Depression occurs in about one third of patients with stroke and cardiac arrest. Hyperactivity of the stress system is the most commonly observed neuroendocrine change in major depressive disorder (MDD), which involves elevated levels in the cerebrospinal fluid of corticotropin-releasing hormone (CRH), a key stress neurohormone. Substantial evidence suggests that normalization of the stress system may be a requirement for successful treatment of MDD through region-specific changes in the mesocorticolimbic circuitry. Thus, alteration in the stress system may underlie the emotional and functional impairments observed following brain ischemic events. In addition, recent findings suggest that ischemic brain injury triggers a restorative process, creating a cerebral environment similar to that of early brain development, a period characterized by rapid neuronal growth and neuroplasticity, critical to optimize functional recovery of individuals post stroke. In particular brain-derived neurotrophic factor (BDNF), has been shown to play an important role in the pathophysiology of major depression and cerebral ischemia. However, whether CRH can mediate the expression of BDNF in the reparative process triggered by ischemic injury remains to be characterized. Therefore, the purpose of the current thesis is to characterize the effect of pharmacological blockade of CRH signaling at the onset of a global ischemic stroke, on emotional and cognitive behaviors, alteration in the neuroendocrine stress system, and markers of neuroplasticity including BDNF. To do this, an animal model of global cerebral ischemia with subsequent behavioral testing and postmortem brain analysis was used to determine underlying biochemical and behavioral changes modulated by CRH signaling following brain ischemia. This doctoral work will help elucidate the relationship between CRH and BDNF in the context of cerebral ischemia, and may provide insights for therapies targeting the stress system. These studies address considerations such as: the interplay between stress, neuroplasticity and emotionality, and whether global ischemia can affect mood via changes in the HPA axis response.

Les astrocytes deviennent réactifs dans les maladies neurodégénératives (MND) comme la maladie d’Alzheimer (MA) et de Huntington (MH) mais les conséquences fonctionnelles de cette réactivité sont peu connues. Dans cette étude, nous avons évalué 1) les voies de signalisation impliquées dans la réactivité astrocytaire, 2) la contribution des astrocyte réactifs (AR) à la dysfonction neuronale dans des modèles de MND et 3) les caractéristiques fonctionnelles des AR.Nous avons montré que la voie JAK2/STAT3 est responsable de la réactivité astrocytaire dans des modèles murins de la MA et la MH. Nous avons développé de nouveaux vecteurs viraux ciblant cette voie dans les astrocytes, in vivo. Grâce à ces outils, nous avons étudié la contribution des AR à la dysfonction neuronale dans deux modèles murins de la MH. Nos résultats suggèrent que les AR ne jouent pas un rôle central dans ces modèles de pathologie. En ciblant la voie JAK2/STAT3, nous avons induit la réactivité astrocytaire chez la souris sauvage et avons montré que cette voie régule la transcription de gènes impliqués dans des fonctions cellulaires importantes. De plus, nous avons observé que l’activation des astrocytes conduit à une diminution de la plasticité synaptique dans le cerveau de souris.En conclusion, nous avons montré que la voie JAK2/STAT3 est une voie centrale dans les AR. Nous avons développé des vecteurs viraux innovants pour évaluer 1) la contribution des AR à la dysfonction neuronale dans des modèles de MND et 2) les propriétés fonctionnelles des AR in vivo. L’étude des AR permettra d’identifier de nouvelles cibles moléculaires pour manipuler ces cellules pléiotropes à des fins thérapeutiques. / Astrocyte reactivity is a hallmark of pathological conditions in the CNS including neurodegenerative diseases (ND) such as Alzheimer’s (AD) and Huntington’s (HD) diseases. Reactive astrocytes (RA) are identified by morphological changes but their functional features and influence on neurons are poorly understood, especially in ND. Therefore, we aimed at 1) identifying the signaling cascades involved in astrocyte reactivity in ND, 2) evaluating RA contribution to disease phenotype in ND models and 3) deciphering RA functional features. The JAK2/STAT3 pathway is a known trigger of astrocyte reactivity in CNS injuries. Here, we show that this pathway is a common inducer of astrocyte reactivity in AD and HD models. We developed new viral vectors to target this cascade in astrocytes and manipulate astrocyte reactivity in vivo. We used these vectors to determine the contribution of RA to neuronal dysfunction in HD mouse models. We found that RA do not primarily influence disease phenotype in HD. Last, we targeted the JAK2/STAT3 pathway in WT mice to characterize RA functional features in vivo. We show RA undergo transcriptional changes of numerous genes involved in metabolism, protein degradation pathways and immune response. Moreover, we show that astrocyte reactivity alters synaptic plasticity in the mouse hippocampus. Our results identify the JAK2/STAT3 pathway as a central cascade for astrocyte reactivity. The viral vectors developed in this project represent powerful tools to decipher the roles of RA in various ND models and to characterize RA functional features in vivo. Better understanding RA functions may lead to the identification of new therapeutic targets for ND.

L’infection à Helicobacter pylori est responsable d’une inflammation gastrique chronique qui pourrait contribuer à l’apparition ou l’aggravation de pathologies extradigestives comme la maladie d’Alzheimer (MA). A partir des données de la cohorte PAQUID explorant les facteurs de risque de démence dans une population de patients de plus de 65 ans, nous avons montré que la prévalence de la démence augmentait chez les sujets infectés. Après 20 ans de suivi, l’infection à H. pylori était associée à une augmentation de l’incidence de démence après ajustement aux facteurs de risque connus de MA. Dans une deuxième étude incluant 53 patients atteints de MA, l’infection à H. pylori était associée à des performances cognitives plus sévères et le taux d’homocystéine était positivement corrélé aux lésions cérébrovasculaires et au taux d’anticorps anti-­‐H. pylori. Pour s’affranchir de possibles biais confondant comme le niveau socio-­‐économique, nous avons ensuite évalué l’impact de l’infection à H pylori sur le cerveau de souris sauvages (C57BL/6J) non prédisposées à la MA. Après 18 mois d’infection, alors que l’infection était associée à une inflammation gastrique importante, il n’a pas été retrouvé de plaque amyloïde ou de majoration de la neuroinflammation. Pour aller plus loin, nous avons étudié l’impact de l’infection à H. pylori sur le comportement et les lésions cérébrales de souris transgéniques prédisposées à la MA (APPswe/PS1dE9). Après 6 mois d’infection, les souris transgéniques présentaient plus de plaques amyloïdes sans majoration de la neuroinflammation ni des troubles du comportement.Bien que les études épidémiologiques apportent de nouveaux éléments en faveur d’une association entre la MA et l’infection à H. pylori, les études sur modèle animal ne mettent pas en évidence de majoration des troubles cognitifs ni de la neuroinflammation des souris infectées malgré une majoration du nombre de plaques amyloïdes. D’autres études sont nécessaires pour conclure à une association. / Helicobacter pylori infection seems to play a critical role in extra-­‐gastric diseases including Alzheimer’s dementia (AD). Chronic H. pylori infection could worsen AD lesions via atherosclerosis and inflammation.In a cohort study with 603 non-­‐institutionalized individuals aged 65 and older followed from 1989 to 2008, dementia was more prevalent in the H. pylori-­‐positive group at baseline compared to non-­‐infected group. After 20 years of follow-­‐up, H. pylori infection was determined to be a risk factor for developing dementia after controlling for AD risk factors. In a second study, including 53 AD patients, H. pylori infection was associated with a more pronounced cognitive impairment. Homocysteine levels were positively correlated to cerebrovascular lesions and to H. pylori immunoglobulin levels. To bypass possible confounding biases concerning socio-­‐economic conditions for instance, we evaluated the impact of H. pylori infection on the brain of non-­‐AD predisposed C57BL/6J mice. After an 18-­‐month infection, H. pylori SS1 and H. felis induced a significant gastric inflammation but no brain Aβ deposit was observed in their brain and the infection did not lead to neuroinflammation. To go further, we studied the impact of Helicobacter species infection on cerebral lesions and behaviour of AD transgenic (APPswe/PS1dE9) mice and their wild type littermates. H. pylori infection was associated with an increased number of brain amyloid plaques, but not with an increased neuroinflammation nor a worsening behaviour at 6 and 10 months of age.Although epidemiological studies provided new elements for an association between AD and H. pylori infection, animal model studies did not display a worsening behaviour or an increased neuroinflammation despite an increased number of amyloid plaques. More studies are needed to firmly conclude that there is an association between H. pylori infection and AD.

La dépression est une pathologie multifactorielle induisant des troubles psychiques et physiques. De nouvelles thérapies visant à enrichir l’environnement des patients par des activités physiques, sociales et cognitives aident à la rémission en complément des traitements pharmacologiques. Cependant les bases moléculaires sous-jacentes aux bénéfices observés dans ces thérapies sont méconnues. C’est dans ce contexte que nous avons étudié les effets de ces thérapies via la mise en place d’un modèle murin d’environnement enrichi (EE). L’objectif de ma thèse a été d’évaluer les effets antidépresseurs de l’EE sur un modèle murin de dépression et d’identifier une nouvelle cible thérapeutique. J’ai montré que l’administration chronique de corticostérone induit un état dépressif et une neuroinflammation qui peuvent être réversés par l’EE. De plus, mes travaux ont mis en évidence, l'adiponectine (ApN), comme étant un acteur clef des effets de l'EE. J’ai montré que l’EE via l’ApN était capable de limiter la neuroinflammation. Par ailleurs, la caractérisation de souris n’exprimant pas l’ApN a montré que ces souris étaient insensibles en partie aux effets de l’EE. Par la suite, je me suis intéressée à la voie de signalisation de l’ApN impliquée dans ses effets anti-inflammatoires, j’ai montré que l’ApN inhibe l’activation de la microglie en se liant à son récepteur AdipoR1. Enfin, j’ai testé l’effet de l’AdipoRon, un agoniste des récepteurs de l’adiponectine, sur des souris traitées par la corticostérone. J’ai montré que l’AdipoRon réduisait l’état « dépressif » de ces souris. Mon travaille suggère que les effets antidépresseurs de l’AdipoRon sont dus à sa pléiotropie car il agit simultanément sur différents systèmes altérés dans la dépression dont la neurogenèse hippocampique, la neurotransmission sérotoninergique et la neuroinflammation. Pour conclure ce travail met en avant les effets bénéfiques de l’EE sur la dépression et la neuroinflammation. De plus, ils identifient l’ApN et sa voie de signalisation comme de nouvelles cibles prometteuses dans le traitement de la dépression. / Major depression is a complex disorder characterized by behavioral and cognitive impairments triggered by various factors including genetic predispositions, stress and environment. The pathophysiology of depression is poorly understood. Numerous evidence suggests that neuroinflammation is associated with depression. Alternative therapeutic strategies are needed and "positive" life experiences could be an efficient way to help the remission of the disorder. To study the potential antidepressant effects of such “positive” living conditions, we used the enriched environment (EE) paradigm on mice. The aim of our work was to fully characterize the antidepressant and anti-inflammatory effects of EE in a well-characterized murine model of depression-like behavior induced by long-term administration of corticosterone. We showed that EE efficiently reverses the anxiety/depression‐like state of mice and reduces neuroinflammation. Moreover, we identified the adipokine Adiponectin as a key player in the beneficial effects of EE. We reported that increased levels of Adiponectin in the brain led to microglia phenotype and activation state regulation, thus reducing global brain inflammation in mice. Indeed, the anti-inflammatory and antidepressants effects of EE are abolished in Adiponectin deficient mice. We demonstrated that anti-inflammatory actions of Adiponectin on microglia is mediated through the Adiponectin Receptor 1. Those results highlight the key role of the adiponergic system in the treatment of psychiatric disorders. Therefore, we tested the effect of AdipoRon, a potent Adiponectin receptors 1 and 2 agonist on corticosterone-treated mice. AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission and neuroinflammation, which can explain its antidepressant properties. Together, our findings bring insight into the beneficial effects of "positive" life experiences in depression and neuroinflammation, highlight the pivotal role of Adiponectin pathway and emphasizes that AdipoRon or other Adiponectin receptor agonist may constitute a promising novel antidepressant.

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Puberty is a critical period for sexual maturation during which the sex-specific reorganization and remodelling of the pubertal brain facilitate sex biases in stress sensitivity. Pubertal (i.e., six-week-old) CD-1 mice treated with the bacterial endotoxin lipopolysaccharide (LPS; 1.5 mg/kg body weight, ip) show several sex-specific changes to the neuroendocrine and behavioural systems of several reproductive and non-reproductive functions. One promising explanation for the elusive mechanisms driving the sex-specific outcomes of pubertal immune challenge may lie in the cascade of neuroimmune events induced by this systemic immune stressor. This doctoral thesis tested the hypothesis that sex-specific responses of the pubertal neuroimmune network contribute to sex differences in the enduring outcomes of pubertal immune challenge on hippocampus-dependent cognitive processes. Male and female CD-1 mice are equally vulnerable to enduring impairments in spatial memory following pubertal LPS exposure. Across brain regions for cognition and stress regulation, pubertal LPS treatment alters baseline sex differences in microglial expression and morphology in a sex-dependent manner. The temporary female-specific increase in whole-brain blood-brain barrier permeability during LPS-induced sickness may have facilitated the apparent female bias in LPS-induced changes to pubertal microglia. In the context of sex- and region-specific residual effects of pubertal LPS-induced sickness on microglial expression and morphology, pubertal LPS treatment may accelerate certain neurodevelopmental processes in males but not females. The innate sex differences in the pubertal neuroimmune network highlighted by these studies underscore how a systemic immune challenge precipitates sex biases in immune-mediated disorders of brain and behaviour during adulthood.

Increased neuroinflammation has been shown in individuals diagnosed with schizophrenia (SCHZ). This study evaluated a novel immune modulator (PD2024) that targets the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) to alleviate sensorimotor gating deficits and microglial activation employing two different rodent models of SCHZ. In Experiment 1, rats were neonatally treated with saline or the dopamine D2-like agonist quinpirole (NQ; 1 mg/kg) from postnatal day (P) 1-21 which produces increases of dopamine D2 receptor sensitivity throughout the animal's lifetime. In Experiment 2, rats were neonatally treated with saline or the immune system stimulant polyinosinic:polycytidylic acid (Poly I:C) from P5-7. Neonatal Poly I:C treatment mimics immune system activation associated with SCHZ. In both experiments, rats were raised to P30 and administered a control diet or a novel TNFα inhibitor PD2024 (10 mg/kg) in the diet from P30 until P67. At P45-46 and from P60-67, animals were behaviorally tested on auditory sensorimotor gating as measured through prepulse inhibition (PPI). NQ or Poly I:C treatment resulted in PPI deficits, and PD2024 treatment alleviated PPI deficits in both models. Results also revealed that increased hippocampal and prefrontal cortex microglial activation produced by neonatal Poly I:C was significantly reduced to control levels by PD2024. In addition, a separate group of animals neonatally treated with saline or Poly I:C from P5-7 demonstrated increased TNFα protein levels in the hippocampus but not prefrontal cortex, verifying increased TNFα in the brain produced by Poly I:C. Results from this study suggests that that brain TNFα is a viable pharmacological target to treat the neuroinflammation known to be associated with SCHZ.

This review is a brief summary of the effects of nicotine on neural plasticity and behavior, with a focus on the preclinical literature and the effects of nicotine on neurotrophic factors. Focus areas include underlying mechanisms of nicotine addiction and the therapeutic potential for nicotine and nicotinic receptor agonists in Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, as well as cutting across these different areas of research with a brief review of the antiinflammatory effects of nicotine. It is clear that agonists at nicotinic receptors have therapeutic potential, but this should be weighed in the context of the effects of nicotine across the brain and its enhancement of neurotrophic factors. Although nicotine may have neuroprotective properties, it is important to keep in mind that these same effects underlie its addictive characteristics.

Stem cell therapy may present an effective treatment for metastatic brain cancer and glioblastoma. Here we posit the critical role of a leaky blood-brain barrier (BBB) as a key element for the development of brain metastases, specifically melanoma. By reviewing the immunological and inflammatory responses associated with BBB damage secondary to tumoral activity, we identify the involvement of this pathological process in the growth and formation of metastatic brain cancers. Likewise, we evaluate the hypothesis of regenerating impaired endothelial cells of the BBB and alleviating the damaged neurovascular unit to attenuate brain metastasis, using the endothelial progenitor cell (EPC) phenotype of bone marrow-derived mesenchymal stem cells. Specifically, there is a need to evaluate the efficacy for stem cell therapy to repair disruptions in the BBB and reduce inflammation in the brain, thereby causing attenuation of metastatic brain cancers. To establish the viability of stem cell therapy for the prevention and treatment of metastatic brain tumors, it is crucial to demonstrate BBB repair through augmentation of vasculogenesis and angiogenesis. BBB disruption is strongly linked to metastatic melanoma, worsens neuroinflammation during metastasis, and negatively influences the prognosis of metastatic brain cancer. Using stem cell therapy to interrupt inflammation secondary to this leaky BBB represents a paradigm-shifting approach for brain cancer treatment. In this review article, we critically assess the advantages and disadvantages of using stem cell therapy for brain metastases and glioblastoma. / National Institutes of Health / Revisión por pares

Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new approach and may add to current rehabilitation therapies. By reviewing the pathophysiology of stroke and the mechanisms by which stem cells and rehabilitation attenuate this inflammatory process, we hypothesize that a combined therapy will provide better functional outcomes for patients. Using current preclinical data, we explore the prominent types of stem cells, the existing theories for stem cell repair, rehabilitation treatments inside the brain, rehabilitation modalities outside the brain, and evidence pertaining to the benefits of combined therapy. In this review article, we assess the advantages and disadvantages of using stem cell transplantation with rehabilitation to mitigate the devastating effects of stroke. / Revisión por pares