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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.

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.

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.

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.