Tau ist ein Mikrotubuli-assoziiertes Protein, das die Polymerisation von Tubulin fördert und die Mikrotubuli stabilisiert. Folglich wird angenommen, dass Tau essentiell für die neuronale Morphogenese ist, vor allem für die Axonenausbildung und -aufrechterhaltung. Mittels tangentieller Nissl-gefärbter Schnitte von Mäusegehirnen konnte in der vorliegenden Arbeit gezeigt werden, dass Tau-knockout Mäuse die regelhafte thalamokortikale Barthaar-projektion („Barrel“ Konfiguration) entwickeln. Der Einfluss von Tau auf die Entstehung von Dendriten wurde anhand von Golgi-gefärbten Präparaten untersucht. Die Sholl-Analyse der gefärbten CA1-Pyramidenzellen zeigte, dass die Komplexität apikaler Dendriten durch das Fehlen von Tau reduziert wurde, während die Basaldendriten unbeeinflusst blieben. Das Tau-Protein scheint demzufolge unwesentlich für die Entstehung von axonalen Verbindungen im embryonalen Gehirn zu sein, ist aber beteiligt an der Steuerung des dendritischen Verzweigungsmusters. Ferner wurde beobachtet, dass sowohl die adulte Neurogenese, als auch die Mikrotubuli-Stabilität in den Apikal- und Basaldendriten und die Synapsen von dem Fehlen des Tau-Proteins unbeeinflusst blieben. In primären Zellkulturen aus dem Kleinhirn von Tau-knockout und Tau-wildtyp Mäusen konnten zwischen den zwei Genotypen keine signifikanten Unterschiede in der Länge oder im Verzweigungsmuster der Dendriten und der Axone von Körnerzellen beobachtet werden. Die Untersuchung der Effekte einzelner Tau-Isoformen auf die Morphologie von N2A-Zellen zeigte, dass es Unterschiede sowohl zwischen Tau-defizienten und Tau-positiven Zellen, als auch zwischen Zellen mit den verschiedenen Tau-Isoformen gibt. Das Tau-Protein übt demnach in vivo einen wichtigen Einfluss auf die Morphologie der Nervenzellen und besonders der Dendriten aus, welcher in vitro weiter analysiert wurde.

Due to two different mutations in the gene that encodes the a1A subunit of voltage-activated CaV 2.1 calcium ion channels, the compound heterozygous tottering/leaner (tg/tgla) mouse exhibits numerous neurological deficits. Human disorders that arise from mutations in this voltage dependent calcium channel are familial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6. The tg/tgla mouse exhibits ataxia, movement disorders and memory impairment, suggesting that both the cerebellum and hippocampus are affected. To gain greater understanding of the many neurological abnormalities that are exhibited by the 90-120 day old tg/tgla mouse the following aspects were investigated: 1) the morphology of the cerebellum and hippocampus, 2) proliferation and death in cells of the hippocampal dentate gyrus and 3) changes in basic biochemical parameters in granule cells of the cerebellum and hippocampus. This study revealed no volume abnormalities within the hippocampus of the mutant mice, but a decrease in cell density with the pyramidal layer of CA3 and the hilus of the dentate gyrus. Cell size in the CA3 region was unaffected, but cell size in the hilus of the dentate gyrus did not exhibit the gender difference seen in the wild type mouse. The cerebellum showed a decrease in volume without any decrease in cerebellar cellular density. Cell proliferation and differentiation in the subgranular zone of the hippocampal dentate gyrus remained normal. This region also revealed a decrease in cell death in the tg/tgla mice. Basal intracellular calcium levels in granule cells show no difference within the hippocampus, but an increase in the tg/tgla male cerebellum compared to the wild type male cerebellum. There was no significant difference in granule cell mitochondrial membrane potential within the wild type and mutant animals in either the hippocampus or cerebellum. The rate of reactive oxygen species (ROS) production in granule cells revealed no variation within the hippocampus or cerebellum. The amount of ROS was decreased in cerebellar granule cells, but not granule cells of the hippocampus. Inducing ROS showed no alteration in production or amount of ROS produced in the hippocampus, but did show a ceiling in the amount of ROS produced, but not rate of production, in the cerebellum.

Studies have shown that there is a strong correlation between aging and neurodegenerative diseases. Aging is considered the number one risk factor to develop neuropathologies such as memory loss, senile dementia, Alzheimer's disease (AD), and Parkinson's disease. Neurodegenerative diseases tend to start during adulthood, and aggravate over time, making them difficult to prevent and to treat. In the Unites States, demographic studies by U.S. Bureau of the Census have determined that our aging population of >65 years is expected to increase from the present 35 million to 78 million in 2030. This would result, not only to an increase of age-related chronic illness, and mental disability, but to a decrease of quality of life, and an elevation of medical cost. Thus, this dissertation has focused on investigating the molecular mechanisms during the process of aging and its correlation to chronic inflammation and cognitive impairments. The etiology of neurodegenerative diseases is not very well understood, but research has shown that the process of aging is a key factor, which involved oxidative stress, an over reactive microglia, and increased production of pro-inflammatory cytokines. All these factors are known to decrease cell proliferation, which limit neuroplasticity and they might lead the transition from normal aging to more severe cognitive dysfunction associated with neurodegenerative diseases. Previously, we have shown that natural compounds such as polyphenols from blueberry, and green tea, and amino acids like carnosine are high in antioxidant and anti-inflammatory activity that decreases the damaging effects of reactive oxygen species (ROS), in the blood, brain, and other tissues of the body. Therefore, we examined the hypothesis that the pro-inflammatory cytokine TNF-[U+F061] may be a critical factor that modulates classical conditioning behavior, the effects of NT-020 on adult neurogenesis, inflammatory markers of the CNS, and the effect of NT-020 on cognitive function as shown using spatial navigation task. The results show that in aged rats, endogenous production of pro-inflammatory cytokine TNF-α impairs the acquisition of learning and memory consolidation in the delay eyeblink classical conditioning task (EBC). It was shown that this effect can be replicated by infusing young rats with exogenous TNF-α prior to EBC. Using NT-020 as a dietary supplement for one month, it was found that NT-020 ameliorates the age-related impairments typically found in aged rats in the spatial navigation tasks Morris water maze and radial arm water maze. By looking at immunohistochemistry analysis, it was found a decreased number of OX6 MHC II positive cells, increased neurogenesis, and increased number of proliferating cells in the dentate gyrus (DG) of the hippocampus in the aged rats fed with NT-020 relative with their counterpart aged control. In the CNS, Inflammatory markers were analyzed, and it was found that aged rat fed with NT-020 supplemented diet has decrease levels of pro-inflammatory cytokines in compared with aged rats fed with NIH-31 control diet. In conclusion, TNF-α, a pro-inflammatory cytokine has shown to have a modulatory effect during classical conditioning. Moreover, NT-020 may promote a healthy CNS milieu, proliferation of neuronal progenitors, and maintenance of nature neurons in the aged rats and it might exert anti-inflammatory actions which promote a functional stem cell pool in the CNS of aged rats.

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Introduction: Chez les mammifères, la naissance de nouveaux neurones se poursuit à l’âge adulte dans deux régions du cerveau: 1) l’hippocampe et 2) la zone sous-ventriculaire du prosencéphale. La neurogenèse adulte n’est pas un processus stable et peut être affectée par divers facteurs tels que l’âge et la maladie. De plus, les modifications de la neurogenèse peuvent être à l’origine des maladies de sorte que la régulation ainsi que le rétablissement de la neurogenèse adulte doivent être considérés comme d’importants objectifs thérapeutiques. Chez la souris saine ou malade, la neurogenèse hippocampale peut être fortement régulée par l’enrichissement environnemental ainsi que par l’activité physique. Cependant, lors même que l’activité physique et l’enrichissement environnemental pourraient contribuer au traitement de certaines maladies, très peu d’études porte sur les mécanismes moléculaires et physiologiques responsables des changements qui sont en lien avec ces stimuli. Objectifs et hypothèses: Les principaux objectifs de cette étude sont de caractériser les effets de stimuli externes sur la neurogenèse et, par le fait même, d’élucider les mécanismes sous-jacents aux changements observés. En utilisant le modèle d’activité physique volontaire sur roue, cette étude teste les deux hypothèses suivantes: tout d’abord 1) qu’une période prolongée d’activité physique peut influencer la neurogenèse adulte dans le prosencéphale et l’hippocampe, et 2) que l’activité volontaire sur roue peut favoriser la neurogenèse à travers des stimuli dépendants ou indépendants de la course. Méthodes: Afin de valider la première hypothèse, nous avons utilisé un paradigme incluant une activité physique volontaire prolongée sur une durée de six semaines, ainsi que des analyses immunohistochimiques permettant de caractériser l’activité de précurseurs neuronaux dans la zone sous-ventriculaire et l’hippocampe. Ensuite, pour valider la seconde hypothèse, nous avons utlisé une version modifiée du paradigme ci-dessous, en plaçant les animaux (souris) soit dans des cages traditionnelles, soit dans des cages munies d’une roue bloquée soit dans des cages munies d’une roue fonctionnelle. Résultats: En accord avec la première hypothèse, l’activité physique prolongée volontaire a augmenté la prolifération des précurseurs neuronaux ainsi que la neurogenèse dans le gyrus dentelé de l’hippocampe comparativement aux animaux témoins, confirmant les résultats d’études antérieures. Par ailleurs, dans ce paradigme, nous avons aussi observé de la prolifération acrue au sein de la zone sous-ventriculaire du prosencéphale. De plus, en accord avec la seconde hypothèse, les souris placées dans une cage à roue bloquée ont montré une augmentation de la prolifération des précurseurs neuronaux dans l’hippocampe comparable à celle observée chez les souris ayant accès à une roue fonctionnelle (coureurs). Cependant, seuls les animaux coureurs ont présenté une augmentation de la neurogenèse hippocampale. Conclusions: Ces résultats nous ont permis de tirer deux conclusions nouvelles concernant les effets de l’activité physique (course) sur la neurogenèse. Premièrement, en plus de la prolifération et de la neurogenèse dans le gyrus dentelé de l’hippocampe, la prolifération dans la zone sous-ventriculaire du prosencéphale peut être augmentée par l’activité physique sur roue. Deuxièmement, l’environnement dans lequel l’activité physique a lieu contient différents stimuli qui peuvent influencer certains aspects de la neurogenèse hippocampale en l’absence d’activité physique sur roue (course). / Introduction: In mammals, new neurons continue to be produced throughout the adulthood in two brain regions: 1) the hippocampus and 2) the forebrain subventricular zone. Adult neurogenesis is not a stable process, and changes in response to diverse factors such as age and pathology. Furthermore, because changes in neurogenesis may in fact underlie pathogenesis, regulating or restoring neurogenesis is seen as an important therapeutic objective. In healthy and diseased mice, hippocampal neurogenesis can be robustly regulated by environmental enrichment. However, while physical activity and environmental enrichment are potentially important in the treatment of some pathologies, comparatively little is known about the molecular and physiological mechanisms underlying activity/environment-dependent changes in neurogenesis. Objectives and hypotheses: The primary objectives of this study are to characterize the neurogenesis-mediating effects of external stimuli and, in doing so, to elucidate the mechanisms that underlie observed changes. Using voluntary wheel running as a model, this study addresses two hypotheses: 1) that extended periods of physical activity can influence adult neurogenesis in the forebrain and the hippocampus and 2) that voluntary wheel running mediates neurogenesis through both running-dependent and running-independent stimuli. Methods: To address the first hypothesis, we used a prolonged six-week voluntary paradigm and immunohistochemical analyses to characterize neural precursor activity in the subventricular zone and hippocampus. To address the second hypothesis, we used a modified version of the above paradigm, where an additional group of mice were housed in cages with a locked running wheel. Results: With respect to the first hypothesis, prolonged voluntary wheel running was found to increase neural precursor proliferation and neurogenesis in the hippocampal dentate gyrus relative to control animals, confirming the results of previous studies. More importantly, in this paradigm, proliferation in the forebrain subventricular zone was also found to be increased. In keeping with the second hypothesis, mice that were housed in locked-running wheel cages showed an increase in hippocampal neural precursor proliferation comparable to that of running animals. However, only running animals displayed increased hippocampal neurogenesis. Conclusions: These results allow us to draw two novel conclusions regarding the effects of running on neurogenesis. First, proliferation in the forebrain subventricular zone, in addition to proliferation and neurogenesis in the hippocampus, is subject to regulation by wheel-running. Second, the wheel-running environment contains diverse stimuli which can influence some aspects of hippocampal neurogenesis in the absence of wheel running.

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