Hippocampal neurogenesis continues throughout life in mammals. These adult-generated dentate granule cells (DGCs) are generally believed to contribute to hippocampal memory processing and are generated at varying rates in response to neuronal network activity. Deep brain stimulation (DBS) allows clinicians to influence brain activity for therapeutic purposes and raises the possibility of targeted modulation of adult hippocampal neurogenesis. It has recently been shown that DBS may ameliorate cognitive decline associated with Alzheimer’s disease (AD), and while underlying mechanisms are unknown, one possibility is activity-dependent regulation of hippocampal neurogenesis. To this end, whether or not adult-generated DGCs can assume functional roles of developmentally-generated neurons, and stimulation-induced enhanced neurogenesis can benefit memory function in the normal and diseased brain, warrant study. First, we examined separate cohorts of developmentally- and adult-generated DGCs in intact mice and demonstrated similar rates of activation during hippocampus-dependent spatial memory processing, suggesting functional equivalence. Second, we examined the neurogenic and cognitive effects of targeted entorhinal cortex (EC) stimulation in mice using parameters analogous to clinical high frequency DBS. Stimulation increased the generation of DGCs. Moreover, stimulation-induced neurons were functionally recruited by hippocampal spatial memory processing in a cell age-dependent fashion that is consistent with DGC maturation. Importantly, stimulation facilitated spatial memory in the same maturation-dependent manner, and not when stimulation-induced promotion of adult neurogenesis was blocked, suggesting a causal relationship. Finally, we are in the process of testing whether similar stimulation facilitates spatial memory in a transgenic (Tg) disease model of AD that exhibits amyloid neuropathology and cognitive impairment. Preliminary results suggest stimulation promotes neurogenesis and rescues impaired spatial memory in Tg animals. When considered in the context of promising clinical results, this body of work suggests stimulation-induced neurogenesis could provide a novel therapeutic modality in settings where functional hippocampal regenerative therapy is desirable.

Hippocampal neurogenesis continues throughout life in mammals. These adult-generated dentate granule cells (DGCs) are generally believed to contribute to hippocampal memory processing and are generated at varying rates in response to neuronal network activity. Deep brain stimulation (DBS) allows clinicians to influence brain activity for therapeutic purposes and raises the possibility of targeted modulation of adult hippocampal neurogenesis. It has recently been shown that DBS may ameliorate cognitive decline associated with Alzheimer’s disease (AD), and while underlying mechanisms are unknown, one possibility is activity-dependent regulation of hippocampal neurogenesis. To this end, whether or not adult-generated DGCs can assume functional roles of developmentally-generated neurons, and stimulation-induced enhanced neurogenesis can benefit memory function in the normal and diseased brain, warrant study. First, we examined separate cohorts of developmentally- and adult-generated DGCs in intact mice and demonstrated similar rates of activation during hippocampus-dependent spatial memory processing, suggesting functional equivalence. Second, we examined the neurogenic and cognitive effects of targeted entorhinal cortex (EC) stimulation in mice using parameters analogous to clinical high frequency DBS. Stimulation increased the generation of DGCs. Moreover, stimulation-induced neurons were functionally recruited by hippocampal spatial memory processing in a cell age-dependent fashion that is consistent with DGC maturation. Importantly, stimulation facilitated spatial memory in the same maturation-dependent manner, and not when stimulation-induced promotion of adult neurogenesis was blocked, suggesting a causal relationship. Finally, we are in the process of testing whether similar stimulation facilitates spatial memory in a transgenic (Tg) disease model of AD that exhibits amyloid neuropathology and cognitive impairment. Preliminary results suggest stimulation promotes neurogenesis and rescues impaired spatial memory in Tg animals. When considered in the context of promising clinical results, this body of work suggests stimulation-induced neurogenesis could provide a novel therapeutic modality in settings where functional hippocampal regenerative therapy is desirable.

Exposure to ethanol (ETOH) during fetal development results in a range of cognitive/behavioral deficits. There are differences in sensitivity to the effects of ETOH that could be explained by other factors, such as hypoxia. Similar mechanisms of damage underlie both ETOH, more specifically ETOH withdrawal, and hypoxia. Based on this overlap, it was hypothesized that sub threshold levels of these insults may interact to produce increased damage in sensitive brain regions. This study used a rodent organotypic hippocampal slice culture model to investigate the interaction of hypoxia and ETOH withdrawal and to determine possible developmental differences in the sensitivity to these insults. The combination of ETOH and hypoxia produced greater damage in the CA1 and CA3 hippocampal regions, as measured by propidium iodide uptake. Differences in outcome were noted between on postnatal (PND) 2 and PND 8 tissue. ETOH alone caused damage as measured by the neuronal marker NeuN, suggesting the ETOH/hypoxia interaction involves different cell types and that caution should be taken when determining appropriate levels of exposure. This data could explain why some offspring appear more sensitive to ETOH and/or hypoxic challenges during early life.

It was long believed within the scientific community that the adult brain was unable to generate new neurons. In the end of the 1990s the consensus changed and it is since believed that the adult brain can and does generate new neurons after birth, a process referred to as adult neurogenesis. Adult neurogenesis takes place in two places in the adult brain: the subventricular zone (SVZ) in close proximity to the olfactory bulb and the subgranular zone (SGZ) in the hippocampus. The level of adult hippocampal neurogenesis (AHN) can be upregulated and one part of the aim was to examine the effect of voluntary chronic aerobic exercise (VCAE) on AHN. It is clear that voluntary chronic aerobic exercise reliably increases AHN. Still, the function of these new brain cells is under debate. Spatial learning and memory are among the main abilities that have been focused on. The other part of the aim was to examine the effect of VCAE and AHN on spatial learning and memory. The reviewed literature suggests that both AHN and spatial learning and memory increase together from VCAE, although it does not show causation, that an increase of AHN from VCAE causally effects spatial learning and memory. More studies are needed to investigate if a causal relationship exists.

De acordo com Gray (1982) o sistema nervoso monitora o ambiente e o comportamento continuamente, sendo capaz de inibir o comportamento em curso quando se depara com novidades ou com discrepâncias entre expectativas geradas com base em memórias de regularidades passadas e a informação sensorial presente, de modo a explorar a fonte de novidade ou discrepância e, assim, obter informações que possibilitem gerar previsões melhores no futuro. O sistema septo-hipocampal compararia estímulos presentes com informações antecipadas (ou previstas). Tal sistema envolve um comparador, o subículo, que receberia informações do presente através de aferências neocorticais, via córtex entorrinal, e informações \"previstas\" geradas em um \"circuito gerador de previsões\". Gray (1982) propôs que esse circuito gerador de previsões inclui o subículo, os corpos mamilares, o tálamo anteroventral, o córtex cingulado e, novamente, o subículo. Destas estruturas, o tálamo anteroventral encontra-se em posição privilegiada, do ponto de vista hodológico e experimental, para investigar este postulado circuito gerador de previsões. O objetivo do presente trabalho foi investigar o efeito da lesão seletiva no tálamo anteroventral, pela aplicação tópica de ácido N-metil-D-aspártico (NMDA), sobre a habilidade de ratos extrapolarem a partir de padrões seriais de estímulos. Tampão fosfato foi aplicado em sujeitos controle. Ratos da linhagem Wistar, machos, foram treinados a correr em uma pista reta para receberem reforço ao seu final. Em cada sessão (uma sessão por dia), os animais correram 4 tentativas sucessivas, recebendo quantidades diferentes de sementes de girassol em cada tentativa. No padrão monotônico decrescente os sujeitos receberam 14, 7, 3 e 1 sementes de girassol, enquanto os sujeitos expostos ao padrão não-monotônico receberam 14, 3, 7 e 1 sementes de girassol. Os animais foram treinados ao longo de 31 sessões. No 32° dia do experimento, uma quinta tentativa, nunca antes experienciada pelos animais, foi adicionada à sessão. Como esperado, os tempos de corrida na quinta tentativa dos animais controle expostos ao padrão monotônico decrescente foram substancialmente maiores se comparados aos animais controle expostos ao padrão não-monotônico, indicando a ocorrência de extrapolação. Em contraste, os sujeitos lesados expostos ao padrão monotônico não exibiram esse aumento de latência na quinta corrida, indicando que esses animais não extrapolaram. Em conclusão, os resultados indicam que extrapolação a partir de padrões seriais de estímulos é prejudicada pela lesão seletiva do tálamo anteroventral / According to Gray (1982) the brain continuously monitors environment and behavior, being capable of inhibiting ongoing behaviors when facing novelty or detecting discrepancies involving predictions generated from memories of past regularities and the actual sensorial information, in order to explore the source of novelty and/or discrepancy, and thus to gather information for generating better predictions in the future. The septo-hippocampal system compares anticipated and present information. The comparator would be the subiculum. This brain structure would receive present information from neocortical afferents, via the entorhinal cortex, and expected information from a \"generator of predictions system\" including the subiculum, mammillary bodies, anteroventral thalamus, cingulate cortex and, again, the subiculum. The anteroventral thalamus is in a privileged position, both hodologically and experimentally, to allow investigation of this postulated generator of predictions system. This study investigated the effect of selective damage to the anteroventral thalamus, by topical application of N-Methyl-D-Aspartic acid (NMDA), on the ability of rats to extrapolate relying on serial stimulus patterns. Control subjects were injected with phosphate buffer. Male Wistar rats were trained to run through a straight alleyway to get rewarded. In each session (one session per day) the animal run four successive trials, one immediately after the other, receiving different amounts of sunflower seeds in each trial. While subjects exposed to the monotonic decremental schedule received 14, 7, 3, 1 sunflower seeds along trials, subjects exposed to the non-monotonic schedule received 14, 3, 7, 1 sunflower seeds. Subjects were trained along 31 sessions. Then, on the 32nd testing session, a fifth trial never experienced before by all subjects was included immediately after the fourth trial. As expected, running times on the fifth trial for Control subjects exposed to the monotonic schedule were significantly longer as compared to the corresponding scores of Control subjects exposed to the non-monotonic schedule, thus indicating the occurrence of extrapolation. In contrast, lesioned subjects exposed to the monotonic schedule did not exhibit this increase in running times on the fifth trial thus indicating that these subjects did not extrapolate. In conclusion, results indicate that extrapolation relying on serial stimulus patterns is disrupted following selective damage to the anteroventral thalamus

Memory structure, memory assessment, Grober-Buschke paradigm, Alzheimer disease, and vascular dementia were discussed in the first part of the present thesis. Present study aims to examine the relationship between white matter changes, hippocampal atrophy and the performance in Enhanced Cued Recall test in nondemented geriatric population (n = 104). Partial neparametric correlations were used while controlling for age and Fazekas score. Medium correlations were found between left/right hippocampal volumes and free and total recall. No correlations were found between Fazekas score and ECR scores while controlling for age and left and right hippocampal volumes. Keywords: hippocampal atrophy, white matter changes, cued recall, ECR

L'épilepsie est une maladie fréquente affectant 0,5 à 1% de la population générale. Elle est caractérisée par des crises récurrentes responsables d'un sévère handicap médical et psychosocial. Les causes de l'épilepsie sont multiples et peuvent être liées notamment à des lésions cérébrales anténatales ou acquises, des causes génétiques ou métaboliques. L'épilepsie du lobe temporal (ELT) est la forme la plus répandue chez l’adulte, le plus souvent associée à une sclérose de l'hippocampe et réfractaire aux traitements antiépileptiques. Si pendant longtemps l'ELT a été perçue comme une pathologie focale centrée sur l'hippocampe sclérosé, de nombreux travaux montrent que les atteintes associées à l'ELT s'étendent bien au-delà de l'hippocampe et du lobe temporal, suggérant une altération plus globale du réseau cérébral structurel impactant le fonctionnement du cerveau. Toutefois, ces atteintes sont encore mal connues. Le développement récent des séquences et du traitement de l’imagerie de diffusion permettent l’acquisition d’images anatomiques du cerveau et la modélisation des fibres de substance blanche. L’architecture du réseau cérébral peut alors être représentée mathématiquement par un graphe, appelé « connectome » structurel, définissant la force des liens structurels (fibres de substance blanche) entre différentes régions du cerveau.L’objectif principal de la thèse est d’identifier les altérations du réseau structurel liées à l’épilepsie, avec un intérêt particulier à l’ELT. L’objectif secondaire est de développer de nouvelles méthodes d’extraction du connectome structurel pour en améliorer la précision anatomique et mieux identifier et localiser les altérations du réseau structurel.Ainsi, dans un premier temps, nous établissons l’état de l’art des méthodes d’extraction et d’analyse du connectome structurel et discutons leurs limites. Nous présentons alors une nouvelle méthode d’extraction du connectome structurel haute-résolution couvrant l’ensemble du cortex et incluant certaines régions sous-corticales, baptisée « high-resolution structural connectome ». L’objectif est de définir un cadre d’analyse du connectome structurel avec une très bonne précision anatomique et de fournir les outils nécessaires pour des études individuelles ou de groupe en tenant compte des contraintes de temps de calcul et d’utilisation de la mémoire et du disque.Dans un deuxième temps, nous analysons le connectome structurel de patients ELT avec sclérose hippocampique latéralisée dans le but de mettre en évidence le réseau structurel pathologique et d’en distinguer les caractéristiques en fonction de la latéralité de la lésion. Nous validons la stabilité et la reproductibilité du connectome structurel haute-résolution sur des sujets sains. La démonstration de son intérêt clinique potentiel est apportée en observant des différences structurelles subtiles entre deux groupes de sujets sains et en identifiant les sous-structures du striatum. Enfin, notre méthode est appliquée dans un contexte clinique pour identifier les altérations de connectivité structurelle du complexe hippocampo-amygdalien, impliqué dans l’ELT, en lien avec la pathologie. Nos travaux ont ainsi permis d’identifier les altérations globales et diffuses du réseau structurel liées à l’ELT, et plus particulièrement ont mis en évidence des disparités importantes selon la latéralité de la pathologie. Nous avons également présenté une nouvelle méthode d’extraction du connectome structurel augmentant considérablement sa précision anatomique et défini les outils nécessaires à l’analyse haute-résolution du connectome structurel. L’intérêt de cette méthode a été démontré par le gain de précision anatomique obtenu pour l’étude de l’architecture cérébrale du sujet sain ou pour une meilleure identification de réseaux pathologiques, ouvrant ainsi de nombreuses perspectives sur la caractérisation de l’architecture cérébrale et son lien sur le fonctionnement du cerveau. / Epilepsy is a frequent disease affecting 0.5 to 1% of the general population, characterized by recurrent seizures responsible for severe medical and psychosocial handicaps. The causes of epilepsy may be antenatal or acquired brain lesions, genetic history or metabolic disorders. Temporal lobe epilepsy (TLE) is the most common medically intractable epilepsy in adults, often associated with hippocampal sclerosis. Although TLE has been perceived for a long time as a hippocampal disorder, many studies show that the disease actually affects brain regions beyond the hippocampus and temporal lobe suggesting diffuse alteration of the brain structural network. However, these alterations are still unknown. Recent advances in diffusion weighted imaging and processing allow for the acquisition of brain anatomical images and the modeling of white matter fibers. Brain network architecture can then be represented mathematically by means of a graph, called “structural connectome”, defining the strength of the structural links (white matter fibers) across brain regions.The purpose of this thesis is to identify structural network alterations associated with epilepsy, in particular TLE. The secondary objective is to develop new methods for extracting the structural connectome in order to increase the anatomical accuracy and better localize network alterations.Therefore, we first review the state of the art of the methods used for extracting and analyzing the structural connectome and establish their limitations. We then introduce a new method to extract the structural connectome with increased anatomical accuracy, which we called “high-resolution structural connectome”. The purpose is to provide a framework to analyze brain connectivity at high-resolution and to define the necessary tools for individual and group analysis, keeping in mind processing time and memory and disk usages.Then, we analyze the structural connectome of TLE patients with hippocampal sclerosis to reveal underlying pathological network, we also highlight pathological network discrepancies between left and right sided lesions. Inter- and intra-subject stability and repeatability of the high-resolution structural connectome are assessed with a cohort of healthy subjects. We demonstrate potential clinical interest by observing subtle structural differences between two groups of healthy subjects and by delineating the sub-fields of the striatum. Finally, our method is applied to the pathological case of TLE and aims at uncover structural connectivity alterations of the hippocampo-amygdalian complex, known to be involved in TLE.In conclusion, we extend our current knowledge on TLE by showing that this is a network disease involving widespread brain regions, whose pattern largely depends on lesion laterality. We also introduce a new method for extracting the structural connectome at high-resolution, considerably increasing the anatomical accuracy. The interest of this method is demonstrated on healthy subjects to better characterize the healthy brain and on the diseased brain to localize more precisely the brain regions associated with the pathology.

No description available.

Les dernières années témoignent d'une remarquable accélération dans la compréhension des facteurs génétiques impliqués dans la déficience intellectuelle (DI) et de nombreux gènes responsables ont été identifiés. Néanmoins, les mécanismes cellulaires et moléculaires sous-jacents à la DI sont encore mal connus. Une hypothèse attractive est que les mutations à l’origine de DI affectent la neurogenèse hippocampique adulte (NGA), une forme de plasticité qui joue un rôle crucial dans la mémoire. L'objectif de ce projet est d’entreprendre une analyse comparative de la NGA chez trois modèles murins de pathologies d’origine génétique, menant à une DI sévère, impliquant des gènes localisés sur le chromosome X et participant à différentes voies de signalisation susceptibles de moduler la NGA : le syndrome de Coffin-Lowry (gène rsk2), la dystrophie musculaire de Duchenne (gène dmd) et une DI liée au gène pak3. Mes recherches actuelles montrent que ces trois modèles présentent des déficits cognitifs dépendants de l’hippocampe, dont des altérations de la fonction de séparation de patterns. Nous avons également mis en évidence des altérations de la NG adulte, avec, entre autres, des altérations du recrutement des jeunes neurones par l’apprentissage qui pourraient contribuer aux déficits cognitifs observés en particulier dans la fonction de séparation de patterns. Toutefois, selon les gènes en cause, les déficits ne sont pas observés dans les mêmes étapes de la NGA ni dans les mêmes situations comportementales. L’ensemble de ces résultats laisse donc suggérer que chacun des gènes étudiés pourrait jouer un rôle différent dans la NGA, mais qu'in fine des altérations de cette forme de plasticité contribuent, au moins en partie, aux déficits cognitifs associés à la DI dans les trois modèles. Ensemble, ces résultats apportent des informations supplémentaires qui seront directement pertinentes pour d’autres pathologies neuro-développementales conduisant à des déficits cognitifs liés à des altérations de la NG, et pourraient ouvrir de nouvelles pistes thérapeutiques. / Recent years have shown a remarkable acceleration in the understanding of genetic factors involved in intellectual disability (ID) and many genes responsible have been identified. However, the cellular and molecular underlying mechanisms are still poorly understood. An attractive hypothesis is that mutations causing ID may affect adult hippocampal neurogenesis (ANG), a form of plasticity that plays a crucial role in learning and memory. The objective of this project was to undertake a comparative analysis of adult hippocampal neurogenesis in three mouse models of genetic diseases involving genes located on the X chromosome and participating in different signalling pathways that may modulate ANG: the Coffin-Lowry syndrome (rsk2 gene), Duchenne muscular dystrophy (dmd gene) and ID due to mutation of the pak3 gene. My current research shows that these three models present hippocampal dependent cognitive deficits. Among these deficits, major deficits in spatial pattern separation function have been highlighted. We also showed specific alterations of basal ANG, together with alterations in the recruitment of young newborn neurons by learning that could contribute to the observed cognitive deficits, in particular in pattern separation function. However, depending on the genes involved, the deficits are not observed in the same steps of adult NG and in the same behavioural situations. In all, the results suggest that each of the genes plays a different role in ANG, but finally that alterations of this form of plasticity may contribute to the cognitive deficits associated with ID in the three models. Together, these results provide additional information that will be directly relevant to other neurodevelopmental disorders leading to cognitive deficits related to NG alterations, and could open new therapeutic tracks.

No description available.