BACKGROUND:Aging is typically accompanied by memory decline and changes in hippocampal function. Among these changes is a decline in the activity of the dentate gyrus (DG) during behavior. Lasting memory, however, is thought to also require recapitulation of recent memory traces during subsequent rest - a phenomenon, termed memory trace reactivation, which is compromised in hippocampal CA1 with progressive age. This process has yet to be assessed in the aged DG, despite its prominent role in age-related memory impairment. Using zif268 transcription to measure granule cell recruitment, DG activity in adult and aged animals was assessed both during spatial exploration and as animals remained at rest in the home cage in order to detect potential memory-related replay.RESULTS:Consistent with the observation of memory trace reactivation in DG, the probability that an individual granule cell transcribes zif268 during rest in the animal's home cage is increased by recent experience in a novel environment. Surprisingly, a comparable increase was observed in the probability of granule cells in the aged DG expressing zif268 during rest. Moreover, no significant age-related difference was observed in the number of granule cells expressing zif268 during rest. Thus, the number and pattern of granule cell expression of zif268 during rest is preserved in aged animals, despite a significant decline in exploration-related zif268 expression.CONCLUSIONS:These data lead to the hypothesis that the input the aged DG receives from backprojections from CA3 (the region widely hypothesized to mediate reactivation) remains functionally intact despite loss of innervation from the perforant path.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Changes in intracellular redox homeostasis are implicated in both normal cell signaling and as pathophysiological mechanisms contributing to a variety of age-related diseases, including diabetes, atherosclerosis, neurodegenerative conditions, and cancer. Though a variety of well described mechanisms exist to counterbalance the overproduction of cellular oxidants and maintain optimal intracellular redox poise, the understanding of the mechanism(s) through which cellular redox homeostasis regulates cell signaling functions is less well understood. Here, we demonstrate that signaling by the immediate early gene / orphan nuclear hormone receptor NGFI-B (Nur77, TR3), which functions pleiotropically in the regulation of cell growth, metabolism, differentiation and death in diverse tissues, is redox-regulated at both the level of induction and NGFI-B-dependent gene transcription. Using co-immunoprecipitation experiments in cells, we also identified a novel interaction between NGFI-B and the cytoplasmic thiol-reducing catalyst thioredoxin1 (Trx1), that, similar to DTT, blocks NGFI-B-dependent gene expression in a manner that depends on the Trx1 active site cysteines. Together these observations add NGFI-B-dependent gene expression to a growing portfolio of transcription factor pathways that are redox-regulated. NGFI-B, in addition, appears to regulate the mitochondrial membrane potential in L6 skeletal myoblasts. NGFI-B is indispensible for T-cell receptor-mediated apoptosis and induces cell death in a variety of cell types in response to diverse pro-apoptotic stimuli. Like p53, translocation of NGFI-B from the nucleus to the mitochondria may be a critical aspect of its pro-apoptotic function. Interestingly, we found that enforced NGFI-B expression in L6 skeletal muscle myoblasts led to a significant decrease of MMP that peaked 48hr after transfection and did not require a cell death-inducing stimulus. Moreover, NGFI-B transfected cells had no increase in mitochondrial cytochrome C release despite loss of MMP at 48 hr. Combined, these data suggest that loss of MMP in muscle cells may be an early event in the apoptotic process regulated by NGFI-B. This, along with the redox regulation of NGFI-B, provides unique evidence of a relationship between the mitochondria, mitochondrial by-products, ROS, and the regulation of and by the transcription factor NGFI-B. / text

La nouvelle génération de réseaux mobiles (5G) devrait faire face, durant les cinq prochaines années, à une importante croissance du volume de données, échangé entre plusieurs milliards d'objets et d'applications connectés. En outre, l'émergence de nouvelles technologies, telles que Internet of Things (IoT), conduite autonome et réalité augmentée, impose de plus fortes contraintes de performance et de qualité de service (QoS). Répondre aux besoins cités, tout en réduisant les dépenses d'investissement et d'exploitation (CAPEX/OPEX), sont les objectifs poursuivis par les opérateurs télécom, qui ont défini une nouvelle architecture d'accès radio, appelée Cloud Radio Access Network (C-RAN). Le principe du C-RAN est de centraliser, au sein d'un pool, les parties de traitement, BaseBand Unit (BBU), d'un RAN traditionnel. Les BBU sont alors dissociées de la station de base et de la partie radio, Remote Radio Unit (RRU). Ces deux parties restent néanmoins connectées à travers un réseau intermédiaire appelé Fronthaul (FH). Dans cette thèse, nous allons concevoir une nouvelle architecture C-RAN partiellement centralisée qui intègrera une plateforme de virtualisation basée sur un environnement Xen, nommée " Metamorphic Network " (MNet). A travers cette architecture, nous viserons à : i) mettre en place un pool, dans lequel des ressources physiques (processeurs, mémoire, ports réseaux, etc.) seront partagées entre des BBU virtualisées et d'autres applications, ii) établir un réseau FH ouvert aux fournisseurs de services et aux tierces parties, facilitant ainsi le déploiement des services au plus près des utilisateurs, pour une meilleure qualité d'expérience, iii) exploiter, à travers le FH, les infrastructures Ethernet existantes pour réduire les CAPEX/OPEX et enfin, iv) atteindre les performances réseau préconisées pour la 5G. Dans la première contribution, nous allons définir une nouvelle architecture Xen pour la plateforme MNet, intégrant le framework de packet processing, OpenDataPlane (ODP), au sein d’un domaine Xen privilégié, nommé « Driver Domain ». Notre objectif, à travers cette architecture, est d’accélérer le traitement des paquets de données transitant par MNet, en évitant la surutilisation, par ODP, des cœurs du processeur physique (CPU) de la plateforme. Pour cela, des cœurs CPU virtuels (vCPU) seront alloués dans le Driver Domain pour être exploités durant le traitement des paquets par ODP. Cette nouvelle plateforme MNet servira de base pour notre architecture C-RAN. Dans la seconde contribution, nous allons implémenter, au sein du FH, deux solutions réseau. La première solution, consistera à déployer le réseau de couche 2, Transparent Interconnection of Lots of Links (TRILL), pour connecter les différents éléments de notre architecture C-RAN. La seconde solution, consistera à déployer un réseau Software Defined Network (SDN), géré par le contrôleur distribué ONOS, qui sera virtualisé dans le pool BBU. Une comparaison des performances réseau sera réalisée entre ces deux solutions. / Over the next five years, the new generation of mobile networks (5G) would face a significant growth of the data volume, exchanged between billions of connected objects and applications. Furthermore, the emergence of new technologies, such as Internet of Things (IoT), autonomous driving and augmented reality, imposes higher performance and quality of service (QoS) requirements. Meeting these requirements, while reducing the Capital and Operation Expenditures (CAPEX/OPEX), are the pursued goals of the mobile operators. Consequently, Telcos define a new radio access architecture, called Cloud Radio Access Network (C-RAN). The C-RAN principle is to centralize, within a pool, the processing unit of a radio interface, named BaseBand Unit (BBU). These two units are interconnected through a Fronthaul (FH) network. In this thesis, we design a new partially centralized C-RAN architecture that integrates a virtualization platform, based on a Xen environment, called Metamorphic Network (MNet). Through this architecture, we aim to: i) implement a pool in which physical resources (processors, memory, network ports, etc.) are shared between virtualized BBUs and other applications; ii) establish an open FH network that can be used by multiple operators, service providers and third parties to deploy their services and Apps closer to the users for a better Quality of Experience (QoE); iii) exploit, through the FH, the existing Ethernet infrastructures to reduce CAPEX/OPEX; and finally iv) provide the recommended network performance for the 5G. In the first contribution, we define a new Xen architecture for the MNet platform integrating the packet-processing framework, OpenDataPlane (ODP), within a privileged Xen domain, called Driver Domain (DD). This new architecture accelerates the data packet processing within MNet, while avoiding the physical CPUs overuse by ODP. Thus, virtual CPU cores (vCPU) are allocated within DD and are used by ODP to accelerate the packet processing. This new Xen architecture improves the MNet platform by 15%. In the second contribution, we implement two network solutions within the FH. The first solution consist of deploying a layer 2 network protocol, Transparent Interconnection of Lots of Links (TRILL), to connect multiple elements of our C-RAN architecture. The second solution consists of implementing a Software Defined Network (SDN) model managed by Open Network Operating System (ONOS), a distributed SDN controller that is which is virtualized within BBU pool. Moreover, a network performance comparison is performed between these two solutions.

Stroke is a common and multifactorial disease influenced by genetic and environmental risk factors. It is a highly heterogeneous entity consisting of two main types, ischemic (80%) and hemorrhagic (20%) stroke. The most common form of hemorrhagic stroke is intracerebral hemorrhage (ICH). Ischemic stroke mainly results from thrombotic or embolic events, while ICH is caused by the rupture of an artery in the brain. The mean age of first-ever stroke is 75 years (73 vs. 78 years, for men and women, respectively) and the age-specific stroke incidence is higher for men as compared to women, suggesting that hormonal factors confer protection. A large body of experimental and observational studies shows that estrogens exert beneficial effects in the cardiovascular system. However, large, recent, clinical randomized trials have failed to demonstrate a lower risk of stroke with hormone replacement therapy (HRT) in elderly postmenopausal women. It is possible that HRT may only protect a subgroup of women. Here, genetic predisposition might be involved. Stroke incidence is 50% higher in northern compared to southern Sweden, suggesting a genetic predisposition in this population. This relatively homogeneous population displays founder effects, making it well suited for genetic studies. Since 1985, the MONICA and VIP projects have conducted large-scale cardiovascular health surveys in this population. Information about conventional stroke risk determinants and also DNA have been collected, and two prospective, nested case-referent cohorts (113 cases and 226 controls; 275 cases and 549 controls) have been sampled. To investigate whether genes of the estrogen signaling system may be important in stroke development, we performed genetic association studies, including specific functional single nucleotide polymorphisms in the genes for estrogen receptor alpha (ERα, ESR1), and its target genes osteoprotegerin (OPG, TNFRS11B) and interleukin-6 (IL-6, IL6). We found a significant association between the common c.454-397T/T genotype in ESR1 and ICH, remaining after adjustments for conventional stroke risk factors. The c.454-397T/T genotype also associated with increased systolic (SBP) and diastolic blood pressure (DBP). The combination of c.454- 397T/T and either hypertension, increased SBP, or increased DBP boosted this association substantially and significant synergistic effects on ICH risk between this genotype and increased blood pressure were demonstrated. In a second study, we found a similar association between the common OPG-1181C/C genotype and ICH. Cognitive impairments, including spatial memory and learning deficiencies, are common after stroke. Estrogens improve cognitive functions, including memory and learning processes, in postmenopausal women and ovariectomized rodents. Post-ischemic housing of rats in an enriched environment (EE) improves recovery of spatial memory and learning impairments. Both estrogen and EE induce neuroplasticity in the hippocampus. We hypothesized that 17β- estradiol combined with EE would accelerate recovery after experimental focal brain ischemia in ovariectomized rats and that such improvements could be related to expression of nerve growth factor-induced gene A (NGFI-A) in the hippocampus. Five to six weeks after middle cerebral artery occlusion, 17β-estradiol–treated rats housed in an EE showed significant improvements in cognitive function (i.e., shorter latency and path in the Morris water maze task) and significantly higher NGFI-A mRNA expression in bilateral cornu ammonis 1 (CA1) and ipsilateral dentate gyrus (DG) compared to placebo-treated animals in EE. In conclusion, we present evidence for the association between polymorphic variants in the ESR1 and TNFRS11B genes and ICH and show that 17β-estradiol in combination with EE accelerates cognitive functions in a rat stroke model, putatively through upregulation of NGFI-A in hippocampal subregions. These findings may contribute to an increased understanding of the underlying genetic etiology of ICH and may be informative for the primary prevention of this disease. They also provide hope for 17β-estradiol combined with early environmental enrichment as a novel therapeutic option following ischemic stroke.