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Mutations in the coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) gene have been associated with a large clinical spectrum including myopathy, cardiomyopathy and amyotrophic lateral sclerosis (ALS). Herein, we analyzed the metabolic changes induced by the p.S59LCHCHD10mutation to identify new therapeutic opportunities. Using metabolomic, lipidomic and proteomic analysis we observed a strong alteration of metabolism in plasma and heart ofChchd10S59L/+mice compared to their wild type littermates at pre-symptomatic and symptomatic stages. In plasma, levels of phospholipids were decreased while those of carnitine derivatives and most of amino acids were increased. The cardiac tissue fromChchd10S59L/+mice showed a decreased Oxidative Phosphorylation (OXPHOS) and β-oxidation proteins levels as well as tricarboxylic acid cycle (TCA) intermediates and carnitine pathway metabolism. In parallel, lipidomics analysis reveals a drastic change in the lipidome, including triglycerides, cardiolipin and phospholipids. Consistent with this energetic deficiency in cardiac tissue, we show that L-acetylcarnitine supplementation improves the mitochondrial network length in IPS-derived cardiomyocytes from a patient carrying theCHCHD10S59L/+mutation. These data indicate that a bioenergetic intermediate such as L-acetylcarnitine may restore mitochondrial function inCHCHD10-related disease, due to the reduction in energy deficit that could be compensated by carnitine metabolic pathways.

Background: Others and we have shown that T cells have an important role in hippocampal synaptic plasticity, including neurogenesis in the dentate gyrus, spinogenesis, and glutamatergic synaptic function in the CA of the hippocampus. Hippocampus plasticity is particularly involved in the brain effects of the enriched environment (EE), and interestingly CD4+ and CD8+ T cells play essential and differential roles in these effects. However, the precise mechanisms by which they act on the brain remain elusive. Objectives: We searched for a putative mechanism of action by which CD4+ T cells could influence brain plasticity and hypothesized that they could regulate protein transport at the level of the blood-CSF barrier in the choroid plexus. Method: We compared mice housed in EE and deprived of CD4+ T cells using a depleting antibody with a control group injected with the control isotype. We analyzed in the hippocampus the gene expression profiles using the Agilent system, and the expression of target proteins in plasma, CSF, and the choroid plexus using ELISA. Results: We show that CD4+ T cells may influence EE-induced hippocampus plasticity via thyroid hormone signaling by regulating in the choroid plexus the expression of transthyretin, the major transporter of thyroxine (T4) to the brain parenchyma. Conclusions: Our study highlights the contribution of close interactions between the immune and neuroendocrine systems in brain plasticity and function.

International audience; We previously showed that injection of recombinant human group IIA secreted phospholipase A2 (hGIIA sPLA2) to Plasmodium chabaudi-infected mice lowers parasitaemia by 20%. Here, we show that transgenic (TG) mice overexpressing hGIIA sPLA2 have a peak of parasitaemia about 30% lower than WT littermates. During infection, levels of circulating sPLA2, enzymatic activity and plasma lipid peroxidation were maximal at day-14, the peak of parasitaemia. Levels of hGIIA mRNA increased in liver but not in spleen and blood cells, suggesting that liver may contribute as a source of circulating hGIIA sPLA2. Before infection, baseline levels of leukocytes and pro-inflammatory cytokines were higher in TG mice than WT littermates. Upon infection, the number of neutrophils, lymphocytes and monocytes increased and were maximal at the peak of parasitaemia in both WT and TG mice, but were higher in TG mice. Similarly, levels of the Th1 cytokines IFN-γ and IL-2 increased in WT and TG mice, but were 7.7- and 1.7-fold higher in TG mice. The characteristic shift towards Th2 cytokines was observed during infection in both WT and TG mice, with increased levels of IL-10 and IL-4 at day-14. The current data are in accordance with our previous in vitro findings showing that hGIIA kills parasites by releasing toxic lipids from oxidized lipoproteins. They further show that hGIIA sPLA2 is induced during mouse experimental malaria and has a protective in vivo role, lowering parasitaemia by likely releasing toxic lipids from oxidized lipoproteins but also indirectly by promoting a more sustained innate immune response.

L’adiponectine (ApN) est une hormone produite par le tissu adipeux dont le taux plasmatique est diminué chez les personnes en surpoids ou obèses ainsi que chez les patients diabétiques. En périphérie, cette baisse du taux circulant d’ApN induit l’établissement d’un état inflammatoire chronique à bas bruit, le développement d’une résistance à l’insuline et de plaques d’athérome. Inversement, des conditions de vie « favorables », la perte de poids et la pratique régulière d’exercice physique permettent d’augmenter la concentration sanguine d’ApN. Certaines formes d’ApN peuvent gagner le cerveau par le biais du liquide cérébrospinal. À ce niveau, l’augmentation de l’ApN exerce de puissants effets anti-dépresseurs et anxiolytiques, notamment en réduisant la neuroinflammation.

Thyrotropin Releasing Hormone (TRH) is a tripeptide that induces the release of Thyroid Stimulating Hormone (TSH) in the blood. Besides its role in the thyroid system, TRH has been shown to regulate several neuronal systems in the brain however its role in hippocampus remains controversial. Using electrophysiological recordings in acute mouse brain slices, we show that TRH depresses glutamate responses at the CA3-CA1 synapse through an action on NMDA receptors, which, as a consequence, decreases the ability of the synapse to establish a long term potentiation (LTP). TRH also induces a late increase in AMPA/kainate responses. Together, these results suggest that TRH plays an important role in the modulation of hippocampal neuronal activities, and they contribute to a better understanding of the mechanisms by which TRH impacts synaptic function underlying emotional states, learning and memory processes.

Inflammation is considered as a major contributor to brain injury following cerebral ischemia. The therapeutic potential of both MLC601/MLC901, which are herbal extract preparations derived from Chinese Medicine, has been reported both in advanced stroke clinical trials and also in animal and cellular models. The aim of this study was to investigate the effects of MLC901 on the different steps of post-ischemic inflammation in focal ischemia in mice. In vivo injury was induced by 60 minutes of middle cerebral artery occlusion (MCAO) followed by reperfusion. MLC901 was administered in post-treatment 90 min after the onset of ischemia and once a day during reperfusion. MLC901 treatment resulted in a reduction in infarct volume, a decrease of Blood Brain Barrier leakage and brain swelling, an improvement in neurological scores and a reduction of mortality rate at 24 hours after MCAO. These beneficial effects of MLC901 were accompanied by an inhibition of astrocytes and microglia/macrophage activation, a drastically decreased neutrophil invasion into the ischemic brain as well as by a negative regulation of pro-inflammatory mediator expression (cytokines, chemokines, matrix metalloproteinases). MLC901 significantly inhibited the expression of Prx6 as well as the transcriptional activity of NFκB and the activation of Toll-like receptor 4 (TLR4) signaling, an important pathway in the immune response in the ischemic brain. MLC901 effects on the neuroinflammation cascade induced by cerebral ischemia probably contribute, in a very significant way, in its potential therapeutic value.

Others and we have shown that T cells have an important role in hippocampal synaptic plasticity, including neurogenesis in the dentate gyrus, spinogenesis, and glutamatergic synaptic function in the CA of the hippocampus. Hippocampus plasticity is particularly involved in the brain effects of the enriched environment (EE), and interestingly CD4+ and CD8+ T cells play essential and differential roles in these effects. However, the precise mechanisms by which they act on the brain remain elusive.We searched for a putative mechanism of action by which CD4+ T cells could influence brain plasticity and hypothesized that they could regulate protein transport at the level of the blood-CSF barrier in the choroid plexus.We compared mice housed in EE and deprived of CD4+ T cells using a depleting antibody with a control group injected with the control isotype. We analyzed in the hippocampus the gene expression profiles using the Agilent system, and the expression of target proteins in plasma, CSF, and the choroid plexus using ELISA.We show that CD4+ T cells may influence EE-induced hippocampus plasticity via thyroid hormone signaling by regulating in the choroid plexus the expression of transthyretin, the major transporter of thyroxine (T4) to the brain parenchyma.Our study highlights the contribution of close interactions between the immune and neuroendocrine systems in brain plasticity and function.

Adiponectin (ApN) is a hormone produced by adipose tissue, yet the plasma level of ApN is decreased in overweight and obese people, as well as in people with diabetes. In the periphery, this decrease in circulating levels of ApN induces the establishment of a chronic low-grade inflammatory state and is involved in the development of insulin resistance and atheromas. Conversely, "favorable" living conditions, weight loss and regular physical exercise increase ApN blood concentration. Some forms of ApN can reach the brain parenchyma through the cerebrospinal fluid. In the brain, the increase in ApN exerts powerful antidepressant and anxiolytic effects, in particular by fighting against neuroinflammation.

Living in an enriched environment (EE) benefits health by acting synergistically on various biological systems including the immune and the central nervous systems. The dialog between the brain and the immune cells has recently gained interest and is thought to play a pivotal role in beneficial effects of EE. Recent studies show that T lymphocytes have an important role in hippocampal plasticity, learning, and memory, although the precise mechanisms by which they act on the brain remain elusive. Using a mouse model of EE, we show here that CD4+ T cells are essential for spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. However, CD4+ lymphocytes do not influence EE-induced neurogenesis in the DG of the hippocampus, by contrast to what we previously demonstrated for CD8+ T cells. Importantly, CD4+ T cells located in the choroid plexus have a specific transcriptomic signature as a function of the living environment. Our study highlights the contribution of CD4+ T cells in the brain plasticity and function.

International audience; Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4 + T cells have been shown to be involved in brain plasticity processes. Here, we show that CD8 + T cells are required for EE-induced brain plasticity in mice, as revealed by measurements of hippocampal volume, neurogenesis in the DG of the hippocampus, spinogenesis and glutamatergic synaptic function in the CA of the hip-pocampus. As a consequence, EE-induced behavioral benefits depend, at least in part, on CD8 + T cells. In addition, we show that spleen CD8 + T cells from mice housed in standard environment (SE) and EE have different properties in terms of 1) TNFa release after in vitro CD3/CD28 or PMA/Iono stimulation 2) in vitro proliferation properties 3) CD8 + CD44 + CD62L low and CD62L hi T cells repartition 4) transcrip-tomic signature as revealed by RNA sequencing. CD8 + T cells purified from the choroid plexus of SE and EE mice also exhibit different transcriptomic profiles as highlighted by single-cell mRNA sequencing. We show that CD8 + T cells are essential mediators of beneficial EE effects on brain plasticity and cogni-tion. Additionally, we propose that EE differentially primes CD8 + T cells leading to behavioral improvement.

Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4

Enriched environment (EE) is characterized by improved conditions for enhanced exploration, cognitive activity, social interaction and physical exercise. It has been shown that EE positively regulates the remodeling of neural circuits, memory consolidation, long-term changes in synaptic strength and neurogenesis. However, the fine mechanisms by which environment shapes the brain at different postnatal developmental stages and the duration required to induce such changes are still a matter of debate. In EE, large groups of mice were housed in bigger cages and were given toys, nesting materials and other equipment that promote physical activity to provide a stimulating environment. Weaned mice were housed in EE for 4, 6 or 8 weeks and compared with matched control mice that were raised in a standard environment. To investigate the differential effects of EE on immature and mature brains, we also housed young adult mice (8 weeks old) for 4 weeks in EE. We studied the influence of onset and duration of EE housing on the structure and function of hippocampal neurons. We found that: (1) EE enhances neurogenesis in juvenile, but not young adult mice; (2) EE increases the number of synaptic contacts at every stage; (3) long-term potentiation (LTP) and spontaneous and miniature activity at the glutamatergic synapses are affected differently by EE depending on its onset and duration. Our study provides an integrative view of the role of EE during postnatal development in various mechanisms of plasticity in the hippocampus including neurogenesis, synaptic morphology and electrophysiological parameters of synaptic connectivity. This work provides an explanation for discrepancies found in the literature about the effects of EE on LTP and emphasizes the importance of environment on hippocampal plasticity.

Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1β, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice.

Environmental enrichment (EE) that combines voluntary physical exercise, sensory and social stimuli, causes profound changes in rodent brain at molecular, anatomical and behavioral levels. Here, we show that EE efficiently reduces anxiety and depression-like behaviors in a mouse model of depression induced by long-term administration of corticosterone. Mechanisms underlying EE-related beneficial effects remain largely unexplored; however, our results point toward adiponectin, an adipocyte-secreted protein, as a main contributor. Indeed, adiponectin-deficient (adipo(-/-)) mice did not benefit from all the EE-induced anxiolytic and antidepressant-like effects as evidenced by their differential responses in a series of behavioral tests. Conversely, a single intravenous injection of exogenous adiponectin restored the sensitivity of adipo(-/-) mice to EE-induced behavioral benefits. Interestingly, adiponectin depletion did not prevent the hippocampal neurogenesis induced by EE. Therefore, antidepressant properties of adiponectin are likely to be related to changes in signaling in the hypothalamus rather than through hippocampal-neurogenesis mechanisms. Additionally, EE did not modify the plasma levels of adiponectin but may favor the passage of adiponectin from the blood to the cerebrospinal fluid. Our findings provide advances in the understanding of the anxiolytic and antidepressant-like effects of EE and highlight adiponectin as a pivotal mediator.

Background Genetic and environmental factors are critical elements influencing the etiology of major depression. It is now accepted that neuroinflammatory processes play a major role in neuropsychological disorders. Neuroinflammation results from the dysregulation of the synthesis and/or release of pro- and anti-inflammatory cytokines with central or peripheral origin after various insults. Systemic bacterial lipopolysaccharide (LPS) challenge is commonly used to study inflammation-induced depressive-like behaviors in rodents. In the present study, we investigated immune-to-brain communication in mice by examining the effects of peripheral LPS injection on neuroinflammation encompassing cytokine and chemokine production, microglia and central nervous system (CNS)-associated phagocyte activation, immune cell infiltration and serotonergic neuronal function. Methods LPS was administered to C57BL/6 J mice by intraperitoneal injection; brains were collected and pro-inflammatory cytokine mRNA and proteins were measured. To examine the relative contribution of the different populations of brain immune cells to the occurrence of neuroinflammation after acute systemic inflammation, we precisely characterized them by flow cytometry, studied changes in their proportions and level of activation, and measured the amount of cytokines they released by Cytometric Bead Array™ after cell sorting and ex vivo culture. Because of the central role that the chemokine CCL2 seems to play in our paradigm, we studied the effect of CCL2 on the activity of serotonergic neurons of the raphe nucleus using electrophysiological recordings. Results We report that systemic LPS administration in mice caused a marked increase in pro-inflammatory IL-1β, IL-6, TNFα and CCL2 (monocyte chemoattractant protein-1) mRNA and protein levels in the brain. Moreover, we found that LPS caused microglia and CNS-associated phagocyte activation characterized by upregulation of CCR2, TLR4/CD14, CD80 and IL-4Rα, associated with overproduction of pro-inflammatory cytokines and chemokines, especially CCL2. LPS also induced a marked and selective increase of CCR2+ inflammatory monocytes within the brain. Finally, we showed that CCL2 hyperpolarized serotonergic raphe neurons in mouse midbrain slices, thus probably reducing the serotonin tone in projection areas. Conclusion Together, we provide a detailed characterization of the molecular and cellular players involved in the establishment of neuroinflammation after systemic injection of LPS. This highlights the importance of the CCL2/CCR2 signaling and suggests a possible link with depressive disorders.

International audience; The prion protein (PrP) is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP(-/-)) mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt) control mice. Conversely, compared to wt mice, those over-expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion) to ethanol inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potentials in hippocampal slices developed slower in PrP(-/-) mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP-dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP(-/-) mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP(-/-) mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions.

Neurodegenerative diseases are more and more prevalent in our aging societies. There is strong evidence that glycogen synthase kinase (GSK)-3b plays a crucial role in Alzheimer's disease (AD). Indeed, it is involved in the regulation of the two major neuropathological hallmarks present in the brains of AD patients. Interestingly, the kinase has been implicated in multiple cellular processes and linked with the pathogenesis and neuronal loss in several neurodegenerative diseases, including Parkinson's and Huntington's diseases, in which abnormally elevated levels of GSK-3b activity have been reported. In this review, we will provide an overview of the current data pointing out the convergent role of GSK-3b in the neuropathological pathways of these diseases. We will also discuss the rationale for the development of specific inhibitors with therapeutic potentials for such devastating human diseases.

Neurodegenerative diseases are more and more prevalent in our aging societies. There is strong evidence that glycogen synthase kinase (GSK)-3b plays a crucial role in Alzheimer's disease (AD). Indeed, it is involved in the regulation of the two major neuropathological hallmarks present in the brains of AD patients. Interestingly, the kinase has been implicated in multiple cellular processes and linked with the pathogenesis and neuronal loss in several neurodegenerative diseases, including Parkinson's and Huntington's diseases, in which abnormally elevated levels of GSK-3b activity have been reported. In this review, we will provide an overview of the current data pointing out the convergent role of GSK-3b in the neuropathological pathways of these diseases. We will also discuss the rationale for the development of specific inhibitors with therapeutic potentials for such devastating human diseases.

We are interested in elucidating how the brain controls the immune system. To this aim, we have established an environmental enriched (EE) paradigm in which C57BL/6 mice experience higher levels of sensory, motor, social, and cognitive stimuli, compared to animals housed in a standard environment (EE). In agreement with previous studies, EE mice exhibited increased hippocampal neurogenesis and synaptogenesis, and decreased anxiety, and increased exploratory activity. EE housing did not result in gross alterations in the frequency of neutrophils, dendritic cells (DC), macrophages, CD4+ and CD8+ T cells and B lymphocytes in the lymphoid organs of immunologically naive animals. However, spleen DCs expressed a more mature phenotype in EE animals compared to SE mice. Furthermore, EE mice exhibited both a Th2-biaised T response upon immunization with OVA and a more robust memory T cell response. To elucidate the mechanisms that were responsible for these latter phenomena, we compared the levels of various metabolites in the serum of EE and SE mice. EE animals exhibited increased levels of adiponectin, a cytokine that is mainly secreted by adipose tissue and that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation. Most importantly, adiponectin-deficient mice housed in EE did not exhibit the Th2-biaised immune response that was observed in wild-type mice therefore suggesting a critical role of this cytokine in EE-induced immune alterations.

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.; 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.; 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.

Cerebral plasticity is a remarkable ability of brain cells to adapt their structure and function in response to experience and the environment. This cerebral plasticity is enhanced by favorable living conditions that can be modeled in the rodent by the Enriched Environment (EE) model. The EE consists in large number of mice in large cages including numerous objects (nests, tunnels, wheels ...) which are changed frequently. EE induces increased voluntary physical activity, optimal conditions for stimulation of social interactions, exploratory behavior and cognitive functions. EE has beneficial effects on physiological processes in many systems (hormonal, cardiovascular, immune system...). EE reduces anxio-depressive behavior, improves learning and memory. These effects are underpinned by changes in the brain and particularly in the hippocampus, where EE induce more neurogenesis and synaptogenesis. Interestingly, in immunodeficient mice, memory performance and neurogenesis are highly impaired, suggesting a bidirectional interaction between the immune system and the brain. Among the cells of the immune system, T cells appear to play a major role in neuronal plasticity mechanisms. Our objective was to characterize the role of T cells in EE’s effects on cerebral plasticity and to investigate whether these effects imply a modification of T cells by EE.; La plasticité cérébrale est une capacité remarquable des cellules du cerveau à adapter leur structure et fonction en réponse à l’expérience et l’environnement. Cette plasticité cérébrale est favorisée par des conditions de vie favorables qui peuvent être modélisées chez le rongeur par le modèle de l’Environnement Enrichi (EE). L’EE consiste à mettre un grand nombre de souris dans de grandes cages comprenant de nombreux objets (nids, tunnels, roues…) qui sont changés régulièrement. L’EE induit une activité physique volontaire accrue, des conditions optimales pour la stimulation des interactions sociales, du comportement exploratoire et des fonctions cognitives. L’EE exerce des effets bénéfiques sur les processus physiologiques au niveau de nombreux systèmes (hormonal, cardiovasculaire, immunitaire…). L’EE réduit les comportements anxio-dépressifs, améliore l'apprentissage et la mémorisation. Ces effets sont sous-tendus par des changements au niveau du cerveau et en particulier de l’hippocampe, où l’on observe en EE plus de neurogenèse et synaptogenèse. De manière intéressante, chez les souris immunodéficientes, les performances mnésiques et la neurogenèse sont très altérées, suggérant une interaction bidirectionnelle entre le système immunitaire et le cerveau. Parmi les cellules du système immunitaire, les lymphocytes T (LT) semblent jouer un rôle particulièrement important dans les mécanismes de plasticité neuronale. Notre objectif a été de caractériser le rôle des LT dans les effets de l’EE sur la plasticité cérébrale et de chercher si ces effets impliquent une modification des LT par l’EE.