Inhibition of PI3K-Akt Signaling Blocks Exercise-Mediated Enhancement of Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

Physical exercise has been shown to increase adult neurogenesis in the dentate gyrus and enhances synaptic plasticity. The antiapoptotic kinase, Akt has also been shown to be phosphorylated following voluntary exercise; however, it remains unknown whether the PI3K-Akt signaling pathway is involved in exercise-induced neurogenesis and the associated facilitation of synaptic plasticity in the dentate gyrus.To gain insight into the potential role of this signaling pathway in exercise-induced neurogenesis and LTP in the dentate gyrus rats were infused with the PI3K inhibitor, LY294002 or vehicle control solution (icv) via osmotic minipumps and exercised in a running wheel for 10 days. Newborn cells in the dentate gyrus were date-labelled with BrdU on the last 3 days of exercise. Then, they were either returned to the home cage for 2 weeks to assess exercise-induced LTP and neurogenesis in the dentate gyrus, or were killed on the last day of exercise to assess proliferation and activation of the PI3K-Akt cascade using western blotting.Exercise increases cell proliferation and promotes survival of adult-born neurons in the dentate gyrus. Immediately after exercise, we found that Akt and three downstream targets, BAD, GSK3beta and FOXO1 were activated. LY294002 blocked exercise-induced phosphorylation of Akt and downstream target proteins. This had no effect on exercise-induced cell proliferation, but it abolished most of the beneficial effect of exercise on the survival of newly generated dentate gyrus neurons and prevented exercise-induced increase in dentate gyrus LTP. These results suggest that activation of the PI3 kinase-Akt signaling pathway plays a significant role via an antiapoptotic function in promoting survival of newly formed granule cells generated during exercise and the associated increase in synaptic plasticity in the dentate gyrus

Antibiotic prophylaxis for the prevention of infective endocarditis for dental procedures is not associated with fatal adverse drug reactions in France

One of the major reasons to stop antibiotic prophylaxis (AP) to prevent infective endocarditis (IE) in the United Kingdom but not in the rest of the world was that it would result in more deaths from fatal adverse drug reactions (ADRs) than the number of IE deaths. The main aim of this study was to quantify and describe the ADRs with amoxicillin or clindamycin for IE AP. The second aim was to infer a crude incidence of anaphylaxis associated with amoxicillin for IE AP. The Medical Dictionary for Regulatory Activities (MedDRA) was used to group ADRs for IE AP using the broad Standardized MedDRA Queries ?Anaphylactic reaction, Amoxicillin, Clindamycin, Clostridium Difficile infection? to the French Pharmacovigilance Database System. From this first-line collection, we selected all cases occurring for IE AP and ultimately, the cases for IE AP for a dental procedure. Then, each case was analyzed. Of 11639 first-line recorded ADRs, 100 were for IE AP but no fatal anaphylaxis to amoxicillin or clindamycin and no C. difficile infection associated with clindamycin were identified. Only 17 cases of anaphylaxis to amoxicillin related to dental procedures were highlighted. The estimation of the crude incidence rate of anaphylaxis associated with amoxicillin for IE AP for invasive dental procedure was 1/57 000 (95% CI 0.2-0.6). Fatal or severe ADRs with amoxicillin or clindamycin is not a rational argument to stop IE AP before invasive dental procedures

CRMP5 Regulates Generation and Survival of Newborn Neurons in Olfactory and Hippocampal Neurogenic Areas of the Adult Mouse Brain

The Collapsin Response Mediator Proteins (CRMPs) are highly expressed in the developing brain, and in adult brain areas that retain neurogenesis, ie: the olfactory bulb (OB) and the dentate gyrus (DG). During brain development, CRMPs are essentially involved in signaling of axon guidance and neurite outgrowth, but their functions in the adult brain remain largely unknown. CRMP5 has been initially identified as the target of auto-antibodies involved in paraneoplasic neurological diseases and further implicated in a neurite outgrowth inhibition mediated by tubulin binding. Interestingly, CRMP5 is also highly expressed in adult brain neurogenic areas where its functions have not yet been elucidated. Here we observed in both neurogenic areas of the adult mouse brain that CRMP5 was present in proliferating and post-mitotic neuroblasts, while they migrate and differentiate into mature neurons. In CRMP5−/− mice, the lack of CRMP5 resulted in a significant increase of proliferation and neurogenesis, but also in an excess of apoptotic death of granule cells in the OB and DG. These findings provide the first evidence that CRMP5 is involved in the generation and survival of newly generated neurons in areas of the adult brain with a high level of activity-dependent neuronal plasticity

Olfactory Enrichment Influences Adult Neurogenesis Modulating GAD67 and Plasticity-Related Molecules Expression in Newborn Cells of the Olfactory Bulb

The olfactory bulb (OB) is a highly plastic region of the adult mammalian brain characterized by continuous integration of inhibitory interneurons of the granule (GC) and periglomerular cell (PGC) types. Adult-generated OB interneurons are selected to survive in an experience-dependent way but the mechanisms that mediate the effects of experience on OB neurogenesis are unknown. Here we focus on the new-generated PGC population which is composed by multiple subtypes. Using paradigms of olfactory enrichment and/or deprivation combined to BrdU injections and quantitative confocal immunohistochemical analyses, we studied the effects of olfactory experience on adult-generated PGCs at different survival time and compared PGC to GC modulation. We show that olfactory enrichment similarly influences PGCs and GCs, increasing survival of newborn cells and transiently modulating GAD67 and plasticity-related molecules expression. However, PGC maturation appears to be delayed compared to GCs, reflecting a different temporal dynamic of adult generated olfactory interneuron integration. Moreover, olfactory enrichment or deprivation do not selectively modulate the survival of specific PGC phenotypes, supporting the idea that the integration rate of distinct PGC subtypes is independent from olfactory experience

Cerveau et mémoire : des nouveaux neurones pour se souvenir

Une des caractéristiques fondamentales du cerveau est sa capacité de modifiabilité fonctionnelle et structurale par des mécanismes de plasticité qui sont au cœur de nos fonctions d’apprentissage et de mémoire. Il est aujourd’hui largement admis qu’un des mécanismes fondamentaux de la formation des souvenirs repose sur des modifications acquises de la force synaptique et le remodelage des réseaux de neurones activés par l’apprentissage. De nombreuses études montrent qu’une forme particulièrement durable de plasticité des synapses, connue sous le nom de potentialisation à long terme, ou LTP, et les modifications structurales des réseaux neuronaux qui lui sont associées, jouent un rôle crucial dans la formation de traces mnésiques stables. Au-delà de ces mécanismes de plasticité au niveau de la synapse, la genèse continuelle de nouveaux neurones chez l’adulte est une autre forme de plasticité qui se produit dans certaines aires du cerveau comme le gyrus denté de l’hippocampe. Dans cette revue, sur la base des recherches réalisées dans l’hippocampe, nous résumons les principaux mécanismes de la genèse et de la sélection des nouveaux neurones dans le cerveau adulte ainsi que les données récentes qui montrent que cette forme de plasticité est essentielle à la consolidation de nombreuses formes de mémoire dépendantes des fonctions hippocampiques

The main and accessory olfactory systems of female mice are activated differentially by dominant versus subordinate male urinary odors.

Previous studies have shown that female preferences for male pheromones depend on the female's reproductive condition and the dominance status of the male. However, it is unknown which olfactory system detects the odors that result in a preference for a dominant male. Therefore, in the present study, we asked whether dominant versus subordinate male urinary odors differentially activate the main and accessory olfactory systems in female (C57Bl/6j) mice by monitoring the induction of the immediate early gene, c-fos. A more robust induction of Fos was observed in female mice which had direct nasal contact with dominant male urinary odors in four specific segments of the accessory olfactory system, i.e., the posteroventral part of the medial amygdala, the bed nucleus of the stria terminalis, the medial part of the preoptic nucleus and the ventrolateral part of the ventromedial hypothalamus, compared to females that were exposed to subordinate male urine. This greater activation of the accessory olfactory pathway by dominant male urine suggests that there are differences in the nonvolatile components of dominant versus subordinate male urine that are detected by the vomeronasal organ. By contrast, subordinate male urinary odors induced a greater activation in the piriform cortex which is part of the main olfactory system, suggesting that female mice discriminate between dominant and subordinate male urine using their main olfactory system as well

Mécanismes moléculaires de régulation de la neurogenèse dans le système olfactif de souris adulte

La neurogenèse (prolifération de cellules souches neurales, migration des neuroblastes, différenciation neuronale) persiste tout au long de la vie dans certaines régions du cerveau adulte, dont le bulbe olfactif. L identification des mécanismes moléculaires caractérisant cette neurogenèse adulte ou assurant sa régulation est un objectif important dans le cadre de l étude de la neuroplasticité du cerveau adulte. Les enjeux sont multiples et incluent des développements thérapeutiques potentiels dans le cadre du traitement des pathologies neurodégénératives. Dans un premier temps et en collaboration avec le Centre de Recherche Pierre Fabre, nous avons évalué chez la souris le rôle du système noradrénergique du locus coeruleus dans la neurogenèse du bulbe olfactif adulte. La stimulation de ce système par des antagonistes a2-adrénergiques limite la mort neuronale, l activation gliale et la prolifération induite dans le bulbe olfactif par une axotomie olfactive, confirmant le potentiel neuroprotecteur de cette classe d agents pharmacologiques. Le système noradrénergique du locus coeruleus est également sollicité lorsque des animaux sont soumis à un protocole d enrichissement olfactif (stimulation olfactive quotidienne par un stimulus odorant nouveau). Dans ces conditions, une augmentation du taux de noradrénaline dans le bulbe olfactif est corrélée avec une meilleure survie des neurones néoformés et une amélioration des performances mnésiques olfactives. Toutefois, ces effets ne sont pas supprimés par un traitement chronique au DSP-4, un neurotoxique sélectif des neurones noradrénergiques. Ils sont bloqués, en revanche, par un traitement chronique avec un antagoniste a2 -adrénergique. Ces données confirment l importance du système noradrénergique afférent au bulbe olfactif dans la régulation de la neurogenèse bulbaire, et plus globalement dans la plasticité neuronale caractérisant ce cortex. Cette thèse a ensuite été consacrée à l étude de l implication des CRMPs (Collapsin-response-mediator-proteins) dans la neurogenèse de la souris adulte. Dans la muqueuse et le bulbe olfactif, CRMP 1, 2 et 5 sont exprimées uniquement dans les cellules post-mitotiques du lignage neuronal. On les observe dans les neurones néoformés encore immatures, avec des distributions intracellulaires laissant supposer des implications fonctionnelles distinctes. Lorsque les neurones acquièrent leur phénotype mature, seules CRMP1 et CRMP 2 restent exprimées, avec une localisation différente de celle observée dans les neurones immatures. Enfin, nous avons étudié l implication spécifique de CRMP5 dans la différenciation neuronale au sein de deux zones neurogènes du cerveau adulte, la zone de prolifération sous-ventriculaire du télencéphale et l hippocampe. Dans ces deux régions, CRMP5 est abondante dans les progéniteurs neuronaux. Le blocage in vitro de son expression par des siRNA, au sein de neurosphéres issues de la zone de prolifération sous-ventriculaire du télencéphale, modifie le phénotype des cellules néoformées, indiquant que cette protéine contribue certainement à l orientation des cellules souches vers le phénotype neuronal aux dépens du phénotype glialThe olfactory bulb is the target of neural progenitors produced throughout life in the subventricular zone of the adult forebrain. The identification of molecular mechanisms involved in the control of adult neurogenesis could provide new insights in mechanisms of neuronal plasticity and lay the foundations for potential treatments of neurodegenerative disorders. First, in collaboration with the Centre de Recherche Pierre Fabre, we have assessed in the mouse brain the implication of noradrenergic afferents from the locus coeuruleus in the control of olfactory bulb neurogenesis. Stimulating this system with selective a-2-adrenoceptor antagonists resulted in a decrease of neuronal death, glial activation and cell proliferation induced by a section of the afferent olfactory nerve. The noradrenergic system is also stimulated when animals are submitted to an olfactory enrichment (daily olfactory stimulation with a new odour). Following a long-term olfactory enrichment, the increased noradrenergic release was correlated with a better survival of newborn neurons and enhanced olfactory performances. These effects were not counteracted by a treatment with DSP4, a selective neurotoxin of noradrenergic neurons, but they were suppressed by a pharmacological treatment with an a2-adrenoceptor antagonist. These data support a role of the noradrenergic system in regulating neurogenesis and neuronal plasticity in the olfactory bulb. Then, we have studied the implication of Collapsin Response Mediator Proteins (CRMPs) in the olfactory neurogenesis of the adult mouse. In the olfactory mucosa and bulb, CRMP1, 2 and 5 expressions are restricted to postmitotic cells of the neuronal lineage. In newly generated immature neurons, the selective intracellular distribution of each CRMP suggests differential functional involvements of the members of the family. In mature olfactory neurons, CRMP5 expression is down-regulated while CRMP1, 2 are still expressed but display a new sub-cellular distribution. Finally, we further investigated the specific involvement of CRMP5 in neuronal differentiation, in two neurogenetic areas of adult brain: the forebrain subventricular zone and the dentate gyrus of the hippocampal formation. In both areas, CRMP5 is abundant in neuronal progenitors. The reduction of CRMP5 expression by selective siRNAs in neurospheres influenced the fate of neuronal progenitors by facilating neuronal versus glial differentiationLYON1-BU.Sciences (692662101) / SudocSudocFranceF

The transcription factor zif268/egr1, brain plasticity and memory.

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Noradrenergic control of odor recognition in a nonassociative olfactory learning task in the mouse

The present study examined the influence of pharmacological modulations of the locus coeruleus noradrenergic system on odor recognition in the mouse. Mice exposed to a nonrewarded olfactory stimulation (training) were able to memorize this odor and to discriminate it from a new odor in a recall test performed 15 min later. At longer delays (30 or 60 min), the familiar odor was no longer retained, and both stimuli were perceived as new ones. Following a post-training injection of the α2-adrenoceptor antagonist dexefaroxan, the familiar odor was still remembered 30 min after training. In contrast, both the α2-adrenoceptor agonist UK 14304 and the noradrenergic neurotoxin DSP-4 prevented the recognition of the familiar odor 15 min after the first exposure. Noradrenaline release in the olfactory bulb, assessed by measurement of the extracellular noradrenaline metabolite normetanephrine, was increased by 62% following dexefaroxan injection, and was decreased by 38%–44% after treatment with UK 14304 and DSP-4. Performance of mice in the recall test was reduced by a post-training injection of the β-adrenoceptor antagonist propranolol or the α1-antagonist prazosin, thus implicating a role for β- and α1-adrenoceptors in the facilitating effects of noradrenaline on short-term olfactory recognition in this model