Le projet de cette thèse s'est attaché à caractériser le rôle de l'IL-1 beta et les récepteurs P2X7 dans la dépression. Les résultats suggèrent que chez les souris stressés et les perturbation comportementaux, l'activation microgliales et endocriniennes sont reversées par l'antagoniste des P2X7Rs. Ces résultats mettent en évidence que l'antagoniste des récepteurs P2X7 a des effets comportementaux et neuroendocriniens. / Research work of this thesis was aimed to characterize role of IL-1 beta and P2X7 receptors in depressive illness. Results suggest that i stressed mice the behavioral and neurobiochemical changes are reversed by use of P2X7R antagonist. It is an evidence of antidepressant of these compounds.

O envelhecimento, processo iminente a todo ser vivo, no SNC é caracterizado por alterações como, por exemplo, a neuroinflamação crônica, que estão associadas a processos de neurodegeneração e ao aumento da incidência de doenças neurológicas ligadas ao surgimento de demência. A insulina, o hormônio anabólico mais importante descoberto até hoje, tem sua sinalização como processo vital que está presente desde bactérias até a espécie humana e desde os tecidos periféricos até o SNC. Mesmo a sinalização cerebral de insulina sendo um tema bem definido na literatura, pouco se sabe sobre a sua função em células da glia, principalmente astrócitos e microglia, componentes chaves do processo de neuroinflamação. A neuroinflamação foi considerada, por muitos anos, tóxica ao SNC, mas atualmente evidências importantes têm sido encontradas sugerindo que processos pró-inflamatórios são primariamente benéficos ao cérebro ou encéfalo e podem assumir papel tóxico à medida que se tornam crônico. Assim, considerando o papel da insulina no SNC, bem como o aumento da expectativa de vida da população mundial que acarreta o aumento dramático da incidência de doenças neurodegenerativas, foi investigada, na presente tese a relação da sinalização fisiológica de insulina com processos cognitivos, neurotróficos e neuroinflamatórios e também a resistência na sinalização da mesma causada pelo envelhecimento cerebral. Foi demonstrado que a administração intracerebroventricular de insulina melhora a cognição de animais jovens, mas o mesmo não ocorre no envelhecimento. A nível celular e molecular, foi visto um distúrbio na conexão da sinalização de insulina e BDNF, bem como na ativação microglial e sinalização pró-inflamatória da insulina que parecem estar comprometidos no envelhecimento. Além disso, foi observado que a microglia é sensível à sinalização direta de insulina via PI3K e que essa sinalização microglial é adaptada e sofre mudanças na vida adulta. Em conjunto com a literatura, foi demostrado por esta tese que existe uma ruptura de paradigmas na interpretação dos processos neuroinflamatórios, que deixam de ser vistos somente como um fator tóxico ao cérebro, mas também como um artifício elementar de adaptação do SNC aos diversos estímulos que as células nervosas recebem durante o curso da vida, desde o nascimento até o envelhecimento. / Aging is a process that is found in all living being in the CNS. It is characterized by modifications, such as chronic neuroinflammation, which are associated with neurodegeneration and represent a risk factor for neurological diseases. Insulin is the most important anabolic hormone ever discovered. Insulin signaling represents an essential process that is present from bacteria to humans and from the periphery to the brain. Insulin signaling in the CNS is a well-defined topic in the literature. Most of the knowledge regarding brain insulin signaling still report findings in neurons and little is known about insulin function in glia, especially astrocytes and microglia that are key players of neuroinflammation. Neuroinflammation has been considered a toxic factor to the CNS, however, in the last few years, important evidences have been found that proinflammatory processes are primarily beneficial and may play a toxic role as soon as they become chronic. Thus, considering the role of insulin in the CNS, as well as the increased populational life spam worldwide, the present thesis investigated the relation of physiological insulin signaling and the brain insulin signaling caused by aging in cognition, neurochemistry and neuroinflammation. We showed that insulin intracerebroventricular administration improved the cognition of young animals, but the same was not observed in aging. At the cellular and molecular level, we found a disruption in the connection of insulin and BDNF signaling. We also show that a microglial activation and pro-inflammation triggered by insulin in young brain appear to be lost during aging. In addition, it was observed that microglia is sensitive to direct insulin signaling via PI3K and that this microglial signaling suffers adaptations and changes during life. Together with the recently changes in the literature, the findings of this work demonstrate that there is a rupture of paradigms in the interpretation of neuroinflammatory processes, which are no longer seen only as a toxic factor to the brain, but also as an smart adaptation of the CNS to the various stimuli that brain cells receive during the course of life, from birth to aging.

O envelhecimento, processo iminente a todo ser vivo, no SNC é caracterizado por alterações como, por exemplo, a neuroinflamação crônica, que estão associadas a processos de neurodegeneração e ao aumento da incidência de doenças neurológicas ligadas ao surgimento de demência. A insulina, o hormônio anabólico mais importante descoberto até hoje, tem sua sinalização como processo vital que está presente desde bactérias até a espécie humana e desde os tecidos periféricos até o SNC. Mesmo a sinalização cerebral de insulina sendo um tema bem definido na literatura, pouco se sabe sobre a sua função em células da glia, principalmente astrócitos e microglia, componentes chaves do processo de neuroinflamação. A neuroinflamação foi considerada, por muitos anos, tóxica ao SNC, mas atualmente evidências importantes têm sido encontradas sugerindo que processos pró-inflamatórios são primariamente benéficos ao cérebro ou encéfalo e podem assumir papel tóxico à medida que se tornam crônico. Assim, considerando o papel da insulina no SNC, bem como o aumento da expectativa de vida da população mundial que acarreta o aumento dramático da incidência de doenças neurodegenerativas, foi investigada, na presente tese a relação da sinalização fisiológica de insulina com processos cognitivos, neurotróficos e neuroinflamatórios e também a resistência na sinalização da mesma causada pelo envelhecimento cerebral. Foi demonstrado que a administração intracerebroventricular de insulina melhora a cognição de animais jovens, mas o mesmo não ocorre no envelhecimento. A nível celular e molecular, foi visto um distúrbio na conexão da sinalização de insulina e BDNF, bem como na ativação microglial e sinalização pró-inflamatória da insulina que parecem estar comprometidos no envelhecimento. Além disso, foi observado que a microglia é sensível à sinalização direta de insulina via PI3K e que essa sinalização microglial é adaptada e sofre mudanças na vida adulta. Em conjunto com a literatura, foi demostrado por esta tese que existe uma ruptura de paradigmas na interpretação dos processos neuroinflamatórios, que deixam de ser vistos somente como um fator tóxico ao cérebro, mas também como um artifício elementar de adaptação do SNC aos diversos estímulos que as células nervosas recebem durante o curso da vida, desde o nascimento até o envelhecimento. / Aging is a process that is found in all living being in the CNS. It is characterized by modifications, such as chronic neuroinflammation, which are associated with neurodegeneration and represent a risk factor for neurological diseases. Insulin is the most important anabolic hormone ever discovered. Insulin signaling represents an essential process that is present from bacteria to humans and from the periphery to the brain. Insulin signaling in the CNS is a well-defined topic in the literature. Most of the knowledge regarding brain insulin signaling still report findings in neurons and little is known about insulin function in glia, especially astrocytes and microglia that are key players of neuroinflammation. Neuroinflammation has been considered a toxic factor to the CNS, however, in the last few years, important evidences have been found that proinflammatory processes are primarily beneficial and may play a toxic role as soon as they become chronic. Thus, considering the role of insulin in the CNS, as well as the increased populational life spam worldwide, the present thesis investigated the relation of physiological insulin signaling and the brain insulin signaling caused by aging in cognition, neurochemistry and neuroinflammation. We showed that insulin intracerebroventricular administration improved the cognition of young animals, but the same was not observed in aging. At the cellular and molecular level, we found a disruption in the connection of insulin and BDNF signaling. We also show that a microglial activation and pro-inflammation triggered by insulin in young brain appear to be lost during aging. In addition, it was observed that microglia is sensitive to direct insulin signaling via PI3K and that this microglial signaling suffers adaptations and changes during life. Together with the recently changes in the literature, the findings of this work demonstrate that there is a rupture of paradigms in the interpretation of neuroinflammatory processes, which are no longer seen only as a toxic factor to the brain, but also as an smart adaptation of the CNS to the various stimuli that brain cells receive during the course of life, from birth to aging.

Les maladies à polyglutamines (polyQ) sont des maladies neurodégénératives héréditaires dominantes causées par une expansion de CAG traduite en longue expansion de polyglutamine dans la protéine correspondante. Ces maladies comprennent l’ataxie spinocérébélleuse 7 (SCA7) et la maladie de Huntington (MH) causées par une expansion de polyQ dans les protéines ataxine-7 (ATXN7) et huntingtine (htt), respectivement. Les souris SCA7 et MH développent des rétinopathies similaires suggérant des pathomécanismes communs toujours inexpliqués. Durant ma thèse, j’ai trouvé qu’en réponse à la toxicité des polyQ, les photorécépteurs (PR) perdent leur différenciation alors que d’autres migrent ou meurent. De plus, cette mortalité cellulaire active la prolifération des cellules gliales de Müller et leur différenciation en PR. Récemment, j’ai trouvé que l’ATXN7 et la htt se trouvent dans le cil primaire et leur mutation mène à une perte des protéines endogènes des cils associée à des défauts du cil. / Polyglutamine (polyQ) disorders are dominantly inherited neurodegenerative disorders caused by the expansion of CAG repeats translated into long polyQ tracts in the corresponding proteins. These diseases include Spinocerebellar ataxia 7(SCA7) and Huntington’s Disease (HD), caused by polyQ expansion ataxin-7 (ATXN7) and huntingtin (htt), respectively. SCA7 and HD mouse models develop similar retinopathies suggesting common pathomechanisms. In my thesis, I found that, in response to polyQ toxicity, SCA7 photoreceptors (PR) undergo several cell fates ranging from their deconstruction, to their migration and their death. Moreover, this cell death activates the proliferation of Müller glial cells and their differentiation into PR like cells. The pathomechanisms underlying HD and SCA7 are still unknown. Recently, I found that ATXN7 and htt are localized to the PR cilia and that the mutant proteins lead to a progressive loss of the wild-type proteins that correlates with defects in the PR cilia.

No final do século 19, o neurônio foi descrito como a unidade funcional básica do sistema nervoso e sua formação era considerada inexistente na fase adulta, explicando a ausência de recuperação significativa em doenças neurológicas. Evidências de geração de neurônios em mamíferos adultos surgiram na década de 1960 e foram confirmadas três décadas depois. Atualmente, predomina a visão de que mamíferos adultos possuem dois nichos neurogênicos independentes: a zona subventricular (ZSV) e a zona subgranular (ZSG) do giro denteado. No entanto, a existência de nichos neurogênicos em humanos adultos é controversa. Nossa hipótese foi de que o mapeamento de nichos neurogênicos no lobo temporal humano poderia esclarecer aspectos sobre a neurogênese adulta. A detecção destes nichos foi buscada em 28 lobos temporais através de imuno-histoquímica para nestina, o marcador mais comum de células-tronco neurais, que são aquelas capazes de se autorrenovar e de gerar novas células neurais. A neurogênese foi pesquisada no hipocampo pelo uso de DCX (do inglês \"doublecortin\"), o principal marcador de neuroblastos e neurônios imaturos. Nestina foi observada em uma camada contínua formada pela ZSV, zona subpial do lobo temporal medial e ZSG, terminando no subículo. A partir do subículo, uma intensa expressão de DCX ocorreu através da principal via eferente do hipocampo até a fímbria. A visão panorâmica das marcações por nestina e DCX mostrava em conjunto uma linha que circundava as estruturas límbicas do lobo temporal. Por isto, foi denominada linha externa de células do sistema límbico (LECEL). Uma possível explicação para os resultados é que a LECEL seja um nicho neurogênico no qual a ZSV, a zona subpial do lobo temporal medial e a ZSG formam uma unidade contendo células-tronco neurais que se diferenciam em neurônios no subículo. Curiosamente, a área identificada previamente como sendo a corrente migratória rostral humana (formada por células neurais imaturas migrando a partir da ZSV do corno frontal) pode ser na verdade o fórnix, que contém axônios originados no subículo. A implicação mais intrigante dos resultados é que se as características da LECEL seguirem além do lobo temporal, então o encéfalo humano pode conter um anel neurogênico límbico, em que a neurogênese ocorreria principalmente no subículo e seria modulada pelas estruturas relacionadas à fissura coroideia. Este estudo sugere que a neurogênese ocorre de maneira orquestrada em uma área ampla do lobo temporal humano / At the end of the 19th century, the neuron was described as the basic functional unit of the nervous system. The formation of neurons was thought to be absent in adulthood, thus explaining the lack of significant recovery from neurological diseases. Evidence for the generation of neurons in adult mammals was reported in the 1960s and confirmed three decades later. Currently, the prevailing view is that adult mammals harbour two neurogenic niches: the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ). Nonetheless, the existence of these niches in adult humans is controversial. We hypothesised that mapping neurogenic niches in the human temporal lobe could clarify this issue. The presence of neurogenic niches was examined in 28 temporal lobes via immunostaining for nestin, the most common marker for neural stem cells, which are cells with the capacities of self-renewal and the generation of neural cells. The presence of neurogenesis was examined in the hippocampus with doublecortin (DCX), a prominent marker for neuroblasts and immature neurons. Nestin was observed in a continuous layer that was formed by the SVZ, the subpial zone of the medial temporal lobe and the SGZ, terminating in the subiculum. In the subiculum, remarkable DCX expression was observed through the principal efferent pathway of the hippocampus to the fimbria. A panoramic view of nestin and DCX staining collectively displayed a line that surrounded the limbic structures of the temporal lobe. Hence, we termed it the external line of cells of the limbic system (EXCEL). A possible explanation for the results is that the EXCEL is a neurogenic niche, in which the SVZ, the subpial zone of the medial temporal lobe and the SGZ form a unit containing neural stem cells that differentiate into neurons in the subiculum. Curiously, the area previously identified as the human rostral migratory stream (formed by immature neural cells that migrate from the SVZ of the frontal horn) may in truth be the fornix, which contains axons that originate in the subiculum. Perhaps most intriguingly, if the EXCEL acts as a neurogenic niche beyond the boundaries of the temporal lobe, the human brain may contain a limbic neurogenic ring, in which neurogenesis would occur in the subiculum through the modulation of choroid fissure-related structures. This study suggests that neurogenesis may occur in an orchestrated manner in a broad area of the human temporal lobe

Abstract This essay examines which role functional oriented music therapy, which is supposed to help sensorimotor development, can have in schools and in health care. To find this out, research about what kinds of effects exercise can have on academic achievements and in recovery from brain injuries has been brought up. The research concerning academic achievements was conducted with school children; some children without difficulties, some with sensory integration problems, and some with motor skill difficulties. In addition to this, research about the brain structure superior colliculus, which lies behind sensory integration, is also brought up. The results showed that children who were given more exercise had significantly better scores in academic skills than the children with normal academic education. Thus, it might be reasonable to practise functional oriented music therapy in schools, both as helping general development, but also for children with different types of difficulties. The research concerning exercise and injuries has made clear that the adult brain can change via neurogenesis, plasticity and cortical reorganization. These three aspects are important when practicing a skill or when recovering from an injury. Exercise has been shown to affect these three aspects positively and can therefore also aid the recovery from injuries. Thus, there seems to be many theoretical aspects supporting the FMT- method. However, the question is if the results of one treatment form can generalize over such a wide range of injuries and defects that the FMT –adepts usually have. It is therefore also discussed if further experiments on the FMT-method could help make it a more effective tool for rehabilitation.

La neurogenèse adulte permet la formation de nouveaux neurones dans les bulbes olfactifs de la souris. Les propriétés des cellules souches neurales situées dans la zone sous-ventriculaire (ZSV) et des précurseurs sont régulées par la niche contenant des cellules de support et une matrice extracellulaire (MEC). Des facteurs contenus dans le liquide cérébrospinal (LCS), produits par les plexus choroïdes (PC), contrôlent aussi la niche. L'homéoprotéine Otx2 est secrétée dans le LCS par les PC, et internalisée spécifiquement par certaines cellules du parenchyme cérébral. Otx2 est impliquée dans différentes étapes du développement du cerveau, dont celui des PC, et peut agir de manière non-cellulaire-autonome. Ma thèse vise à comprendre comment Otx2 régule les fonctions des PC et participe à la neurogenèse adulte. Grâce à des études génomiques d'un modèle murin knockdown (KD) d'Otx2 dans les PC adultes, nous avons montré que (i) les PC de différents ventricules présentent des profils d'expression différents (ii) le KD d'Otx2 modifie l'expression de gènes impliqués dans des fonctions importantes des PC (iii) la dérégulation de certains gènes après KD est spécifique d'un type de PC. Une étude protéomique suggère (iv) qu'Otx2 pourrait être impliquée à d'autres niveaux que la régulation transcriptionnelle. L'étude de la neurogenèse adulte dans des modèles murins KD d'Otx2 nous a permis de montrer que (i) l'expression d'Otx2 dans les PC régule la neurogenèse adulte (ii) Otx2 transfère dans les astrocytes de la ZSV (iii) le transfert d'Otx2 est suffisant pour réguler la neurogenèse (iv) le KD d'Otx2 dans les PC modifie l'expression de protéines de la MEC secrétées par les astrocytes. / Adult neurogenesis in mice involves neural stem cells in the subventricular zone (SVZ) whose progenitors integrate into the olfactory bulbs. The neurogenic niche, which contains supporting cells and extracellular matrix (ECM), regulates the properties (proliferation, migration and differentiation) of progenitor cells. This niche is influenced by factors from cerebrospinal fluid (CSF), which is produced by the choroid plexus (CP) in the brain ventricles. The Otx2 homeoprotein transcription factor is secreted into CSF by CP, and taken up by a specific subset of cells within the brain parenchyma. Otx2 is involved in various stages of brain development, including CP development, and has non-cell autonomous functions. The aim of my thesis is to understand how Otx2 regulates adult CP function and participates in adult SVZ neurogenesis. Through genomic studies, we investigated the consequence of Otx2 knockdown (KD) in adult CP and found: (i) adult CP from different ventricles exhibit different expression profiles; (ii) Otx2 KD alters the expression of genes with important CP functions; and (iii) deregulation of certain genes after Otx2 KD can be CP specific. Through proteomics studies, we found that (iv) adult Otx2 could be involved in functions beyond transcriptional regulation, such as RNA processing.To evaluate the role of Otx2 in SVZ neurogenesis, we also used Otx2 KD mouse models. We found that: (i) the expression of Otx2 in CP regulates adult neurogenesis; (ii) Otx2 transfers to astrocytes of the SVZ; (iii) Otx2 transfer is sufficient to regulate adult neurogenesis; and (iv) Otx2 KD in CP alters the expression of ECM proteins secreted by astrocytes in the neurogenic niche.

L’hypothalamus joue un rôle crucial dans le contrôle de l’homéostasie énergétique. Chez l’adulte, cette zone est plastique afin de s’adapter rapidement aux pressions environnementales. Ces remodelages hypothalamiques sont perturbés lors de pathologies métaboliques comme l’obésité. Nous nous sommes demandé si un régime gras provoquant des pathologies de surcharges à long terme, provoquait des modifications rapides du réseau hypothalamique chez l’individu adulte. Pour répondre à cette question, nous avons mis en place un modèle de souris présentant une réponse homéostatique rapide à un régime gras, et nous avons évalué deux types de plasticités hypothalamiques: la plasticité synaptique et la neurogenèse. Nos résultats montrent une stimulation des neurones anorexigènes dès les 3 premiers jours sous régime. Ce phénomène implique la polysialisation de la protéine d’adhésion NCAM. Nous avons également démontré que le remaniement de ces connexions synaptiques s’accompagne d’une augmentation de la prolifération cellulaire. Le blocage de cette prolifération avec l’anti-mitotique araC empêche la réponse homéostatique et accélère de manière drastique l’apparition de l’obésité. Ceci suggère que les nouvelles cellules produites sont essentielles pour le maintien de l’équilibre énergétique. Ces nouvelles cellules se différencient majoritairement en neurones quelque soit le régime, mais le régime gras va diriger la maturation des nouveaux neurones vers un phénotype anorexigène. Nos expériences montrent que suite à un déséquilibre énergétique, l’hypothalamus subit une succession de modifications plastiques conduisant à un rapide rétablissement de l’homéostasie énergétique / The hypothalamus plays a crucial role in the control of energy balance. In adult brain, this area remain plastic and the cellular network can be rapidly modified under environmental pressures. Studies show than hypothalamic remodeling are disturbed when metabolic diseases such as obesity or type II diabetes are declared. In this study we hypothesized that a high fat diet (HFD) inducing obesity could rapidly causes cell modifications in the adult hypothalamus network. To answer this question, we have established a one week HFD mouse model, and evaluated to type of hypothalamic plasticity which are synaptic plasticity and neurogenesis. Our results show that HFD leads to an increase of the excitatory pre-synaptic tonus on the POMC neurons. This phenomenon implies polysialisation of the adhesion protein NCAM. We also demonstated than this rapid rewiring is reinforced by the increase of cell renewal, and more specifically by an increase of cell proliferation. Blockade of proliferation with the anti-mitotic araC prevent food intake regulation observed in control mice and accelerate the onset of obesity. These results suggest that neoformed cells are crucial for the maintenance of energy balance. In fact, new cells mainly differenciate into neurons, and the proportion of new POMC neurones of the arcuate nucleus (ARC) is twice the one of mice under standard diet (STD). HFD directs maturation of new neurons toward anorexigenic phenotype. Our experiments demonstrate than the hypothalamus rapidly remodels after an energy imbalance, and establish a succession of changes leading to a rapid restablishment of energy homeostasis

Il est maintenant bien établi que le vieillissement est lié à l’apparition de troubles cognitifs. Ces altérations mnésiques liées à l’âge peuvent être mises en évidence à la fois chez l’Homme et l’animal. Plusieurs études ont pu mettre en évidence le rôle bénéfique des polyphénols sur les fonctions mnésiques et en particulier sur le déclin mnésique lié au vieillissement. Ainsi, le projet Neurophénols a pour objectif de mettre au point des actifs nutritionnels riches en polyphénols provenant de raisin et de bleuet, et d’objectiver leur rôle bénéfique sur le déclin cognitif lié à l’âge chez l’Homme et les animaux de compagnie. L’objectif de cette thèse était de mettre en évidence des effets bénéfiques d’un mélange de polyphénols de raisin et de bleuet, l’extrait Neurophenol®, sur les performances d’apprentissage et de mémoire chez la souris âgée et mieux comprendre les mécanismes neurobiologiques sous-tendant ces performances. Nous avons plus spécifiquement ciblé l’hippocampe, structure cérébrale clé impliquée dans les processus d’apprentissage et de mémoire, et particulièrement altérée au cours du vieillissement. Ces travaux précliniques permettront par la suite d’objectiver les résultats obtenus chez l’Homme. Nos principaux résultats montrent une altération des capacités d’apprentissage et de mémoire dépendant de l’hippocampe au cours du vieillissement qui sont récupérées par une supplémentation en polyphénols. Nous montrons également que ces troubles mnésiques liés à l’âge sont associés à une diminution d’expression de marqueurs moléculaires impliqués dans les voies de signalisation sous-tendant les processus mnésiques ainsi qu’à une diminution de la neurogenèse hippocampique. La supplémentation en polyphénols permet de rétablir les niveaux d’expression de certains gènes et également de sur-réguler l’expression de neurotrophines au niveau hippocampique. De plus, cette supplémentation a un effet bénéfique sur la neurogenèse hippocampique chez les souris âgées. Enfin, nous montrons qu’une supplémentation en Neurophenol® permet de réduire la mortalité des souris âgées. Ces résultats mettent en évidence l’efficacité du mélange Neurophenol® sur le maintien des performances mnésiques au cours du vieillissement chez la souris, via leur action sur la plasticité synaptique et la neurogenèse. Le développement d’une étude clinique visant à supplémenter des personnes âgées avec l’extrait Neurophenol® et à évaluer leurs performances mnésiques a également fait partie de ce travail de thèse et les résultats encourageant obtenus chez les souris âgées apportent des arguments favorables quant au bienfait des polyphénols sur la mémoire au cours du vieillissement. / It is now well accepted that aging is linked to the onset of cognitive impairments. Among them, age-related memory alterations can be brought in evidence both in humans and animals. Several studies have highlighted the beneficial role of polyphenols on memory functions and particularly on age-related memory decline. Thus, the Neurophenols project aims at developing nutritional assets rich in polyphenols from grape and blueberry, and to objectify their beneficial role on the age-related cognitive decline in humans and pets. The aim of this thesis was to highlight beneficial effects of a polyphenol mix from grape and blueberry, the Neurophenol TM extract, on learning and memory performances in aged mice and to better understand the neurobiological mechanisms underlying these performances. More specifically, we have focused on the hippocampus, a key brain structure involved in learning and memory processes that is particularly altered during aging. This preclinical work will subsequently objectify the results in humans. Our main results show that hippocampal-dependent learning and memory alterations during aging are recovered by a polyphenol supplementation. We also show that these age-related memory deficits are linked to a decrease of gene expression of proteins involved in signaling pathways underlying memory processes and to a decrease of hippocampal neurogenesis. The polyphenol supplementation can restore the expression level of some genes and up-regulate neurotrophin expression in the hippocampus. Moreover, this supplementation has a beneficial impact on hippocampal neurogenesis in aged mice. Finally, we show that a Neurophenol TM supplementation can reduce mortality in aged mice. These results demonstrate the efficiency of the mix Neurophenol TM on the maintenance of memory performances in mice during aging, through their action on synaptic plasticity and neurogenesis. These promising results in aged mice provide positive arguments on the benefits of polyphenols on memory during aging. Thus, it was also developed a clinical study aiming at supplementing elderly subjects with the Neurophenol TM extract in order to evaluate their memory performances.

Le gène Prss56 code pour une sérine protéase impliquée dans le développement de l'oeil humain et certaines de ses pathologies. Le patron d'expression et la fonction de Prss56 dans le reste du système nerveux central sont cependant inconnus. Dans cette étude, j'utilise l'allèle murin Prss56Cre, comportant l'insertion de la recombinase Cre au sein du locus, pour établir le patron d'expression de ce gène et tracer le devenir des cellules exprimant Prss56. Je montre que Prss56 est spécifiquement exprimé dans trois niches neurogéniques : le gyrus dentelé (GD), la zone sous-ventriculaire (SVZ) et la zone ventriculaire de l'hypothalamus (ZVH). Dans le GD embryonnaire, Prss56 est exprimé par une sous-population de glie radiaire. La migration et la différenciation des cellules tracées récapitulent les étapes successives de la neurogenèse du GD et l'établissement d'une sous-population de cellules souches neurales adultes (CSNa). Dans la SVZ, Prss56 est exprimé après la naissance dans une sous-population de CSNa principalement localisée dans la partie médio-ventrale du mur latéral. Cette sous-population génère préférentiellement des cellules granulaires profondes et des cellules périglomérulaires Calbindin-positives du bulbe olfactif. Enfin, Prss56 est exprimé par une sous-population de tanycytes alpha-2, les potentielles cellules souches de la ZVH adulte. Je montre que certains tanycytes tracés déplacent leur soma vers le parenchyme et pourraient être à l'origine d'un nouveau type cellulaire de ce territoire. A travers ces diverses observations, ce travail établit que la lignée Prss56Cre constitue un outil idéal pour l'étude de nombreux aspects de la neurogenèse adulte. / The Prss56 gene encodes a serine protease involved in eye pathologies and development in humans. Prss56 expression pattern and function in the rest of the central nervous system were however unknown. Here, I used a knock-in allele in the mouse, Prss56Cre, carrying a Cre recombinase insertion in the locus, to establish the pattern of expression of the gene and to trace the derivatives of Prss56-expressing cells. I found that, in the adult mouse, Prss56 is specifically expressed in three neurogenic niches: the dentate gyrus (DG), the subventricular zone (SVZ) and the hypothalamus ventricular zone (HVZ). In the prospective DG, Prss56 is expressed during embryogenesis in a subpopulation of radial glia. Consistently, the pattern of migration and differentiation of traced cells during development recapitulates the successive steps of DG neurogenesis, including the formation of a subpopulation of adult neural stem cells (aNSC). In the SVZ, Prss56 is expressed after birth in a subpopulation of aNSC mainly localized in the medial-ventral region of the lateral wall. This subpopulation preferentially gives rise to deep granule and calbindin-positive periglomerular cells in the olfactory bulb. Finally, Prss56 is also expressed in a subpopulation of alpha2-tanycytes, potential aNSC of the adult HVZ. My observations reveal that some traced tanycytes translocate their soma into the parenchyma and might give rise to a novel cell type in this territory. In conclusion, this study establishes the Prss56Cre line as a novel and efficient tool to study various aspects of adult neurogenesis in the mouse.