Dans de nombreuses espèces doiseaux chanteurs (ou Passériformes), dont fait partie le canari domestique (Serinus canaria), le comportement de chant est produit à la fois pour défendre un territoire ou attirer un partenaire. Le Système de Conntrôle du Chant est un réseau nerveux central spécialisé, principalement localisé au niveau du télencéphale et associé au contrôle de lapprentissage, la perception et la production du chant. Ce comportement a été décrit subir la modulation de facteurs externes, tels que la testostérone, la photopériode et les interactions sociales. En parallèle avec le comportement de chant, certains des noyaux appartenant au Système de Contrôle du Chant (HVC, RA et Area X) présentent un phénomène de plasticité saisonnière nerveuse fascinante. Le volume de ces noyaux augmente notamment par espacement des cellules, agrandissement de la taille du neuropile et de larborisation dendritique et, dans le cas particulier dHVC, par incorporation de neurones nouveaux-nés. Nous proposons ici une synthèse de la littérature concernant ce phénomène tout à fait particulier ; en effet, la régénération des neurones du système nerveux central est considérée comme inexistante -ou uniquement limitée à la production de quelques interneurones- chez les mammifères. Létude de la neuroplasticité chez loiseau chanteur constitue dès lors un modèle tout à fait remarquable et offrant des perspectives nouvelles dans létude du cerveau des vertébrés.

Therapeutic strategies of stroke can take two directions: to prevent brain damage from stroke or aid in its repair after a stroke. In this thesis, a rat stroke model, which mimics the human small vessel stroke, was used. Two potential repair strategies were investigated with this model, reduction of inflammatory processes with the aid of minocycline treatment and replacing necrotic neurons with new ones with the aid of neurogenesis of endogenous progenitor cells. <p>The stroke model is induced by disrupting the medium-size pial vessels within a 5mm-circular brain surface of adult Wistar rats. This leads to a cone-shaped cortical lesion. Therefore it mimics the clinical situation of lacunar infarction, the most frequent outcome of small vessel stroke. <p>Minocycline, a second-generation tetracycline, prevented cavitation and facilitated the repopulation of the lesion by reactive astrocytes. However, I could not identify the molecular target as the number of activated microglia, infiltrating leukocytes and CD3+ lymphocytes as well as interleukin-1β expression were not significantly altered. Doublecortin (DCX) is a microtubule-associated protein expressed by migrating neuroblasts and immature neurons. After injury, DCX-positive cells appeared in the neocortex at the base of the lesion. These cells exhibit a morphology resembling differentiated post-migratory neurons with long branched processes. Some of the DCX-positive cells were also immunoreactive for βIII-tubulin, another marker of immature neurons. This might indicate a migratory pathway for developing neuroblasts from the subventricular zone (SVZ) through the corpus callosum to the lesion. SVZ cells were labeled with carboxyfluorescein diacetate, succinimidyl ester (CFSE) stereotaxical injections. Although rostral migratory stream and olfactory bulb were intensely labeled, no CFSE containing cells were found in the cortex underneath the lesion. These results suggest that the DCX-positive cells may not originate from neural precursors from the SVZ, but might be generated from local progenitor cells. In summary, using the PVD II model, which mimics the lacunar stroke, I found that neuroblasts appeared spontaneously near the lesion in the cerebral cortex and were attempting to upregulate neuronal properties. Reducing inflammation with post-stroke minocycline treatment prevented cavitation. I think both findings open up exciting new avenues for treatment of lacunar infarctions.

Therapeutic strategies of stroke can take two directions: to prevent brain damage from stroke or aid in its repair after a stroke. In this thesis, a rat stroke model, which mimics the human small vessel stroke, was used. Two potential repair strategies were investigated with this model, reduction of inflammatory processes with the aid of minocycline treatment and replacing necrotic neurons with new ones with the aid of neurogenesis of endogenous progenitor cells. <p>The stroke model is induced by disrupting the medium-size pial vessels within a 5mm-circular brain surface of adult Wistar rats. This leads to a cone-shaped cortical lesion. Therefore it mimics the clinical situation of lacunar infarction, the most frequent outcome of small vessel stroke. <p>Minocycline, a second-generation tetracycline, prevented cavitation and facilitated the repopulation of the lesion by reactive astrocytes. However, I could not identify the molecular target as the number of activated microglia, infiltrating leukocytes and CD3+ lymphocytes as well as interleukin-1β expression were not significantly altered. Doublecortin (DCX) is a microtubule-associated protein expressed by migrating neuroblasts and immature neurons. After injury, DCX-positive cells appeared in the neocortex at the base of the lesion. These cells exhibit a morphology resembling differentiated post-migratory neurons with long branched processes. Some of the DCX-positive cells were also immunoreactive for βIII-tubulin, another marker of immature neurons. This might indicate a migratory pathway for developing neuroblasts from the subventricular zone (SVZ) through the corpus callosum to the lesion. SVZ cells were labeled with carboxyfluorescein diacetate, succinimidyl ester (CFSE) stereotaxical injections. Although rostral migratory stream and olfactory bulb were intensely labeled, no CFSE containing cells were found in the cortex underneath the lesion. These results suggest that the DCX-positive cells may not originate from neural precursors from the SVZ, but might be generated from local progenitor cells. In summary, using the PVD II model, which mimics the lacunar stroke, I found that neuroblasts appeared spontaneously near the lesion in the cerebral cortex and were attempting to upregulate neuronal properties. Reducing inflammation with post-stroke minocycline treatment prevented cavitation. I think both findings open up exciting new avenues for treatment of lacunar infarctions.

Cognitive aging is a biological process characterized by physical changes in the brain and subsequent alterations in cognitive function. While neurodegenerative diseases result in extensive neuronal death and anatomical abnormalities, normal aging has subtle changes resulting in a range of cognitive abilities. Early studies of cognitive aging focused on changes in the neuronal population, but evidence has demonstrated that forebrain neurons are largely preserved with age. Furthermore, the proliferation of new neurons in the adult brain has generated great speculation regarding the role and contribution of new neurons to cognitive function. Conversely, both imaging and ultrastructural analyses have shown that age-related alterations in white matter and myelin are good predictors of cognitive impairment, suggesting that alterations in connectivity between brain regions may result in cognitive decline. In this dissertation, a rhesus monkey model of normal aging was used to assess the contribution of adult-neurogenesis and oligodendrogenesis to cognitive function. First, cell proliferation and adult neurogenesis were assessed in the subgranular zone of the hippocampal dentate gyrus. Aged animals demonstrated a decline in proliferating cells and neurogenesis but only limited correlations with behavioral impairment. Immature neurons were also identified in temporal lobe cortices, but results indicate these immature cortical neurons are most likely not adult-generated. Moreover, despite an age-related decline in numbers, they persist throughout the lifespan and many differentiate into Calretinin neurons. Further investigation of white matter alterations used immunohistochemistry and diffusion spectrum imaging to correlate oligodendrocyte numbers with white matter connectivity. In the corpus callosum and cingulum bundle, there were no correlations with age, but cognitive impairment was associated with increased oligodendrocyte number and decreased white matter connectivity. These correlations were only present in the anterior aspect of the cingulum bundle, not the posterior cingulum suggesting differential oligodendrocyte responses along the anterior-posterior axis of the brain. Together, these data demonstrate an age-related decline in adult neurogenesis may be only a small contributor to cognitive impairment. Additionally, a reserve pool of immature neurons continues to differentiate in the temporal cortex potentially contributing to local plasticity. Furthermore, cognitive impairment rather than aging has a stronger correlation with oligodendrocytes alterations and connectivity.

The main goal of this study was to further explore the hypothesis that experience-dependent neural network activity and neurotransmission can modulate adult OPC proliferation and differentiation. More specifically, we used stereology to establish whether extensive reference memory training and system-wide administration of GABAergic agonists and antagonists could influence the proliferation and differentiation of adult OPCs, as well as the prevalence of OPC-neuron pairs. Analysis of the effects of reference memory training on OPC proliferation and differentiation corresponds to experiment 2, analysis of the effects of GABAergic agents on OPC proliferation and differentiation corresponds to experiment 3, and analysis of the effects of both reference memory training and GABAergic agents on OPC-neuron pairs, as well as an histological analysis of these closely apposed cells, corresponds to experiment 4.

One mechanism of plasticity within the adult mammalian brain is the dynamic process of adult neurogenesis that is functionally important in physiological and pathological conditions. During this process, neurons develop from adult neural stem cells (NSCs) via intermediate neural progenitors (NPCs) through several processes including proliferation, survival, differentiation, migration and integration. Despite neurogenesis during development sharing these same processes, there is growing evidence highlighting unique mechanisms that regulate adult versus embryonic neurogenesis. The studies in this thesis test the cell-intrinsic function of genes that have defined roles in embryonic neurogenesis and undefined roles in adult hippocampal neurogenesis using a combination of transgenic inducible mice and in vivo retroviral techniques. The first study examines the microtubule associated protein Doublecortin (DCX), which is transiently expressed by NPCs and is critical for neuronal migration. Our results show that, in the context of adult hippocampal neurogenesis, DCX is not required for the survival or differentiation of the NPCs within the subgranular zone (SGZ). The second study examines the functional role of the autophagy-associated gene 5 (Atg5) which is critical for embryonic neurogenesis and survival. Our findings demonstrate that the intracellular recycling process of autophagy is active throughout maturation of adult hippocampal NPCs and that ablation of Atg5 produces a drastic reduction in NPC survival, without altering the neuronal fate of these cells. The third study examines the requirement of the familial-Alzheimer’s disease associated genes, presenilin 1 and presenilin 2 (PS1 & PS2), which are critical for embryonic NSC maintenance and differentiation. Similar to the findings with DCX, our results demonstrate that presenilins are dispensable for adult neurogenesis. Altogether, these studies add to the growing evidence suggesting differences in the regulation of adult versus embryonic neurogenesis, and highlight autophagy as a novel regulator of survival for adult generated granule neurons in the hippocampus.

No description available.

No description available.

Introduction: One characteristic of Alzheimer’s disease is the formation of amyloid-b plaques, which are typically linked to neuroinflammation and surrounded by inflammatory cells such as microglia and infiltrating immune cells. Methods: Here, we describe nonneurogenic doublecortin (DCX) positive cells, DCX being generally used as a marker for young immature neurons, at sites of amyloid-b plaques in various transgenic amyloid mouse models and in human brains with plaque pathology. Results: The plaque-associated DCX1 cells were not of neurogenic identity, instead most of them showed coexpression with markers for microglia (ionized calcium-binding adapter molecule 1) and for phagocytosis (CD68 and TREM2). Another subpopulation of plaque-associated DCX1 cells was negative for ionized calcium-binding adapter molecule 1 but was highly positive for the panleukocyte marker CD45. These hematopoietic cells were identified as CD3-and CD8-positive and CD4-negative T-cells. Discussion: Peculiarly, the DCX1/ionized calcium-binding adapter molecule 11 microglia and DCX1/CD81 T-cells were closely attached, suggesting that these two cell types are tightly interacting and that this interaction might shape plaque pathology.

Deep brain stimulation (DBS) is currently being investigated as a therapy for treatment-resistant depression, with promising results. However, it is not clear whether or not DBS works via the same mechanisms as those induced by antidepressant medications. Processes currently implicated in antidepressant effects include neuroplastic changes and promotion of neurogenesis. We investigated the effects of chronic treatment with three different classes of antidepressants and DBS on markers of neuroplasticity (brain-derived neurotrophic factor, (BDNF), and phosphorylated cyclic-AMP regulatory element binding protein, (pCREB)) and neurogenesis (Ki-67, bromodeoxyuridine (BrdU) and doublecortin) in the rat hippocampus. No clear treatment effects were seen on BDNF, pCREB and Ki-67 levels. However all treatments caused increased levels of BrdU (range: 46%-96%) and doublecortin (8%-61%), although these effects were statistically significant only for DBS and amitriptyline, respectively. This overall pattern of results may suggest that diverse antidepressant treatments could possibly share common mechanisms involving cell survival and neuronal differentiation. Potentiated effects of DBS on cell survival may underlie its efficacy in treatment-resistant depression.