Opioid medications are medicine's best weapon against severe intractable pain, but prolonged use of these medications can be complicated by side effects like tolerance and mental clouding which, themselves, can be disabling. The present study examined the independent and combined effects of inflammatory pain and opioid medication on spatial memory for a well learned task in Sprague-Dawley rats. The Hargreaves method was used to verify the pain state of the animals after complete Freund's adjuvant injection and morphine treatment. Whereas pain had little effect on spatial memory, morphine had profound detrimental effects that persisted beyond the analgesic effectiveness of the drug. However, morphine-induced cognitive deficits were absent when morphine was provided to animals in chronic pain. Also, analgesic tolerance was significantly attenuated in these animals. Taken together, these results suggest that chronic pain activates a neural mechanism that antagonizes the unwanted effects of opioids.

Cette thèse s’inscrit dans la thématique de l’identification des bases neurobiologiques du déclin de la mémoire déclarative (MD) lié au vieillissement. Deux difficultés principales sont à noter : 1) la modélisation animale de la MD, mémoire typiquement humaine et 2) le manque d’intégration des différents niveaux d’analyse du fonctionnement cérébral. Nos travaux ont contribué à résoudre ces deux problèmes par le développement d’un modèle murin du déclin de MD lié au vieillissement, associé une approche d’imagerie fonctionnelle de l’expression de la protéine Fos. Une première série de résultats montre que la perturbation du système cholinergique au cours du vieillissement s’accompagne d’une modification de l’activité des systèmes de mémoire. Une deuxième série montre que le déficit de MD observé au cours du vieillissement est attribuable au dysfonctionnement d’un composant de la mémoire à court terme/de travail, le tampon épisodique, sous-tendu par le CA1 hippocampique. / Abstract

Zentall, Steirn, and Jackson-Smith (1990) found evidence for dual coding in pigeons in a radial maze analog task. Specifically, they found that pigeons used retrospective coding in which previously chosen keys were remembered when a delay was interpolated early in a trial and prospective coding in which to-be-visited keys were remembered when a delay was interpolated late in a trial. An alternative explanation, the criterion shift hypothesis proposed by Brown, Wheeler, and Riley (1989), suggests that these data are consistent with dual coding because of an artifact of the correction procedures used by Zentall et al. The criterion hypothesis suggests that retrospective coding is used and that pigeons make choices more carefully after many choices have been made on delay trials as compared to control trials, which creates the appearance of prospective coding later in a trial. The present experiments tested this hypothesis using a new testing trial procedure and new, more conservative control trials. In experiment 1, the results of Zentall et al. were replicated using a fixed delay procedure instead of their original progressive delay procedure. Experiment 2 used a forced choice procedure after the delay to make the probability of making an error 50% on each trial type. Control trials also included a forced choice procedure to eliminate the assumptions required by the corrections procedure used by Zentall et al. The results were inconsistent with the retrospective coding account predicted by the criterion shift hypothesis and with the dual coding hypothesis. Instead, the results were consistent with a prospective coding account in which to-be-visited keys were remembered. These results were replicated in Experiment 3 using the pigeons from Experiment 1. The present findings have important implications for the field of comparative cognition.

Despite very extensive studies related to molecular processes underlying memory formation, still little known about the potential differences in the brain biochemistry between &ldquo / good&rdquo / and &ldquo / poor&rdquo / learners belonging to a random population of young animals. In the present study, an attempt was taken to correlate the individual variation in short- and long-term spatial memory in three different lines of young, healthy rats: inbred Wistar (W), outcrossed Wistar/Spraque Dawley (W/S) and pigmented Long-Evans rats, with hippocampal levels of selected enzymes known as &ldquo / memory molecules&rdquo / including neuronal (n), endothelial (e) and inducible (i) NOS, CaMKII&alpha / , PKA and ChAT. Additionally, in order to indirectly estimate the activity of CaMKII&alpha / and PKA, hippocampal levels of their phosphorylated forms (pCaMKII&alpha / and pPKA) were assessed. Rats were classified as &ldquo / good&rdquo / and &ldquo / poor&rdquo / learners on the basis of their performance in a partially baited 12-arm radial maze. The hippocampal protein levels were measured using Western Blot technique. In addition to individual variation in animals&rsquo / learning capacity, strain-depended differences have also been observed. Deficient performance recorded in inbred W rats compared to outcrossed W/S rats, and &ldquo / poor&rdquo / learners from both rat groups had predominantly related to the higher frequency of reference memory errors. The results of biochemical assays showed strain-depended differences in the NOS expression. The overall NOS levels were significantly higher in outcrossed W/S rats compared to inbred W rats. In both rat lines, the rate of learning positively correlated with hippocampal levels of nNOS and negatively correlated with iNOS levels. Hippocampal eNOS levels correlated negatively with animals&rsquo / performance but only in the W rats. These results suggested that all 3 NOS isoforms are implemented in the learning process playing, however, different roles in neural signaling. Experiments carried out on Long-Evans rats did not reveal a significant difference in the basal hippocampal levels of the CaMKII&alpha / , however, the level of the pCaMKII&alpha / , was significantly higher in &ldquo / good&rdquo / learners. Also, hippocampal levels of both PKA and pPKA, as well as that of ChAT were significantly higher in &ldquo / good&rdquo / as compared to &ldquo / poor&rdquo / learners. Taken together, the latter findings indicate that low hippocampal expression of PKA and ChAT as well as low CaMKII&alpha / or PKA activation may cause learning deficits in random population of young rats, and thus, these enzymes can be considered target molecules when looking for cognitive enhancers to treat memory deficits in young subjects.

Depuis de nombreuses années, les scientifiques ont étudié les bases neurales de la mémoire. Cependant, une question clé demeure: comment le cerveau distingue t'il les informations suffisamment importantes pour être consolidées en mémoire à long terme des informations stockées de manière temporaire en mémoire à court-terme/mémoire de travail, et qui doivent être effacées afin de ne pas saturer nos ressources cognitives. Contrairement à l'opinion populaire qui considère l'oubli comme nuisible à notre mémoire, de nombreux travaux suggèrent que l'oubli est un processus adaptatif essentiel permettant le filtrage des informations non-essentielles qu'on peut stocker de manière temporaire. Étonnamment, on connaît peu de choses des bases cellulaires et moléculaires de cet oubli adaptatif. Le travail présenté dans cette thèse vise à déterminer les bases de cette forme d'oubli adaptatif, en particulier de celui nécessaire au traitement des informations en mémoire de travail. Avec cette thèse, nous avons ainsi montré que le gyrus denté est une structure clé responsable du traitement des informations non pertinentes en mémoire, un processus essentiel qui permet une utilisation optimale de nos ressources cognitives. Nous pensons que ces travaux nous aident à mieux comprendre comment le cerveau gère les interférences, mais également à identifier les mécanismes responsables de l'oubli « utile » d'informations / For many years, scientists have been investigating the neural bases of memory. However, a key question remains unanswered: how does the brain distinguish information important enough to be consolidated into long-term memory from information required only temporarily, and that needs to be cleared away for not saturating our cognitive resources. In contrast to the popular view considering forgetting as deleterious to our ability to remember, forgetting might be an essential adaptive process allowing the filtering of non-essential information. Surprisingly, very little is known on the cellular and molecular bases of adaptive forgetting. The work presented in this thesis aims to find a way to determine such bases of adaptive forgetting, in particular in the context of Working Memory processing. With this thesis, we thus showed that the dentate gyrus is a critical node in processing the forgetting of irrelevant information, an essential process allowing optimal use of cognitive resources. Our work sheds light not only on the question of how the brain responds to interferences, but also on the mechanisms of "forgetting" what should be forgotten

L'oubli est une perte temporaire ou permanente de mémoire, que l'on perçoit souvent de manière déplaisante lorsqu'elle nous empêche d'accéder à un savoir que l'on a acquis. Cependant, des découvertes récentes suggèrent que l'oubli peut aussi être un processus adaptatif permettant d'optimiser notre mémoire, en effaçant des informations non pertinentes susceptibles d'interférer avec le stockage ou le rappel de nouvelles informations. Ainsi, l'oubli adaptatif est particulièrement essentiel au fonctionnement de notre mémoire à court terme ou mémoire de travail (MT), car les informations qui y sont stockées doivent être oubliées une fois utilisées. A l'inverse, des informations peuvent être stockées pendant toute une vie dans la mémoire à long terme ou mémoire de référence (MR) chez l'animal. Les mécanismes cellulaires et moléculaires sous-tendant le stockage des informations en mémoire mais également leur oubli adaptatif restent mal connus. Au cours de cette thèse, nous avons adopté une approche comparative et utilisé trois tâches comportementales chez le rat au sein d’un même labyrinthe radial : une tâche de MR et deux tâches de MT impliquant un oubli adaptatif plus ou moins efficace. Nous avons étudié la transmission synaptique à la synapse entre le cortex entorhinal et le gyrus denté (voie d’entrée de l’hippocampe, structure clé de la mémoire) entre les deux jours d’apprentissage de ces trois tâches. Nous avons montré que la consolidation mnésique (en MR) induit un phénomène de potentialisation synaptique à long terme (proche d'une LTP), comme attendu d’après la littérature. A l'inverse, nous avons montré pour la première fois que l’oubli adaptatif en MT induirait une dépression synaptique à long terme. De plus, de nombreuses études suggèrent l’implication du sommeil dans la mémoire, mais le rôle des différentes phases de sommeil dans la consolidation mnésique ainsi que leur rôle dans l’oubli adaptatif reste ambigu. Nous avons donc également réalisé des enregistrements polysomnographiques (entre les deux jours des tâches), afin de quantifier la durée des états sommeil et la puissance des oscillations cérébrales. Nous avons ainsi confirmé le rôle du sommeil paradoxal, et plus particulièrement de ses oscillations gamma, pour la consolidation mnésique en MR. A l’inverse, l’oubli adaptatif en MT serait favorisé par les oscillations lentes du sommeil lent. Ces résultats représentent une contribution significative non seulement aux mécanismes neuronaux sous-tendant la mémoire et l’oubli adaptatif, mais également aux modulations de ces mécanismes par le sommeil. Nous avons donc montré que la consolidation mnésique induit un phénomène physiologique de potentialisation synaptique proche d'une LTP. Or l’induction artificielle de LTP par stimulation tétanique est considérée comme un modèle cellulaire de la mémoire. Notre second objectif a été d'évaluer l'impact de la modulation des états de sommeil sur une LTP, cette-fois-ci induite artificiellement (dans les mêmes conditions à la même synapse chez le rat vigile). Nous voulions ainsi comparer l'effet de la modulation du sommeil sur une potentialisation physiologique (après apprentissage) ou sur une LTP artificielle. Nous avons montré de nombreuses similitudes entre ces deux situations de potentialisation synaptique, notamment en ce qui concerne le rôle favorable du sommeil paradoxal, ce qui confirme l’intérêt de la LTP artificielle pour l’étude de la mémoire. Enfin, notre étude montre que non seulement le sommeil, mais également les oscillations de l'éveil contribuent à la mémoire et l’oubli. Nous avons analysé les oscillations locales dans le gyrus denté au cours des trois tâches comportementales déjà décrites. L'importante résolution spatiale et temporelle de cette analyse nous a permis d'identifier l'implication de certaines oscillations locales à des moments cruciaux de prise de décision dans le labyrinthe, au cours de l'encodage et du rappel d'informations stockées en MR ou en MT / Forgetting is a temporary or permanent loss of memory, often perceived as deleterious to our cognitive abilities, especially when it prevents us from accessing information we previously acquired. However, recent studies in Neurosciences suggest that forgetting could also be an adaptive phenomenon that would optimize memory function by erasing non relevant information, that could otherwise interfere with the storage or recall of new information. Therefore, adaptive forgetting would particularly be necessary for daily activities relying on short-term or working memory (WM), as information temporarily stored in WM need to be forgotten once used, so that this temporary information does not interfere in the future with the storage and recall of newer information. On the contrary, information can be stored for a lifetime in long-term or reference memory (RM) in animals. The molecular and cellular mechanisms underlying memory storage of information, but also adaptive forgetting, are still unclear. During this thesis, we used a comparative approach by training rats in three different behavioral tasks in the same radial maze: one RM task and two WM tasks involving a more or less effective adaptive forgetting process of previously stored information. We studied synaptic transmission at the synapse between the entorhinal cortex and the dentate gyrus (gating hippocampus, a key structure for memory) between two days of training in these three tasks. Our results show that memory consolidation (in RM) induces a form of long-term potentiation (LTP-like), confirming previous published work from the literature. However, we showed for the first time that adaptive forgetting in WM could trigger long-term synaptic depression. Moreover, numerous studies suggest that sleep is important for optimal memory processing, but the role of the different sleep phases in memory consolidation and in adaptive forgetting remains to be elucidated. We thus also performed polysomnographic recordings (between the two trainings days in the three behavioral tasks), in order to measure sleep state durations and sleep oscillations associated with these processes. Our results confirm the essential role of paradoxical sleep, and more specifically gamma oscillations during this state, for memory consolidation in RM. On the contrary, we also found that adaptive forgetting in WM would benefit from slow oscillations during slow wave sleep. We believe that these results contribute significantly to our understanding of neuronal mechanisms underlying memory and forgetting, especially concerning the modulation of these mechanisms by the different sleep states following training. On the one hand, we thus here showed that memory consolidation induces an LTP-like physiological phenomenon. On the other hand, the induction of an artificial form of LTP by tetanic stimulation is considered a cellular model of memory. Our second goal was to assess the modulation of an artificial LTP (at the same synapse, in the same conditions, on freely-moving rats) by sleep states. We also wanted to compare the impact of sleep states on a physiological LTP-like process (after learning) or on an artificial LTP. Our results showed many similarities between these two situations of synaptic potentiation, in particular concerning the positive role of paradoxical sleep, confirming the relevance of artificial LTP as a model to study memory processes. Finally, our study shows that not only sleep, but also oscillations during waking, could contribute to memory and forgetting. We therefore analyzed local spontaneous oscillations in the dentate gyrus while rats were performing the three behavioral tasks previously described. The high spatial and temporal resolution of this analysis allowed us to show the role of different local spontaneous oscillations at critical moments of training in the maze, in particular during decision making, and during encoding or retrieval of information stored in RM or WM

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