Acute or chronic administrations of high doses of ethanol in mice are known to produce severe cognitive deficits linked to hippocampal damage. However, we recently reported that chronic and moderate ethanol intake in C57BL/6J mice induced chromatin remodeling within the Bdnf promoters, leading to both enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal neurogenesis under free-choice protocol. We performed here a series of cellular and behavioral studies to analyze the consequences of these modifications. We showed that a 3-week chronic free-choice ethanol consumption in C57BL/6J mice led to a decrease in DNA methylation of the Bdnf gene within the CA1 and CA3 subfields of the hippocampus, and upregulated hippocampal BDNF signaling pathways mediated by ERK, AKT and CREB. However, this activation did not affect long-term potentiation in the CA1. Conversely, ethanol intake impaired learning and memory capacities analyzed in the contextual fear conditioning test and the novel object recognition task. In addition, ethanol increased behavioral perseveration in the Barnes maze test but did not alter the mouse overall spatial capacities. These data suggested that in conditions of chronic and moderate ethanol intake, the chromatin remodeling leading to BDNF signaling upregulation is probably an adaptive process, engaged via epigenetic regulations, to counteract the cognitive deficits induced by ethanol.

High ethanol intake is well known to induce both anxiolytic and anxiogenic effects, in correlation with chromatin remodeling in the amygdaloid brain region and deficits in cell proliferation and survival in the hippocampus of rodents. Whether only moderate but chronic ethanol intake in C57BL/6J mice could also have an impact on chromatin remodeling and neuroplasticity was addressed here. Chronic ethanol consumption in a free choice paradigm was found to induce marked changes in the expression of genes implicated in neural development and histone post-translational modifications in the mouse hippocampus. Transcripts encoding neural bHLH activators and those from Bdnf exons II, III and VI were upregulated, whereas those from Bdnf exon VIII and Hdacs were downregulated by ethanol compared with water consumption. These ethanol-induced changes were associated with enrichment in both acetylated H3 at Bdnf promoter PVI and trimethylated H3 at PII and PIII. Conversely, acetylated H3 at PIII and PVIII and trimethylated H3 at PVIII were decreased in ethanol-exposed mice. In parallel, hippocampal brain-derived neurotrophic factor (BDNF) levels and TrkB-mediated neurogenesis in the dentate gyrus were significantly enhanced by ethanol consumption. These results suggest that, in C57BL/6J mice, chronic and moderate ethanol intake produces marked epigenetic changes underlying BDNF overexpression and downstream hippocampal neurogenesis.

La consommation chronique et excessive d’ethanol provoque des modifications neurobiologiques adaptatives. Les mecanismes qui les controlent sont multiples et certains ont ete relies a des regulations epigenetiques conduisant a des modifications structurelles et fonctionnelles. L’ethanol induit egalement une neurodegenerescence de l’hippocampe responsable de deficits cognitifs. Parmi l’ensemble des modeles animaux qui sont utilises pour etudier les effets d’une consommation chronique d’alcool, figurent les souris de la lignee C57BL/6J. Ces souris possedent une appetence naturelle pour l’ethanol faisant d’elles un modele de choix pour etudier les consequences de la consommation chronique d’ethanol. Le but de ce travail de these a ete d’etudier les relations entre les mecanismes epigenetiques et la modulation de la neuroplasticite de l’hippocampe a la suite d’une consommation chronique d’ethanol chez les souris C57BL/6J, et d’en evaluer les consequences comportementales. Nous avons montre que la consommation chronique d’ethanol induit, au niveau de l’hippocampe, des modulations epigenetiques globales correlees a un remodelage chromatinien au sein du gene du BDNF, impliquant a la fois les modifications post-traductionnelles des histones et la methylation de l’ADN. Ces modifications epigenetiques sont certainement responsables de l’augmentation d’expression proteique du BDNF observee dans l’hippocampe, et plus particulierement dans le gyrus dente, apres 3 semaines de consommation chronique d’ethanol en libre choix. L’accroissement de l’expression du BDNF induit une stimulation des voies de la signalisation intracellulaire dependantes de l’activation du recepteur TrkB du BDNF, et une augmentation de la neurogenese du gyrus dente. Les effets de l’antagoniste specifique du recepteur TrkB, ANA 12, demontrent que l’augmentation de la neurogenese observee chez les souris C57BL/6J apres la prise chronique d’ethanol, est sous le controle unique du complexe BDNF/TrkB. L’analyse comportementale des souris C57BL/6J ayant consomme de l’ethanol, montre une deterioration des capacites d’apprentissage et de memoire sans modification de la plasticite synaptique dans l’hippocampe, suggerant ainsi que d’autres mecanismes sont impliques dans ces deficits cognitifs. L’ensemble de ces donnees apporte de nouveaux elements de comprehension concernant la stimulation de la neurogenese hippocampique chez les souris C57BL/6J lors d’une consommation chronique en libre choix d’ethanol. Il est probable que cette apparente augmentation de plasticite soit un mecanisme adaptatif et compensatoire a la deterioration des fonctions cognitives induite par une consommation chronique d’alcool.

Stress-induced alterations in neuronal plasticity and in hippocampal functions have been suggested to be involved in the development of mood disorders. In this context, we investigated in the hippocampus the activation of intracellular signaling cascades, the expression of epigenetic markers and plasticity-related genes in a mouse model of stress-induced hyperactivity and of mixed affective disorders. We also determined whether the antidepressant drug agomelatine, a MT1/MT2 melatonergic receptor agonist/5-HT2C receptor antagonist, could prevent some neurobiological and behavioral alterations produced by stress. C57BL/6J mice, exposed for 3 weeks to daily unpredictable socio-environmental stressors of mild intensity, were treated during the whole procedure with agomelatine (50 mg kg−1 per day, intraperitoneal). Stressed mice displayed robust increases in emotional arousal, vigilance and motor activity, together with a reward deficit and a reduction in anxiety-like behavior. Neurobiological investigations showed an increased phosphorylation of intracellular signaling proteins, including Atf1, Creb and p38, in the hippocampus of stressed mice. Decreased hippocampal level of the repressive epigenetic marks HDAC2 and H3K9me2, as well as increased level of the permissive mark H3K9/14ac suggested that chronic mild stress was associated with increased gene transcription, and clear-cut evidence was further indicated by changes in neuroplasticity-related genes, including Arc, Bcl2, Bdnf, Gdnf, Igf1 and Neurod1. Together with other findings, the present data suggest that chronic ultra-mild stress can model the hyperactivity or psychomotor agitation, as well as the mixed affective behaviors often observed during the manic state of bipolar disorder patients. Interestingly, agomelatine could normalize both the behavioral and the molecular alterations induced by stress, providing further insights into the mechanism of action of this new generation antidepressant drug.

The present study was aimed at analyzing the effects of physical exercise on mitochondrial physiology, anxio-depressive-like behaviors and neuroplasticity in mice. Adult C57BL/6J male mice were isolated in home cages equipped or not with free-running wheels. After 6 weeks of exercise, mice were tested in various behavioral paradigms to evaluate anxiety- and depressive-like behaviors. The hippocampi were dissected for neurochemical assays, including mitochondrial activity, monoamines content and the expression of genes involved in energy metabolism and brain-derived neurotrophic factor (BDNF) regulation. Exercise decreased anxiety-like behaviors in the open field and elevated plus maze, and exerted antidepressant-like effects in the tail suspension test. Exercise stimulated brain mitochondrial activity and increased resistance against rotenone, an inhibitor of complex I activity. Furthermore, mRNA expression of Bdnf, Gdnf, Tfam (mitochondrial transcription factor A), and Ndufa6 (mitochondrial I subunit) genes, as well as the phosphorylation of cAMP response element-binding protein were increased after exercise. In summary, exercise appears to engage mitochondrial pathways and to potentiate neuroplasticity and might be associated to mood improvement.