Effets de la L-DOPA, du piribédil et de l'inhibition du VMAT2 sur la neurotoxicité induite par le MPP+ ou la 6-OHDA, chez le rongeur

L'hydroxy-6-dopamine (6-OHDA) et le méthyl-4-phénylpyridinium (MPP+) sont deux neurotoxines qui, injectées chez la souris, induisent une lésion massive (>50%) des neurones dopaminergiques nigro-striataux, constituant ainsi des modèles murins de la maladie de Parkinson. En clinique, la L-DOPA demeure le meilleur traitement symptomatique de cette maladie. Nous avons observé qu'une injection aiguë de L-DOPA chez la souris potentialisait la toxicité induite par la 6-OHDA alors qu'elle prévenait la toxicité induite par la 6-OHDA alors qu'elle prévenait la toxicité induite par le MPP+. Contrairement à la 6-OHDA, le MPP+ n'a pas lésé les neurones noradrénergiques de l'hypothalamus. La réduction d'efficacité de la L-DOPA au cours des années de son utilisation et l'apparition d'effets indésirables a contribué à la prescription d'agonistes dopaminergiques dans les phases précoces de la maladie. Nous avons observé que la co-administration de L-DOPA et d'un agoniste direct des récepteurs dopaminergiques de type D2, le piribédil, ne prévenait pas l'effet potentialisateur exercé par la L-DOPA sur la toxicité induite par la 6-OHDA. Ensuite, nous avons étudié les effets d'une administration aiguë ou chronique, chez le rat ou la souris. Nous n'avons pas trouvé d'effet protecteur du piribédil ; cependant, nous avons observé qu'une administration aiguë de piribédil augmentait le taux de liaison striatale de l'[3H]mazindol. Enfin, en recherchant ce qui pouvait différencier les mécanismes neurotoxiques des deux toxines et expliquer les effets opposés de la L-DOPA, nous avons remarqué l'absence d'études consacrées à la capture vésiculaire de la 6-OHDA. Nous avons montré que la capture vésiculaire de la 6-OHDA, comme celle du MPP+, protégeait les neurones de leur toxicité. Cette dernière étude nous a également permis de montrer qu'une forte hypothermie prévenait à la fois les effets neurotoxiques du MPP+ et ceux de la 6-OHDA.6-hydroxydopamine (6-OHDA)and 1-methyl-4-phenylpiridinium (MPP+) are two neurotoxins which injected in mice, induce marked lesions (>50%)of nigro-striatal dopaminergic neurons, thus constituting murine models of Parkinson's disease. In human, L-DOPA remains the best symptomatic treatment of this disease. We observed that an acute injection of L-DOPA in mice, worsened 6-OHDA induced toxicity while it prevented MPP+ induced toxicity. Contrary to 6-OHDA, MMP+ did not damage hypothalamic noradrenergic neurons?ROUEN-BU Sciences (764512102) / SudocSudocFranceF

Prefrontal high-frequency stimulation prevents sub-conditioning procedure-provoked, but not acute stress-provoked, reemergence of extinguished fear

We have recently shown that post-extinction exposure of rats to a sub-conditioning procedure (SCP, i.e. retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) or to acute stress provokes reemergence of extinguished fear. Furthermore, this SCP effect can be abolished by high-frequency stimulation (HFS) of the medial prefrontal cortex (mPFC), when applied following the SCP. The aim of the present study was to test whether HFS of the mPK is effective in preventing both SCP-induced and acute stress-provoked fear reemergence. Rats implanted with stimulating electrodes in the mPFC were trained to acquire high levels of freezing to conditioned auditory cue. This fear response was then extinguished. Three weeks later, no spontaneous recovery was observed, but rats exposed to either the SCP or acute stress again exhibited high levels of freezing. HFS of the mPFC, applied before provoking fear reemergence, prevented the effects of SCP, but not acute stress. These data suggest that acute stress may have more impact on functions of the mPFC and/or associated structures than a situational reminder of fear conditioning. (C) 2013 Elsevier Inc. All rights reserved

Why considering sexual differences is necessary when studying encephalopathy of prematurity through rodent models

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Low-frequency stimulation of the ventral hippocampus facilitates extinction of contextual fear

International audienceDifficulties to treat fear-associated disorders, including posttraumatic stress disorder, are thought to result from dysfunction in fear extinction learning and/or memory. Animal studies on extinction modulation are therefore promising for the development of new treatments. Recent rat studies, including ones using low-frequency stimulation (LFS), have demonstrated that the ventral hippocampus (VH) modulates extinction memory. The present study explores whether the VH also modulates extinction learning. For this, rats were implanted with stimulating electrodes in the VH and experienced contextual fear conditioning, followed 6 or 24 h later by VH LFS and three sessions of extinction training. We found that, whatever the delay used (6 or 24 h), animals that received VH LFS displayed persistent low levels of freezing from the second extinction session, whereas control rats showed low levels of freezing only during the third session. In animals submitted to a stress condition (provoked by a single inescapable foot-shock followed by three sessions of situational reminders) prior to fear conditioning, VH LFS also reduced freezing levels, which, in contrast, remained high in control rats during the course of extinction training. These data suggest that LFS, targeting the VH, may be useful in reducing fear responses during extinction learning

Time- and sex-dependent efficacy of magnesium sulfate to prevent behavioral impairments and cerebral damage in a mouse model of cerebral palsy

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Experimental and clinical evidence of differential effects of magnesium sulfate on neuroprotection and angiogenesis in the fetal brain

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Prefrontal high-frequency stimulation prevents sub-conditioning procedure-provoked, but not acute stress-provoked, reemergence of extinguished fear

We have recently shown that post-extinction exposure of rats to a sub-conditioning procedure (SCP, i.e. retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) or to acute stress provokes reemergence of extinguished fear. Furthermore, this SCP effect can be abolished by high-frequency stimulation (HFS) of the medial prefrontal cortex (mPFC), when applied following the SCP. The aim of the present study was to test whether HFS of the mPK is effective in preventing both SCP-induced and acute stress-provoked fear reemergence. Rats implanted with stimulating electrodes in the mPFC were trained to acquire high levels of freezing to conditioned auditory cue. This fear response was then extinguished. Three weeks later, no spontaneous recovery was observed, but rats exposed to either the SCP or acute stress again exhibited high levels of freezing. HFS of the mPFC, applied before provoking fear reemergence, prevented the effects of SCP, but not acute stress. These data suggest that acute stress may have more impact on functions of the mPFC and/or associated structures than a situational reminder of fear conditioning. (C) 2013 Elsevier Inc. All rights reserved

Post-extinction fluoxetine treatment prevents stress-induced reemergence of extinguished fear

The post-extinction exposure of rats to a sub-conditioning procedure (SCP; i.e., retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) has been reported to provoke the reemergence of extinguished fear. This phenomenon can be prevented by chronic fluoxetine treatment. We sought to examine another potential inducer of fear reemergence, acute stress, in rats and determine whether fluoxetine prevents this phenomenon. Because in previous studies fluoxetine was administered before extinction, we first analyzed its effect on the SCP-associated reemergence of auditory-cued conditioned fear in rats injected after extinction to avoid any interaction between fluoxetine and extinction learning. Next, we used the same protocol but replaced the SCP with acute stress. We found that the SCP and acute stress, which were carried out 3 weeks after fear extinction, similarly provoked the reemergence of extinguished fear in rats injected with vehicle during the 3-week period. In contrast, the animals treated with fluoxetine during this period behaved similarly to those not exposed to an inducer of fear reemergence. Our data establish acute stress as an inducer of fear reemergence. The results provide further support for the hypothesis that fluoxetine interfered with mechanisms that reactivated extinguished fear, even when administered after fear extinction

In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning

International audienceIn utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD). In addition, the vascular system is known to contribute to controlling gamma-aminobutyric acid (GABA)ergic interneuron migration in the developing neocortex. Thus, alcohol-induced vascular dysfunction may contribute to the neurodevelopmental defects in FASD. The present study aimed at investigating the effects of alcohol on endothelial activity of pial microvessels. Ex vivo experiments on cortical slices from mouse neonates revealed that in endothelial cells from pial microvessels acute alcohol exposure inhibits both glutamate-induced calcium mobilization and activities of matrix metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA). The inhibitory effect of alcohol on glutamate-induced MMP-9 activity was abrogated in tPA-knockout and Grin1flox/VeCadcre mice suggesting that alcohol interacts through the endothelial NMDAR/tPA/MMP-9 vascular pathway. Contrasting with the effects from acute alcohol exposure, in mouse neonates exposed to alcohol in utero during the last gestational week, glutamate exacerbated both calcium mobilization and endothelial protease activities from pial microvessels. This alcohol-induced vascular dysfunction was associated with strong overexpression of the N-methyl-d-aspartate receptor subunit GluN1 and mispositioning of the Gad67-GFP interneurons that normally populate the superficial cortical layers. By comparing several human control fetuses with a fetus chronically exposed to alcohol revealed that alcohol exposure led to mispositioning of the calretinin-positive interneurons, whose density was decreased in the superficial cortical layers II-III and increased in deepest layers. This study provides the first mechanistic and functional evidence that alcohol impairs glutamate-regulated activity of pial microvessels. Endothelial dysfunction is characterized by altered metalloproteinase activity and interneuron mispositioning, which was also observed in a fetus with fetal alcohol syndrome. These data suggest that alcohol-induced endothelial dysfunction may contribute in ectopic cortical GABAergic interneurons, that has previously been described in infants with FASD