayed awake, participants indicated whether “lure” images were exactly the same or merely similar to those they studied. There was better memory discrimination in those who slept, consistent with a bias toward pattern separation following sleep. Experiment 2. In order to discover whether the pattern of memory demonstrated in Experiment 1 would carry over to semantic memories, participants studied textbook material and took a true/false test 12 hours later. There was a shift in the response trends following sleep, such that participants were more likely to mistakenly endorse highly similar false statements as “true” but were also more likely to correctly endorse more dissimilar false statements as “false.” However, we did not detect evidence of an increased bias toward pattern separation or pattern completion following sleep for this material. Our findings appear consistent with the prediction that memory specificity is benefitted by sleep. Experiment 3. Previous research has demonstrated that memories encoded later in the day are consolidated better than memories encoded earlier in the day. However, these studies have not controlled for the differential decay that memories suffer across these two elapsed periods. In this study, we attempted to show the degree of improvement afforded by sleep using a before-sleep comparison group. However, post hoc analyses revealed a significant interaction between the proposed outcomes and whether participants had napped during the day. These preliminary findings may suggest that napping differentially affects the consolidation of information studied before and after napping.

The processes of pattern separation and pattern completion are very important in the correct discrimination of similar memories. Much research has been conducted on these processes, but there are some gaps that need to be addressed. First, there is some debate as to whether false alarms to lure items come about because of a failure to accurately encode a memory or a failure to retrieve a memory. Second, much of the research on pattern separation and pattern completion in humans is done with visual stimuli and contributions of stimulus modality to these processes are not well understood as a result.Study 1 consisted of three experiments conducted using a combination of eye tracking and functional magnetic resonance imaging (fMRI) methods. Analyses of eye tracking data in the experiments examined the contribution of fixation counts at encoding and retrieval, as well as target-lure similarity level, to accuracy on lure trials. Task designs were altered across studies to attempt to replicate specific research previously conducted with a specific answer period, as well as generalize the findings to a broader body of research that allows participants to answer while the stimulus is presented. The three experiments showed mixed support for the contribution of fixation counts at encoding and retrieval to the accurate discrimination of similar lures. Target- lure similarity, however, was a robust predictor of accuracy for all three experiments.Prior research examining activity in the hippocampus demonstrates a reduction of fMRI activity to repetitions of a stimulus. Greater activity is also observed in the dentate gyrus/CA3 (DG/CA3) subregions for correct rejections of lure items compared to lure false alarms. There should be a greater reduction in the DG/CA3 as a function of encoding for lure false alarms than for lure correct rejections if memory encoding drives the activity differences between these outcomes. The fMRI data showed a marked reduction of activity in the left hippocampus to repetition trials as a function of encoding trial fixation count. There was no significant difference between activity as a function of encoding fixation count in the DG/CA3 for lure correct rejections and lure false alarms. There was also no difference in activity for the CA1 either. Overall, the results of the eye tracking and fMRI data give support for the contribution of pattern completion to false alarms to lure stimuli rather than poor encoding.Study 2 examined the contribution of sensory modality to accurate discriminations of lure stimuli. A behavioral task was developed to directly compare discrimination of similar lures on visual and auditory stimuli. Participants were significantly more accurate and more confident of their responses when discriminating visual stimuli as compared to discriminating auditory stimuli.

Episodic memory binds together the people, objects, and locations that make up the specific events of our lives, and allows the recall of our past in the service of current and future goals. Recent models of memory have posited that the hippocampus instantiates computations critical for episodic memory including mnemonic discrimination, relational binding, and holistic retrieval. Collectively, this set of studies aim to chart the ontogeny of each key components of episodic memory. We found robust improvements in children’s abilities to form complex relational structures and to make fine-grained discrimination for individual items from age 4 to age 6. However, relational memory dependent on context discrimination appears to follow a more protracted development. Furthermore, relational binding and mnemonic discrimination (item and context levels) undergo age-related decrements in senescence. Despite relatively poor relational binding capabilities, children as young as age 4 are able to retrieve multi-element events holistically, such as successfully retrieving of one aspect of an event predicts the retrieval success of other aspects from the same event. Critically, the degree of holistic episodic retrieval increases from age 4 to young adulthood. This multi-process approach provides important theoretical insights into lifespan profile of episodic memory. / Psychology