Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis.

The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose-responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this glucoregulatory network is, however, only partly characterized. In a genetic screen of a panel of recombinant inbred mice we previously identified Fgf15, expressed in neurons of the dorsomedial hypothalamus (DMH), as a negative regulator of glucagon secretion. Here, we report on the generation of Fgf15 <sup>CretdTomato</sup> mice and their use to further characterize these neurons. We show that they were glutamatergic and comprised glucose-inhibited and glucose-excited neurons. When activated by chemogenetics, Fgf15 neurons prevented the increase in vagal nerve firing and the secretion of glucagon normally triggered by insulin-induced hypoglycemia. On the other hand, they increased the activity of the sympathetic nerve in the basal state and prevented its silencing by glucose overload. Higher sympathetic tone increased hepatic Creb1 phosphorylation, Pck1 mRNA expression, and hepatic glucose production leading to glucose intolerance. Thus, Fgf15 neurons of the DMH participate in the counterregulatory response to hypoglycemia by a direct adrenergic stimulation of hepatic glucose production while suppressing vagally induced glucagon secretion. This study provides new insights into the complex neuronal network that prevents the development of hypoglycemia

Reducing Glut2 throughout the body does not result in cognitive behaviour differences in aged male mice

Objectives: GLUT2 is a major facilitative glucose transporter, expressed from the SLC2A2 gene, with essential roles in the liver. Recent work in mice has shown that preventing Glut2 production in specific neuronal populations increases sugar-seeking behaviour, highlighting the importance of Slc2a2 gene expression in the brain. It implies that reduced GLUT2 in the brain, due to genetic polymorphisms or disease, impacts health through behaviour change. Defects in glucose transport in the brain are observed in conditions including type-2 diabetes and dementia. Few studies have directly examined the effect of modulating neuronal glucose transporter expression on cognitive function. The aim of this study was to investigate whether inactivating one Slc2a2 allele throughout the body had major effects on cognition. Cognitive tests to assess recognition memory, spatial working memory and anxiety were performed in Slc2a2 whole-body heterozygous mice (i.e. reduced Glut2 mRNA and protein), alongside littermates expressing normal levels of the transporter.Results: No significant effects on neurological functions and cognitive capabilities were observed in mice lacking one Slc2a2 allele when fed a chow diet. This suggests that the minor variations in GLUT2 levels that occur in the human population are unlikely to influence behaviour and basic cognition.</p

Sleep-Deprivation Regulates α-2 Adrenergic Responses of Rat Hypocretin/Orexin Neurons

We recently demonstrated, in rat brain slices, that the usual excitation by noradrenaline (NA) of hypocretin/orexin (hcrt/orx) neurons was changed to an inhibition following sleep deprivation (SD). Here we describe that in control condition (CC), i.e. following 2 hours of natural sleep in the morning, the α2-adrenergic receptor (α2-AR) agonist, clonidine, had no effect on hcrt/orx neurons, whereas following 2 hours of SD (SDC), it hyperpolarized the neurons by activating G-protein-gated inwardly rectifying potassium (GIRK) channels. Since concentrations of clonidine up to a thousand times (100 µM) higher than those effective in SDC (100 nM), were completely ineffective in CC, a change in the availability of G-proteins is unlikely to explain the difference between the two conditions. To test whether the absence of effect of clonidine in CC could be due to a down-regulation of GIRK channels, we applied baclofen, a GABAB agonist known to also activate GIRK channels, and found that it hyperpolarized hcrt/orx neurons in that condition. Moreover, baclofen occluded the response to clonidine in SDC, indicating that absence of effect of clonidine in CC could not be attributed to down-regulation of GIRK channels. We finally tested whether α2-ARs were still available at the membrane in CC and found that clonidine could reduce calcium currents, indicating that α2-ARs associated with calcium channels remain available in that condition. Taken together, these results suggest that a pool of α2-ARs associated with GIRK channels is normally down-regulated (or desensitized) in hcrt/orx neurons to only become available for their inhibition following sleep deprivation

The Temporality of landscape in the Andreï Takrovski's esthetic.

À partir d’un corpus composé de l’ensemble des films de Tarkovski (L'Enfance d'Ivan, Andreï Roubev, Solaris, Le Miroir, Stalker, Nostalghia, Le Sacrifice), de ses travaux d’école (Les Tueurs, Il n’y aura pas de départ demain, Le Rouleau compresseur et le violon) et de certains de ses écrits, il s’agit de questionner le paysage chez le cinéaste et de mettre en lien ces observations avec les différentes temporalités présentes dans ses œuvres.Il est admis, dans les études portant sur Tarkovski, que ses cinq premiers films incarnent le paysage russe, que Nostalghia exprime - dans une certaine mesure - la souffrance à exister dans d’autres paysages, et que, Le Sacrifice permet des retrouvailles avec les vastes paysages présents avant l’exil du cinéaste. Cependant, ces constats peuvent être nuancés en parti par une analyse approfondie des techniques utilisées pour filmer ces paysages, qu’ils soient russes, italiens ou d’une nature autre.La complexité de la perception du paysage appelle l’analyse à prendre en considération les travaux théoriques faits sur le sujet afin d’en voir les limites et les nuances à travers l’esthétique cinématographique. La motivation de ce travail de recherche ne réside pas uniquement dans le fait de savoir si c'est l'homme qui se reflète dans le paysage ou si ce dernier se retrouve en l'homme, mais bien de prendre en considération le fait que c'est cette relation de l'un à l'autre qui intéresse actuellement la pensée du paysage.Il est donc pertinent d'étudier les œuvres filmiques et écrites de Tarkovski au regard des différentes pensées du paysage et de sa temporalité dans les cultures Occidentale et Extrême-Orientale afin d'établir une réflexion interdisciplinaire qui permet, non seulement une étude du paysage et de la temporalité dans l'image filmique, mais aboutit à l'actualisation d'une pensée philosophique et cinématographique en pleine évolution.Based on Tarkovski's filmography (Ivan's Childhood, Andrei Rublev, Solaris, The Mirror, Stalker, Nostalghia, The Sacrifice) as well as on his writings, we are going to question and discuss the russian director's take on scenery and landscapes and their connections to time throughout his works.It is a commonly agreed fact among studies about Tarkovsky that his first five movies embody the russian landscape and that Nostalghia expresses – to a certain extent – the pain of existing in other landscapes, and that The Sacrifice provides a sense of reunion with the vast landscapes that were there before the filmmaker's exile. Nevertheless, this requires to be put in perspective through a thorough analysis of the technics used to film said landscapes whether they be russian, italian, or of some other nature.The complexity of the perception of landscapes and scenery requires to take into consideration the already existing theoretical works made on the subject in order to understand their limits and nuances through cinematographic aesthetics. Not only are we trying to point out whether the scenery reflects manhood or if it works the other way around as well, but we also mean to take into consideration how the relationship between the two determines the use and understanding of landscapes and scenery.Therefore, studying Tarkovsky's written and cinematographic works in regard to the different use and undertstanding of time and scenery in western and far eastern cultures in order to establish an interdisciplinary reflection that will not only allow a study of time and scenery in movies but will also provide an update to constantly evolving philosophical and cinematographic perceptions, does make sense

Acute effects of γ-hydroxybutyrate (GHB) : disinhibition of mesolimbic dopamine neurons by specific GIRK subunit assembly

Durant ma thèse, j'ai mené à bien un projet scientifique au sein du laboratoire du Pr. Lüscher. Je me suis intéressé aux mécanismes cellulaires et moléculaires pouvant expliquer les propriétés addictives de certaines substances. Mes recherches se sont concentrées sur l'aire tegmentale ventrale (ATV), une région du mésencéphale riche en neurones dopaminergiques impliqués dans les processus d'addiction. En effet, toutes les drogues dites addictives ciblent spécifiquement cette région du cerveau. Mes travaux consistaient à comprendre et à expliquer comment une de ces substances, l'acide γ-hydroxybutyrique (GHB), ciblait l'ATV. Mes collègues et moi avons donc démontré pour la première fois que le GHB agissait différemment sur les deux types neuronaux existant au sein de l'ATV. En effet, le couplage entre le récepteur du GHB (le récepteur GABA[β souscrit]) et ses effecteurs (les canaux potassiques GIRK) varie d'un type cellulaire à l'autre du fait d'une composition en sous-unités GIRK différente

Photodetection and photodynamic treatment of ovarian micrometastases : benefits of hypericin-loaded polymeric nanocarriers

Le photodétection par fluorescence et la thérapie photodynamique, exploitant les propriétés des photosensibilisateurs, sont des méthodes alternatives prometteuses qui pourraient améliorer l'issue thérapeutique de cancers à taux de récidive élevé tel que celui de l'ovaire. Ce travail de thèse s'est focalisé sur la valorisation d'une molécule naturelle extraite du millepertuis ("Hypericum perforatum"), l'hypéricine. Certaines limitations des photosensiblisateurs, comme le manque de sélectivité et les difficultés de formulation, persistent et ralentissent leur développement en clinique. Leur incorporation dans des nanoparticules polymériques a été proposée comme stratégie permettant à la fois l'injection des photosensibilisateurs et l'augmentation de leur sélectivité. L'intérêt des NPs pour l'accumulation sélective dans les tumeurs a été étudié et comparé "in vivo" sur deux modèles, un modèle rongeur classique et la membrane chorioallantoïdienne de l'embryon de poulet. La comparaison des résultats obtenus appuie la pertinence du modèle alternatif aux mammifères, simple et économique pour le criblage de photosensibilisateurs

Nanoparticles for photodynamic therapy of cancer

Currently, the limiting factor in cancer chemotherapy is still the lack of selectivity of anticancer drugs towards neoplastic cells. Photosensitizers (PS), the active com pounds used for photodynamic therapy (PDT), have the intrinsic advantage of dis tributing primarily in highly regenerative tissues after intravenous or topical ad ministration. Therefore, they will accumulate preferentially in tumor tissue when present. In addition, these molecules are inactive as such; indeed, the anticancer effect is only attained after irradiation with light at the right wavelength. Compared to other current cancer therapies such as surgery, radiotherapy or chemotherapy, PDT is an effective and selective means of suppressing diseased tissues without altering the surrounding healthy tissue. It also offers a unique opportunity to reach unseen metastasis. As fluorescent molecules, PS may also be used as a tool, namely photodetection (PD), to reveal tum.or tissues that remain unseen by other conventional methods

Benefits of nanoencapsulation for the hypercin-mediated photodetection of ovarian micrometastases

The high recurrence and lethality of ovarian cancer at advanced stages is problematic, especially due to the development of numerous micrometastases scattered throughout the abdominal cavity. Fluorescence photodetection (PD) used in combination with surgical resection of malignant tissues has been suggested to improve recovery. Based on promising in vivo results for the detection of bladder cancer, hypericin (Hy), a natural photosensitizer (PS), stands as a good candidate for the photodetection of ovarian cancer. However, due to its hydrophobicity, systemic administration of Hy is problematic. Polymeric nanoparticles (NPs) help to overcome these delivery and stability problems and enable intravenous administration of Hy. In this study, Hy-loaded NPs of polylactic acid were produced with the following properties: (i) mean size of 268 nm, (ii) negative zeta potential, (iii) low residual surfactant and (iv) drug loading of 3.7 % (w/w). The potential of hypericin-loaded nanoparticles for the fluorescence photodetection of ovarian metastases in Fischer 344 rats bearing ovarian tumours was compared to free drug. The selectivity of Hy administered with both formulations was assessed first by fluorescence endoscopy, and then quantified after tissue extraction. The results showed an improved selective accumulation of Hy in ovarian micrometastases when NPs were used