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Adult neurogenesis is defined as the generation of new nerve cells in the adult central nervous system (CNS). Stimulating neurogenesis may potentially offer a therapeutic approach for neurodegenerative diseases such as Parkinson???s disease. However, it is not clear why neurogenesis does not normally replace neurons lost in these diseases. As a first step to address this problem it is necessary to identify mechanisms that regulate adult neurogenesis in the normal and diseased brain and further, determine if manipulating these mechanisms may offer therapeutic potential. In this thesis, we identify activin A, a member of the transforming growth factor ?? (TGF??) superfamily, as a significant regulator of neurogenesis. We demonstrate that mRNA encoding activin A is expressed after a KA injury, and that inhibition of this activin A profoundly impairs neurogenesis in the hippocampus. Further we demonstrate that activin A impairs gliosis and also has potent anti-inflammatory effects in the injured hippocampus. Finally, we provide evidence that the majority of activin A???s neurogenic effect results from its potent anti-inflammatory actions. Our study draws a clear link between neurogenesis and inflammation in the CNS and is the first to provide evidence that this process is regulated through activin signalling. Since inflammation is now believed to be an important component of many neurological diseases we suggest that therapeutic compounds that enhance activin A signalling may offer a therapeutic approach for treating these diseases by suppressing inflammation and stimulating neurogenesis.

Adult neurogenesis is defined as the generation of new nerve cells in the adult central nervous system (CNS). Stimulating neurogenesis may potentially offer a therapeutic approach for neurodegenerative diseases such as Parkinson???s disease. However, it is not clear why neurogenesis does not normally replace neurons lost in these diseases. As a first step to address this problem it is necessary to identify mechanisms that regulate adult neurogenesis in the normal and diseased brain and further, determine if manipulating these mechanisms may offer therapeutic potential. In this thesis, we identify activin A, a member of the transforming growth factor ?? (TGF??) superfamily, as a significant regulator of neurogenesis. We demonstrate that mRNA encoding activin A is expressed after a KA injury, and that inhibition of this activin A profoundly impairs neurogenesis in the hippocampus. Further we demonstrate that activin A impairs gliosis and also has potent anti-inflammatory effects in the injured hippocampus. Finally, we provide evidence that the majority of activin A???s neurogenic effect results from its potent anti-inflammatory actions. Our study draws a clear link between neurogenesis and inflammation in the CNS and is the first to provide evidence that this process is regulated through activin signalling. Since inflammation is now believed to be an important component of many neurological diseases we suggest that therapeutic compounds that enhance activin A signalling may offer a therapeutic approach for treating these diseases by suppressing inflammation and stimulating neurogenesis.

Adult neurogenesis is defined as the generation of new nerve cells in the adult central nervous system (CNS). Stimulating neurogenesis may potentially offer a therapeutic approach for neurodegenerative diseases such as Parkinson???s disease. However, it is not clear why neurogenesis does not normally replace neurons lost in these diseases. As a first step to address this problem it is necessary to identify mechanisms that regulate adult neurogenesis in the normal and diseased brain and further, determine if manipulating these mechanisms may offer therapeutic potential. In this thesis, we identify activin A, a member of the transforming growth factor ?? (TGF??) superfamily, as a significant regulator of neurogenesis. We demonstrate that mRNA encoding activin A is expressed after a KA injury, and that inhibition of this activin A profoundly impairs neurogenesis in the hippocampus. Further we demonstrate that activin A impairs gliosis and also has potent anti-inflammatory effects in the injured hippocampus. Finally, we provide evidence that the majority of activin A???s neurogenic effect results from its potent anti-inflammatory actions. Our study draws a clear link between neurogenesis and inflammation in the CNS and is the first to provide evidence that this process is regulated through activin signalling. Since inflammation is now believed to be an important component of many neurological diseases we suggest that therapeutic compounds that enhance activin A signalling may offer a therapeutic approach for treating these diseases by suppressing inflammation and stimulating neurogenesis.

The present thesis investigates the hypothesis according to which the arithmetic retrieval deficits observed in children with math disabilities (MD) would be due to an inhibition deficit. In the first chapter, two experiments showed that children with MD (with or without reading disabilities), compared to normally-achieving children, do not present impairments in three inhibition functions (filtering, suppression, and blocking). The second chapter focused on interference in arithmetic tasks. Experiment 3 revealed that, in a multiplication verification task, children with MD were not more sensitive to interference than control children (of the same age or of the same math skills). In contrast, Experiment 4 showed that children with poor math skills were more sensitive to multiplication-related interference (i.e., the negative effect of multiplications on additions) than children with good math skills. Nevertheless, the third chapter established that the arithmetic retrieval deficits of children with MD (as well as the results of Experiment 4) can be accounted for without the recourse to inhibition. Indeed, Experiment 5 demonstrated that children with MD have poor memory representations of difficult single-digit multiplications (i.e., weak and incorrect problem-answer associations), which is sufficient to account for their retrieval deficits. Finally, in the last chapter, we considered the possibility that sensitivity to interference is involved in MD but during the development of arithmetic facts representations (not during their retrieval) and could lead to the poor representations observed in children with MD. In experiment 6, we found that counting to solve an addition might interfere with the memorization of the addition's addends (hence, with the development of problem-answer associations) but there was no evidence that children with MD are more sensitive to this interference than control children. Altogether, these data provide converging evidence against the inhibition-deficit hypothesis and suggest that poor arithmetic representations represent a better candidate as a causal factor of MD. / Le but de cette thèse est d'investiguer l'hypothèse d'un rôle causal des processus d'inhibition dans les Troubles d'Apprentissage de l'Arithmétique (TAA). Selon cette hypothèse, les difficultés de récupération des faits arithmétiques (p.ex., les tables de multiplications) observés dans les TAA seraient dues à des déficits d'inhibition. Le premier chapitre présente deux expériences dans lesquelles nous avons testé trois fonctions d'inhibition (filtrage, suppression et blocage) chez des enfants avec TAA global (avec et sans troubles de lecture associés) et avec troubles spécifiques de récupération de faits arithmétiques (Expériences 1 et 2). Les résultats de ces études n'ont pas mis en évidence de trouble d'inhibition chez ces enfants. Le second chapitre s'est focalisé sur les effets d'interférence classiquement observés dans des tâches arithmétiques. Dans l'expérience 3, nous avons mis en évidence un effet de confusion associative (p.ex., 3 x 7 est plus difficile à rejeter que 3 x 7 = 26) significatif chez des enfants avec troubles de récupération de faits arithmétiques. Néanmoins, cet effet était équivalent à celui observé chez des enfants contrôle. En revanche, dans l'expérience 4, nous avons observé que l'effet interférent de la multiplication sur l'addition était plus important chez des enfants avec faibles capacités de récupération de faits arithmétiques que des enfants avec fortes capacités de récupération. Toutefois, dans le troisième chapitre, nous démontrons que ces derniers résultats, et plus globalement, les troubles de récupération de faits arithmétiques, peuvent être interprétés à la lumière de modèles théoriques qui n'incluent pas de processus d'inhibition. En effet, l'expérience 5 révèle que chez des enfants avec de tels troubles de récupération (en comparaison d'enfants contrôle), les multiplications difficiles (p.ex., 6 x 7) étaient plus faiblement associées à leurs réponses correctes et associées à de réponses incorrectes, ce qui, selon certains modèles théoriques, était suffisant pour rendre compte de déficits de récupération. Ces résultats vont à l'encontre de l'hypothèse de déficits d'inhibition comme facteur causal des troubles de récupération arithmétique dans les TAA. Cependant, dans le dernier chapitre, nous considérons la possibilité que la sensibilité à l'interférence jouait un rôle important dans le développement des représentations arithmétiques (et non dans leur récupération). Dans l'expérience 6, notre hypothèse était que compter pour résoudre une addition pouvait interférer avec la mémorisation des opérandes de cette addition et donc, avec la formation des associations entre problème et réponse correcte. Si les résultats obtenus allaient dans ce sens, nous n'avons trouvé aucune évidence indiquant que cet effet interférent était plus important chez des enfants avec troubles de récupération de faits arithmétiques que chez des enfants contrôle. En conclusion, il semble que de pauvres représentations des faits arithmétiques, plutôt que des déficits d'inhibition, soient à l'origine des troubles de récupération de ces faits dans les TAA.

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.