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Chronic stress and Alzheimer’s disease (AD) both lead to degenerative changes in the hippocampus, a brain structure involved in episodic memory and regulation of the stress response. Mechanisms of aging (inflammation, oxidative stress, membrane damage, mitochondrial dysfunction, and insulin resistance) and a loss of brain-derived neurotrophic factor (BDNF), occur in cases of both stress-related depression and AD. Three studies were conducted using mouse models to determine whether exercise or treatment with an anti-aging multi-ingredient supplement (MDS) designed to counteract these aging mechanisms could protect the hippocampus, and associated behavioural functions, from either stress or AD. The first experiment revealed that the upregulation of neurogenesis by aerobic exercise in c57Bl/6 male mice does not occur after stress exposure. The MDS and exercise, but neither intervention alone, alleviated anhedonia, upregulated BDNF and increased neurogenesis. The other two experiments evaluated whether the MDS could counteract a range of AD behavioural and biological manifestations in both sexes of the 3xTg-AD mouse model. At 3-4 months of age, 2 months of MDS-supplementation protected 3xTg-AD mice from developing deficits in working memory and spatial learning seen in vehicle-treated transgenic mice. The MDS continued to benefit 3xTg-AD females, but not males, on tests of 24-h recall under conditions of high interference until 11-12 months of age, along with upregulating hippocampal BDNF. The MDS also attenuated the splenomegaly seen in 3xTg-AD mice and normalized the previously undiscovered aberrant recruitment of CA1 and CA3 neurons by 3xTg-AD males during spatial encoding. This work supports the use of diet and exercise to buffer against major depressive disorder (MDD) and AD in part by acting upon the hippocampus. It also recommends the use of lifestyle-based interventions to promote functional improvements in MDD or AD, and further elucidates the potential of BDNF and neurogenesis as therapeutic targets in counteracting these debilitating conditions. / Thesis / Doctor of Philosophy (PhD)

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Fundamental to the complexity of the nervous system is the precise regulation in space and time of the production, maturation, and migration of neurons in the developing embryo. This is eloquently seen in the forming cranial sensory ganglia (CSG) of the peripheral nervous system. Placodes, which are transient pseudostratified neuroepithelia in the surface ectoderm of the embryo, are responsible for generating most of the neurons of the CSG. Placodal progenitors commit to the neuronal fate and delaminate from the epithelium as immature, multipolar neuroblasts. These neuroblasts reside in a staging area immediately outside the placode. Differentiation of the neuroblasts is intimately coupled to their adoption of a bipolar morphology and migration away from the staging area to the future site of the CSG. Thus the forming CSG is a highly tractable model to anatomically separate the three phases of a neuroblast’s lifetime: from neuroepithelial progenitor (in the placode), to immature neuroblast (in the staging area), to mature neuron (in the migratory stream). In this thesis, I used the forming CSG as a model to investigate the role of Regulator of G protein Signalling 3 (RGS3) in neuroblast commitment and differentiation. Promoters within introns of the RGS3 locus generate isoforms in which N-terminal sequences are sequentially truncated, but C-terminal sequences are preserved. Intriguingly, I found that expression of these isoforms in the forming CSG is temporally co-linear with their genomic orientation: longer isoforms are exclusively expressed in the progenitor placode; a medium isoform is expressed exclusively in the neuroblast staging area; and the shortest isoforms are expressed in the neuronal migratory stream. Furthermore, through loss- and gain-of-function experiments, I demonstrated that each of these isoforms plays a specific role in the differentiation state in which it is expressed: placode-expressed isoforms negatively regulate neurogenesis; the neuroblast-expressed isoform negatively regulates differentiation; and the neuron-expressed isoforms negatively regulate neuronal migration. The negative regulatory role which all isoforms play in different cell-biological contexts is intriguing in light of the fact that they all share a C-terminal RGS domain, which canonically negatively regulates G protein signalling. Through domain mutation and deletion, I showed that the RGS and N-terminal domains are important for the function of each isoform. Thus temporally co-linear expression within the RGS3 locus generates later-expressed isoforms which lack the regulatory N-terminal domains of the earlier-expressed isoforms, giving them new license to perform different biochemical functions. Lastly, I investigated the conservation and evolution of RGS3 and its isoforms. RGS3 was found to be present in all extant metazoans, and results from this thesis implicate it as the founding member of the R4 subfamily of RGS proteins. Furthermore, in the early vertebrate lineage, a critical domain was lost. This is intriguing in light of the fact that placodes in their stereotypic forms also emerged early in the vertebrate lineage. Ectopic overexpression of the full-length invertebrate RGS3 protein prevented pseudostratification of the vertebrate placode, suggesting that the domain loss in the early vertebrate lineage was important for the evolution of pseudostratified placodes and the expansion of the vertebrate nervous system. In summary, the work in this thesis has uncovered a previously unseen model of transcriptional regulation of a single locus: intragenic temporal co-linearity. Furthermore, the demonstrated functions of this regulation have profound implications on the generation and differentiation of vertebrate neurons, as well as the evolution of the vertebrate nervous system.

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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.

Following traumatic brain injury (TBI), the hippocampus is particularly vulnerable to damage, and BDNF, an endogenous neurotrophin that activates the TrkB receptor, has been shown to play a key role in the brain’s neuroprotective response. Activation of the TrkB signaling pathway by BDNF in the CNS promotes cell survival and aids in cell growth. However, due to its inability to cross the blood brain barrier (BBB), the therapeutic advantages of BDNF treatment following TBI are limited. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid that mimics the effects of BDNF, is a potent TrkB receptor agonist, and can successfully cross the BBB. Our lab has previously demonstrated that administration of 7,8-DHF post-TBI results in improved cognitive functional recovery, increased neuronal survival, and reduced lesion volume. The current study examined the effects of 7,8-DHF on neurogenesis and neuronal migration in the dentate gyrus following TBI. In this study, adult male Sprague-Dawley rats were subjected to moderate controlled cortical impact injury (CCI) or sham surgery. Injured animals received 5 daily single doses of 7,8-DHF treatment (i.p) or vehicle starting either 60 mins after injury or 2 days after injury. BrdU was administered in 3 doses at 2 days post-injury for animals sacrificed at day 15, and single daily doses at days 1-7 post-injury for animals sacrificed at day 28 to label cell proliferation. Animals were sacrificed at 15 days or 28 days post-injury to examine cell proliferation, generation of new neurons, and differentiation of newly generated cells using proliferation marker Ki67, immature neuronal marker DCX, and BrdU double-labeling with markers for mature neurons (NeuN), astrocytes (GFAP) and microglia (Iba1). We found that administration of 5 doses (5mg/kg) of 7,8-DHF beginning two days post-injury had the strongest effect on neurogenesis and migration, but did not have a significant prolonged effect on cell proliferation at 15 days post-injury. We also found that 7,8-DHF treatment given early or 2 days post-TBI did not affect the neuronal differentiation in the granule cell layer. However, a higher percentage of BrdU/GFAP+ and BrdU/IBa1+ cells were found in the hilus regions in 7,8-DHF treated animals, suggesting newly generated cells in this region are mostly glial cell types. Our results suggest that 7,8-DHF has neurotrophic-like therapeutic effects following injury, and due to increased neurogenesis (compared to injured animals treated with vehicle), may effectively contribute to greater cell survival long-term. Additionally, potential long-term survival coupled with increased outward migration from the subgranular zone may result in increased integration of newly formed neurons into existing hippocampal circuitry, further contributing to cognitive recovery.

Il est maintenant bien établi que la vitamine A et son métabolite actif l’aciderétinoïque (AR), joueraient un rôle important dans les fonctions cognitives du cerveau adulte. La diminution de l’activité de la voie de signalisation des rétinoïdes et l’augmentation de celle des glucocorticoïdes (GC), se manifestent de manière concomitante au cours du vieillissementet participeraient aux altérations de plasticité et à l’étiologie du déclin cognitif lié à l’âge. De plus, certaines données ont mis en évidence des effets antagonistes de la voie des rétinoïdessur celle des glucocorticoïdes.L'objectif de ce travail visait donc à mieux comprendre les interactions entre ces deux voies de signalisation et leur impact sur les processus de plasticité cérébrale et les fonctions mnésiques chez le rongeur. L'approche expérimentale a consisté à étudier les effets d'une supplémentation nutritionnelle en vitamine A ou d'un traitement par l’AR sur le niveau corticostérone plasmatique et hippocampique, sur les mécanismes impliqués dans la biodisponibilité de la corticostérone, sur les processus de plasticité cérébrale (neurogenèse et plasticité synaptique) et sur la mémoire hippocampo-dépendante dans un modèle nutritionnel de carence en vitamine A mais également au cours du vieillissement.Nous avons montré qu’une carence en vitamine A entraînait une hyperactivation de la voie des glucocorticoïdes se traduisant par une hypersécrétion de corticostérone au niveau périphérique et hippocampique qui pourrait être liée à une diminution de capacité de liaison de la CBG mais également à une hyperactivation de la 11β-HSD1 au niveau hippocampique.D’autre part, une supplémentation nutritionnelle en vitamine A chez les rats carencés normalise les effets délétères observés sur la voie des glucocorticoïdes et supprime les altérations de neurogenèse hippocampique ainsi que les déficits de mémoire hippocampodépendante.De plus, un traitement par l’AR permettrait de moduler positivement la voie de signalisation des rétinoïdes chez la souris d’âge intermédiaire afin de diminuer l’amplitude de libération de corticostérone intrahippocampique, s’opposant ainsi aux effets délétères d’un excès de glucocorticoïdes sur les processus neurobiologiques et cognitifs au cours du vieillissement.Ce travail contribue à la démonstration d'une modulation de la biodisponibilité des glucocorticoïdes par le statut en vitamine A observée au cours d'une carence en vitamine A et du vieillissement. Il offre de nouvelles perspectives dans le développement d'une prévention du déclin cognitif lié à l'âge axée sur les facteurs nutritionnels tels que la vitamine A. / It is now established that vitamin A and its active metabolite, retinoic acid (RA), are required for cognitive functions in the adult hood. The hyposignaling of retinoic acid and the hyperactivity of the glucocorticoid (GC) pathway appear concomitantly during aging and both would contribute to the deterioration of hippocampal plasticity and functions. Moreover, recent data have evidenced counteracting effects of retinoids on the GC signaling pathway.The goal of the present study has been to shed more light on the interactions between both signaling pathways and their consequences on cerebral plasticity and memory processes.We have investigated them not only in a well-established nutritional model of vitamin A deficiency but also during aging. Indeed, our experimental approach has consisted inmanipulating the status in vitamin A (deficiency and/or supplementation or RA treatment) inrodents to better understand its impact on plasma and intrahippocampal corticosterone levelsand the mechanisms involved in corticosterone bioavailability. Hippocampus-dependentmemory and plasticity (adult neurogenesis and synaptic plasticity-related gene expression)have also been assessed.We have shown a hyperactivity of the glucocorticoid pathway in vitamin A-deficientrats, leading to elevated peripheral and hippocampal corticosterone levels. This is probably due to a decrease in CBG binding capacity and to the hyperactivity of the hippocampal 11β-HSD1. Furthermore, a vitamin A supplementation normalizes glucocorticoid activity and hippocampal neurogenesis levels and corrects memory deficits.Besides, in middle-aged mice, a RA treatment is able to positively modulate the retinoidsignaling pathway inducing a decreased hypersecretion of intrahippocampal corticosterone. It thus counteracts the deleterious effects of an excess of glucocorticoids on neurobiological and memory processes.Altogether, these results contribute to the demonstration that in vitamin A deficiency and during aging, the status in vitamin A modulates GC activity. This work proposes new preventive perspectives based on nutritional factors such as vitamin A in order to delay agerelated cognitive decline.

Le bulbe olfactif est le siège d’une neurogenèse adulte permanente. Le nombre de nouveaux neurones issus de cette neurogenèse adulte est modulé par l’apprentissage, ce qui suggère un rôle des néoneurones dans la mémoire olfactive. Au cours de ce travail, nous avons montré que l’apprentissage olfactif associatif recrute des nouveaux neurones granulaires dans des régions de la couche granulaire du bulbe olfactif spécifiques à l’odeur apprise. Nous avons également mis en évidence un lien entre la force de l’apprentissage olfactif, sa rétention et la modulation de la neurogenèse qui en résulte. En bloquant la neurogenèse bulbaire à l’aide d’un agent antimitotique nous avons montré que les nouveaux interneurones ne sont pas indispensables à l’acquisition d’une tâche olfactive associative, mais le sont pour sa rétention à long terme. Puis, en utilisant une approche comportementale, nous avons aboli l’association olfactive acquise lors d’un apprentissage et nous avons observé que les nouveaux neurones initialement sauvés dans le bulbe olfactif par cet apprentissage disparaissaient prématurément, confirmant ainsi leur rôle dans le support de la mémoire olfactive. Enfin, nous avons montré que suite à un apprentissage olfactif, une régulation locale de la mort cellulaire est mise en jeu qui pourrait être à l’origine de la sélection des néoneurones dans les régions traitant l’odeur apprise. Dans l’ensemble nos données indiquent un rôle crucial des neurones formés à l’âge adulte dans le bulbe olfactif dans la mémoire olfactive / Adult-born neurons are added to the mammalian olfactory bulb, and their number is modulated by learning suggesting that they could play a role in olfactory memory. In this work, we demonstrate that retrieval of an associative olfactory task recruits newborn neurons in odor-specific areas of the olfactory bulb and in a manner that depends on the strength of learning. By blocking neurogenesis during this olfactory task, we then demonstrate that acquisition is not dependent on neurogenesis while long-term retention of the task is abolished by neurogenesis blockade. In a second part, using an ecological approach, we show that behaviorally breaking a previously learned odor-reward association prematurely suppresses newborn neurons selected to survive during initial learning. Our results indicate that the newborn neurons saved by olfactory learning die when the odor looses its associative value, thus confirming that these newborn neurons support the memory trace. Finally, during and after learning, cell death and BrdU positive cells were mapped in the granule cell layer. We find that regions showing high BrdU-positive cell density exhibit the lowest rate of cell death indicating local regulation of cell death shaping the spatial distribution of newborn neurons in the granule cell layer of the olfactory bulb. Taken together, our findings reveal the crucial role of bulbar adult born neurons in olfactory memory