Patients with Alzheimer’s disease (AD) experience sleep disturbances, including disruption in slow-wave sleep (SWS). Slow oscillations (≤1 Hz), a brain rhythm prevalent during SWS, play a role in memory consolidation. Interestingly, patients with AD exhibit slow oscillations of low amplitude, which might contribute to their memory impairments. The mechanisms underlying slow-wave disruptions in AD remain unknown. Slow oscillations originate in the neocortex. Cortical neurons from all layers oscillate between UP and DOWN states during slow oscillations. Astrocytes are known to support neuronal circuit functions, and disruptions in astrocyte activity might contribute to slow-wave aberrations. Here, we investigated astrocytic contributions to slow-wave disruptions in an animal model of beta-amyloidosis (APP mice). First, we monitored astrocytic calcium transients to determine whether astrocytic calcium dynamics were disrupted in APP mice. Fourier transform analysis revealed that the power, but not the frequency of astrocytic calcium transients, was disrupted in young APP mice. This suggested calcium dynamic of astrocytic network was altered and might contribute to the disruption of slow waves in APP mice. Second, we used optogenetics to synchronize cortical astrocyte activity at 0.6 Hz to drive slow oscillations in APP mice. Our results showed that optogenetic activation of ChR2-expressing astrocytes at the endogenous frequency of slow waves restored slow-wave power. Furthermore, chronic optogenetic stimulation of astrocytes at 0.6Hz for 14 or 28 days reduced amyloid plaque deposition, prevented calcium overload in neurites, and improved memory performance in APP mice. These results revealed a malfunction of the astrocytic network driving slow-wave disruptions, and suggested a novel target to restore slow-wave power in APP mice, with translational potential to treat AD.

Unlike other domains of cognition, the acquisition of procedural skills (e.g., the "how to" of memory) is spared by age. However, the consolidation (i.e., the transformation from labile memory to long-term storage) of this type of memory is compromised by age. Optimal memory consolidation for procedural skills is dependent on sleep. Sleep is also negatively impacted by normal, healthy aging. Recent research has identified the neural markers of the lost benefit of sleep for reduced memory consolidation with age. While this is relatively well-established for procedural memory, and for cognitively simple motor skills, the impact of age-related changes in sleep on cognitively complex procedural memory consolidation (i.e., novel cognitive strategies required for "problem-solving skills") remains to be investigated. Furthermore, reduced capacity to solve problems with age has serious mental health-related consequences, including increased depression and suicide attempts, as well as disability in depressed, cognitively impaired older adults. Moreover, problem-solving therapy has been found to improve quality of life in older adults. As such, the aims of these series of studies were to investigate: 1) the behavioural consequences of age on sleep-dependent memory consolidation, 2) identify the electrophysiological markers during sleep of the lost benefit of sleep, 3) identify the age-related changes in brain structure and how this relates to and behavioural outcomes and sleep, and, 4) identify the impact of age on sleep-dependent consolidation of the memory trace for problem-solving skills. Using an innovative combination of EEG, MRI, and behavioural testing in healthy young and older adults, these series of studies revealed novel insights into the breakdown of the normal processes that occur during sleep that support memory. The main objective of this thesis is to identify the neural markers of the very earliest signs under optimal conditions of age-related cognitive decline for problem-solving skills. Investigating the neurophysiological and behavioral consequences of age-related changes in sleep, and their impact on problem-solving skills, will help reveal therapeutic targets for future research that will improve quality of life for seniors. Furthermore, this research will ultimately lead to the development of early interventions targeting sleep that could delay or lessen the severity of the onset of clinically significant cognitive impairment; as those who sleep better, may also age better cognitively.

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.

Le sommeil joue un rôle majeur dans les processus de consolidation des apprentissages. Les performances des sujets lors de la restitution de tests de mémoire sont meilleures lorsque les phases d'apprentissage et de restitution sont séparées par une période de sommeil plutôt que par une période d'éveil. Les effets du sommeil sur ces processus de consolidation ont largement été étudiés chez l'adulte, notamment à l'aide de protocoles de privation de sommeil spécifiques. Néanmoins, l'utilisation de ces protocoles de privation de sommeil est impossible chez les enfants pour des raisons d'éthique. Nos connaissances actuelles relatives aux effets du sommeil sur les processus de consolidation des apprentissages dépendants du sommeil sont donc très limitées chez l'enfant. Les troubles du sommeil touchent une proportion non négligeable des enfants et ont des répercussions diurnes importantes, notamment au niveau académique. De manière surprenante, bien que la majorité des enfants ayant des troubles du sommeil soit en échec scolaire, l'impact de ces troubles du sommeil sur les processus de consolidation des apprentissages dépendants du sommeil a très rarement été évalué. L'objectif de ce projet de thèse était donc d'évaluer l'impact des troubles du sommeil sur ces processus de consolidation. Pour atteindre cet objectif, nous avons sélectionné 3 pathologies présentant des atteintes spécifiques du sommeil : la narcolepsie, le syndrome d'apnées obstructives du sommeil (SAOS) et l'épilepsie bénigne de l'enfant à pointes centro-temporales (EPCT). Nous avons soumis ces groupes d'enfants ainsi qu'un groupe d'enfants contrôles appariés en âge et en sexe à des tests de consolidation mnésique dont la phase d'apprentissage était réalisée le soir avant le coucher et la phase de restitution le matin après la nuit post-apprentissage. Afin d'avoir la vision la plus complète possible de l'impact des troubles du sommeil sur les processus de consolidation des apprentissages, ces tests de consolidation mnésique impliquaient des apprentissages de nature déclarative (tâches verbale, visuo-spatiale et émotionnelle) et non-déclarative (tâche procédurale). Nous avons également mesuré les capacités attentionnelles des enfants avant l'apprentissage et avant la restitution des tests de consolidation mnésique. Les résultats que nous avons obtenus semblent indiquer que la narcolepsie, le SAOS et l'EPCT auraient un impact négatif sur les processus de consolidation des apprentissages visuo-spatiaux dépendants du sommeil. En revanche, ces 3 pathologies ne semblent pas avoir d'influence sur ces processus dans le cadre des apprentissages verbal, émotionnel et procédural. Ces résultats suggèrent donc que les aspects concernant la consolidation nocturne des apprentissages devraient être intégrés dans les évaluations neuropsychologiques rentrant en compte dans le diagnostic des enfants porteurs de ces pathologies. De plus, les suivis pédagogique et rééducatif de ces enfants devraient être reconsidérés / Sleep plays a key role in sleep-dependent memory consolidation processes. Subject’s performances during the restitution phase of memory tests are better when the learning and restitution are separated by a sleep period than by a wake period. Effects of sleep on memory consolidation processes have widely been investigated in adults by using specific sleep deprivation protocols. However, these sleep deprivation protocols can’t be used in children for ethical reasons. Thus, our knowledge about sleep-dependent memory consolidation processes in children is extremely restricted. Sleep disorders concern a large proportion of children and they have an important range of daytime consequences including academic achievement. Surprisingly, despite the fact that the majority of children with sleep disorders display school difficulties, the impact of these sleep disorders on sleep-dependent memory consolidation processes has scarcely been investigated. This thesis project aimed at evaluating the impact of sleep disorders on sleep-dependent memory consolidation processes. In order to reach this objective, we selected 3 pathologies with specific sleep impairments: narcolepsy, obstructive sleep apnea syndrome (OSAS) and benign childhood epilepsy with centro-temporal spikes (BECTS). We have submitted these children, as well as a control group children matched on age and sex, to memory consolidation tests whereby the learning phase took place in the evening before sleep and the restitution phase took place after the post-learning night. In the way to have the more complete understanding of the impact of sleep disorders on memory consolidation processes, these memory consolidation tests included declarative (verbal, visuo-spatial and emotional tasks) and non-declarative (procedural task) learnings. Moreover, attention ability was measured before learning and restitution phases. Results indicated that narcolepsy, SAOS and EPCT impacted sleep-dependent memory consolidation processes of the visuo-spatial task. However, no impact of these pathologies on sleep-dependent memory consolidation processes of the verbal, emotional and procedural tasks has been found. These results suggest that nocturnal consolidation aspects of learning’s should be integrated in neuropsychological assessments accounting for sleep disorders diagnosis. Moreover, pedagogic and re-educational supervisions of these children should be reconsidered

Any disruption of homeostasis causes a stress response that serves to restore balance in the body. Stress hormone levels, such as glucocorticoids, strongly influence the consolidation of episodic memory dependent on the hippocampus. Sleep has beneficial effects on individual types of memory and is necessary for the proper course of consolidation of newly acquired information. Little is known, however, about neuronal processes of memory consolidation for a traumatic event. The topic of this work is to study the combination of these two factors and to determine the effect of elevated levels of corticosterone and sleep on the consolidation of traumatic memory in rats. The theoretical part of this work summarizes the knowledge about memory, sleep and stress. The practical part deals with the experimental procedure combining behavioral (fear conditioning), electrophysiological methods (EEG recording and determination of sleep stages) and pharmacological manipulation (intrahippocampal administration of corticosterone). In summary, we found the effect of high levels of corticosterone in the hippocampus on contextual memory consolidation and on the amount of slow wave sleep. These results can bring new features in the field of traumatic memory consolidation and associated post-traumatic stress disorder....

Previous research investigating the neural circuitry underlying memory consolidation has primarily focused on single “nodes” in the circuit rather than the neural connections between brain regions, despite the likely importance of these connections in mediating different aspects or forms of memory. This focus has, in part, been due to technical limitations; however the advent of optogenetics has altered our capabilities in this regard, enabling optical control over neural pathways with temporal and spatial precision. The current set of experiments took advantage of optogenetics to control activity in specific pathways connecting brain regions in rats immediately after different kinds of learning. Chapter 2 first established the use of optogenetics to manipulate activity in the basolateral amygdala (BLA), which has been shown to modulate memory consolidation for a variety of types of learning likely through its connections to various downstream regions. Using a one-trial inhibitory avoidance task, a simple and robust fear learning paradigm, we found that both post-training stimulation and inhibition of BLA activity could enhance or impair later retention of the task, respectively. Enhancement was specific to stimulation using trains of 40, but not 20, Hz light pulses. Chapters 3 and 4 examined the projections from the BLA to the ventral hippocampus (VH) and medial entorhinal cortex (mEC) as the BLA’s ability to influence the consolidation for many types of memory is believed to be mediated through discrete projections to distinct brain regions. Indeed, the BLA innervates both structures, and prior studies suggest that the mEC and VH have distinct roles in memory processing related to contextual and nociceptive (footshock) learning, such as those involved in contextual fear conditioning (CFC). Optogenetic stimulation or inhibition of the BLA-VH or BLA-mEC pathway after training on a modified CFC task, in which the nociceptive or emotional stimulus (the footshock) and the context are separated, enabled experimental manipulations to selectively affect the consolidation for learning about one component and not the other. Optogenetic stimulation/inhibition was given to each candidate pathway immediately after the relevant training to determine its role in influencing consolidation for that component of the CFC learning. Chapter 3 results showed that stimulation of the BLA-VH pathway following footshock, but not context, training enhanced retention, an effect that was specific to trains of 40 Hz stimulation. Post-footshock photoinhibition of the same pathway impaired retention for the task. Similar investigations of the BLA-mEC pathway in Chapter 4 produced complementary findings. Post-context, but not footshock, stimulation of the pathway enhanced retention. In this particular case, only trains of 8 Hz stimulation were effective at enhancing retention. These results are the first, to our knowledge, to find that BLA inputs to different structures selectively modulate consolidation for different aspects of learning, thus enhancing our understanding of the neural connections underlying the consolidation of contextual fear conditioning and providing a critical foundation for future research.

New memories are labile, but over time some of them are stabilized. This thesis investigates the network mechanisms in the brain underlying the gradual consolidation of memory representations. Specifically, I performed a causal test of the long-standing hypothesis that the offline reactivation of new, memory-representing cell assemblies supports memory consolidation by stabilizing those assemblies and increasing the likelihood of their later reinstatement - and therefore presumably of memory recall. I performed multi-unit extracellular recordings in the dorsal CA1 region of behaving mice, from which I detected short-timescale (25 ms) co-activation patterns of principal neurons during exploration of open-field enclosures. These cell assembly patterns appeared to represent space as their expression was spatially tuned and environment specific; and these patterns were preferentially reactivated during sharp wave-ripples (SWRs) in subsequent sleep. Importantly, after exposure to a novel - but not a familiar - enclosure, the strength with which an assembly pattern was reactivated predicted its later reinstatement strength during context re-exposure. Moreover, optogenetic silencing of hippocampal pyramidal neurons during on-the-fly detected SWRs during the sleep following exposure to a novel - but again not a familiar - enclosure impaired subsequent assembly pattern reinstatement. These results are direct evidence for a causal role of SWR-associated reactivation in the stability of new hippocampal cell assemblies. Surprisingly, offline reactivation was only important for the stability of a subset of the assembly patterns expressed in a novel enclosure. Optogenetic SWR silencing only impaired the reinstatement of "gradually strengthened" patterns that had had a significant increasing trend in their expression strength throughout the initial exposure session. Consistent with this result, a positive correlation between reactivation and subsequent reinstatement was only found for these gradually strengthened patterns and not for the other, "early stabilized" patterns. An interesting interpretation is that the properties of the gradually strengthened patterns are all consistent with the Hebbian postulate of "fire together, wire together". To enable investigation of the relation between interneurons and principal cell assembly patterns from extracellular recordings, as a final contribution this thesis describes a statistical framework for the unsupervised classification of interneurons based on their firing properties alone.

Selon la théorie du replay, le sommeil améliore la consolidation mnésique des apprentissages récents à travers leur réactivation. Pour tester cette hypothèse, nous avons utilisé le modèle de la somniloquie : les paroles nocturnes reflétant le contenu mental du dormeur et les informations qu’il est en train de traiter. La somniloquie survient fréquemment dans le cadre de parasomnies de sommeil lent (somnambulisme) ou de sommeil paradoxal (TCSP). Nous avons d’abord montré comment ces deux parasomnies correspondaient à la mise en gestes et en paroles du contenu mental du dormeur, avec une prédominance en sommeil lent de rêves de catastrophes que les somnambules fuyaient et en sommeil paradoxal, de rêves d’agressions d’animaux ou de personnes que les patients contre-attaquaient. Ceci soutient le concept de la fonction évolutionniste des rêves comme un entraînement virtuel à « fuir ou combattre » les menaces. Ensuite, nous avons utilisé les somniloquies pour tester si un apprentissage verbal récent était consolidé pendant le sommeil mais aussi si certains mots étaient répétés en dormant. Nous avons d’abord montré que la consolidation mnésique verbale liée au sommeil était bien conservée chez les somnambules comme chez les patients atteints de TCSP, même déments, comparée aux sujets normaux. Ensuite, nous n’avons pas identifié de réexécution de phrases apprises la veille lors des somniloquies de sommeil lent, mais avons identifié chez un patient avec TCSP, un élément sémantique évoquant une réutilisation du contexte de l’histoire. Enfin, nous avons collecté 883 verbatim nocturnes et décrit les aspects acoustico-phonétiques, prosodiques et sémantiques du langage nocturne. / According to the replay theory, sleep improves memory consolidation of recent learning through their reactivation. To test this hypothesis, we used the model of sleep-talking: the words uttered reflecting the mental content of the sleeper and the information he is proceeding. Sleep-talking occur frequently within the context of slow wave sleep (sleepwalking) or REM sleep parasomnias (RBD). We first showed how these two parasomnias corresponded to the setting gestures and words of the mental content of the sleeper, with predominance during slow wave sleep of dreams featuring disasters that sleepwalkers fleeing, and during REM sleep of dreams of attacks by animals or people that subjects counterattack. This supports the concept of evolutionary function of dreams as a virtual drive to “fight or flight” threats. Then, we used sleep-talking to test if a recent verbal was not only consolidated during sleep but also if some words were repeated while sleeping. We first showed that verbal memory consolidation related to sleep was preserved in sleepwalkers as in patients with RBD, even with dementia, compared with normal subjects. Then, we haven’t identified rehearsed sentences of the material learned the day before during slow wave sleep parasomnias, but we identified in a subject with RBD, a semantic component evoking a rehearse of the context of the learned history. Finally, we collected 883 verbatim during sleep and describes the acoustic-phonetic, prosodic and semantic aspects of sleep-talking.

S’il est bien établi que le flux sanguin cérébral est distribué en fonction de la demandemétabolique des neurones, aucune étude n’a exploré la contribution du réseauvasculaire au processus de consolidation mnésique qui requiert un dialoguehippocampo-cortical permettant le remodelage progressif des réseaux neuronauxcorticaux sous-tendant la trace mnésique ancienne stabilisée.Utilisant un test comportemental induisant une mémoire olfactive associative chez lerat couplé à des techniques d’imagerie cellulaire ex vivo, nous montrons pour lapremière fois, chez le rat adulte sain, une dissociation fonctionnelle entre réactivité etarchitecture du réseau vasculaire cérébral. Nous mettons en évidence des modificationsde signalisation calcique des artères cérébrales qui suggèrent que leur dynamiques’adapte pour permettre l’expression du souvenir. De plus, suivant une cinétiquedifférente, le réseau vasculaire se densifie par angiogenèse dès le lendemain del’apprentissage, y compris dans les régions du cortex ne prenant en charge le souvenirque plusieurs semaines plus tard. En stimulant spécifiquement cette angiogenèse parinjection d’agents pharmacologiques dans le cortex, nous améliorons les performancesdes rats lors du rappel de mémoire ancienne.Pris dans leur ensemble, nos résultats soulignent l’importance de la plasticitévasculaire dans la modulation de la plasticité neuronale et des fonctions cognitives. Ilssuggèrent en outre que les changements structuraux précoces du réseau vasculairepourraient constituer un mécanisme permissif à l’origine de la régulation des épinesdendritiques corticales impliquées dans la formation et le stockage à long terme dessouvenirs.Mots / While there is consensus that cerebral blood flow is distributed according to themetabolic demand of neurons, the contribution of vascular networks to memoryconsolidation, the process by which memories acquire stability over time, remainsunknown. This process requires a transitory hippocampal-cortical interaction allowingthe progressive remodeling of cortical neuronal networks supporting the remotememory trace.By using a behavioral task requiring an associative olfactory memory coupled to cellularimaging techniques, we first reveal, in adult healthy rats, a functional dissociationbetween the reactivity and the architecture of cerebral vascular networks. We identifycalcium signaling changes that occur in specific cerebral arteries, pointing to theirability to adapt their dynamics upon retrieval to enable the successful expression ofeither recent or remote memories. Moreover, we show that vascular networks undergo atime-dependent densification via an angiogenesis mechanism as early as one day afterlearning, including in cortical regions which will only support memory storage andretrieval weeks later. By specifically stimulating this early cortical angiogenesis, we wereable to improve the performance of rats tested for remote memory.Taken together, our results highlight the importance of vascular plasticity inmodulating neuronal plasticity and cognitive functions. They also suggest that the earlystructural changes within vascular networks could constitute a permissive mechanismwhich regulates the development of cortical dendritic spines thought to support theprogressive formation and storage of enduring memories.

The ability to memorize and recognize edible prey from inedible prey is essential for an individuals survival. Many species use aposematic signals for their defense. These are most often represented by distinctive colors or contrast patterns. The aim of this study was to find out in which time the memory consolidation for aposematic pray is achieved and if color or pattern increase its memorability. The choosen model species was the Great tit (Parus major). The comparision was done between handreared naïve birds and wild-caught adults of different age and sex. During the discriminatory task of consolidation experiment, birds were simultaneously presented with palatable and unpalatable prey in the form of paper dummies of bugs, differing in color (red versus green). The birds were divided into three groups with a different interval (0, 1 or 3 hours) for consolidation. The results of consolidation test show that adult birds were more successfull in solving the task than juvenile birds. The only difference between the experimental groups was that the group with one-hour interval achieved better results than other groups. The effect of color of palatable and unpalatable prey on discrimination learning was also found only in adults. Memorability of warning signals was tested using paper bugs of...