Noyau accumbens | EPFL Graph Search

Les noyaux accumbens, aussi connus sous le terme latin nucleus accumbens septi (qui signifie noyau appuyé contre le septum), sont un ensemble de neurones situés à l'intérieur de la zone corticale prosencéphalique. Il semble qu'ils jouent un rôle important dans le système de récompense et l'assuétude (accoutumance, dépendance), le rire, le plaisir, la peur et l'effet placebo. C'est une structure symétrique c'est-à-dire que chaque hémisphère cérébral a un noyau accumbens. Il est situé à la rencontre de la pointe du noyau caudé et de la partie antérieure du putamen, latéralement au globus pallidus. Le noyau accumbens et le tubercule olfactif forment ensemble le striatum ventral, qui est une partie des ganglions de la base. Les noyaux accumbens peuvent être divisés en deux structures : le cœur (la partie dorsale, près du dos) et la coquille (shell, la partie ventrale). Ces structures ont des morphologies et des fonctions différentes. Le noyau accumbens est aussi responsable de la dopa

How adeno-associated virus Rep78 relocalises Cdc25B to arrest the cell cycle

Florence Magnin

Adeno-associated virus (AAV) is a small DNA virus belonging to the family of the parvoviridae. AAV infects the human population, however no disease has been associated with this virus. On the contrary, AAV was reported to have oncosuppressive activities. The AAV genome contains two genes: the Rep gene encoding four non-structural proteins (Rep78, 68, 52 and 40) and the Cap gene encoding the three capsid proteins. Rep78 is implicated in transcription, replication and site-specific integration of the viral DNA. It has been shown to block the cell cycle in G1, G2 and S phase with a complete inhibition of DNA synthesis. To be able to induce such a strong cell cycle arrest, Rep78 affects several proteins implicated in the regulation of the cell cycle, such as the family of the cell division cycle 25 (Cdc25) phosphatases. Rep78 has been shown to inactivate Cdc25A by binding to it and preventing it from accessing its substrates. Cdc25B shares conserved domains with Cdc25A and moreover has an important role in cell cycle regulation, especially in giving the signal for entry into mitosis. Thus, in this work, the interaction between Cdc25B and Rep78 was examined in more detail. Rep78 was found to bind to Cdc25B and to alter its intracellular localisation. Cdc25B is nuclear, but has to migrate into the cytoplasm at the end of the G2 phase to activate proteins needed for the entry into mitosis. The expression of Rep78, which is nuclear, leads to the sequestration of Cdc25B in the nucleus. Moreover, Rep78 by interacting with Cdc25B not only changes its localisation, but also inhibits its phosphatase activity. Our model is that Rep78 interacts with Cdc25B and thus retains it in the nucleus. This sequestration of Cdc25B in the nucleus prevents it from activating the proteins in the cytoplasm needed to give the entry signal into mitosis, thus contributing to the G2/M arrest induced by Rep78. Moreover, the inhibition of Cdc25B phosphatase activity by Rep78 may also contribute to the cell cycle block. Rep78 also interacts with a number of cellular proteins implicated in DNA replication, DNA repair or recombination. Interactions between Rep78 and mini-chromosome maintenance 3 (MCM3), DNA polymerases α and δ, proliferating cell nuclear antigen (PCNA), Rad50 and Rad51 were identified in this work as well as possible interactions between Rep78 and Ataxia telangiectasia mutated (ATM) or Ataxia telangiectasia and Rad3 related (ATR) proteins. These interactions may contribute to AAV genome replication as well as its integration into the host DNA.

EPFL2009

Automatic target validation based on neuroscientific literature mining for tractography

Jocelyne Bloch, Jean-Cédric Chappelier, Bogdan Draganski, Sean Lewis Hill, Renaud Luc Richardet, David Slater, Xavier Vasques

Target identification for tractography studies requires solid anatomical knowledge validated by an extensive literature review across species for each seed structure to be studied. Manual literature review to identify targets for a given seed region is tedious and potentially subjective. Therefore, complementary approaches would be useful. We propose to use text-mining models to automatically suggest potential targets from the neuroscientific literature, full-text articles and abstracts, so that they can be used for anatomical connection studies and more specifically for tractography. We applied text-mining models to three structures: two well-studied structures, since validated deep brain stimulation targets, the internal globus pallidus and the subthalamic nucleus and, the nucleus accumbens, an exploratory target for treating psychiatric disorders. We performed a systematic review of the literature to document the projections of the three selected structures and compared it with the targets proposed by text-mining models, both in rat and primate (including human). We ran probabilistic tractography on the nucleus accumbens and compared the output with the results of the text-mining models and literature review. Overall, text-mining the literature could find three times as many targets as two man-weeks of curation could. The overall efficiency of the text-mining against literature review in our study was 98% recall (at 36% precision), meaning that over all the targets for the three selected seeds, only one target has been missed by text-mining. We demonstrate that connectivity for a structure of interest can be extracted from a very large amount of publications and abstracts. We believe this tool will be useful in helping the neuroscience community to facilitate connectivity studies of particular brain regions. The text mining tools used for the study are part of the HBP Neuroinformatics Platform, publicly available at http://connectivity-brainer.rhcloud.com/.

Frontiers Research Foundation2015

The impact of anxiety and reward-seeking traits on social competition and the role of the mesolimbic dopaminergic system

Laura Lozano Montes

Social hierarchies are established across a range of different taxa in the animal kingdom. Given that hierarchy inequalities are highly present in nowadays society and the health problems that low rank individuals suffer from this, it is surprising that not much is known about the underlying neurobiological mechanisms that predispose an individual to become dominant or submissive. We aimed to have a better understanding of personality-related factors (such as anxiety and reward-seeking behaviors) and underlying brain mechanisms that predispose rats to become dominant. We aimed to study the neurobiological mechanisms involved in the modulation of dominance by anxiety. Peripheral injection of anxiolytic drugs has been shown to modulate the dopaminergic mesolimbic system by acting in the GABAergic neurons on the ventral tegmental area (VTA). Our studies specifically targeted GABAergic receptors within the VTA modulating both anxiety and dominance. However, the activation of GABAergic receptors in the nucleus accumbens (NAc) affected dominance but had no effect on anxiety. Furthermore, we found that the NAc is required for the effects of the anxiolytic diazepam on the establishment of social dominance. We assessed potential differences on the accumbal dopaminergic system in relation to anxiety. To this end, we assessed catecholamines levels by high performance liquid chromatography (HPLC) and confirmed the existence of differences in accumbal dopamine content between high and low anxious rats. Subsequently, we showed that pharmacological activation of D1 receptors within the NAc enhanced social dominance. In addition, activation of GABAergic receptors in the VTA, in addition to enhancing social dominance, enhanced the accumbal dopaminergic system. These findings lead us to hypothesize a critical role on the observed behavioral effects for the firing of the VTA dopaminergic neurons that project to the NAc. Subsequently, we investigated the consequences of phasically activating VTA dopaminergic neurons projecting to the NAc in a social competition test. To specifically modulate firing properties of dopaminergic neurons within the VTA of behaving animals, we performed optogenetic activation in TH::Cre rats infused with Cre-dependent virus expressing channelrhodopsin-2 (ChR2). Our results showed that phasic activation of the VTA dopaminergic neurons during the social competition test for palatable rewards was not sufficient to modify the output of the encounters. Winners of the social competition tests were found to have a trend for higher reward-seeking phenotype (lower latencies to get rewards on their last day of individual training) which leads us to subsequently study the role of reward-seeking trait on the rank attained in a social hierarchy. Our data indicates a role for reward-seeking behaviors during last day of individual training (on social competition for palatable rewards test) on the output of several social competition tests. Interestingly, the combination of phasic optical activation of VTA dopaminergic neurons during the last two days of training and during social competition increased dominance. Altogether, our studies have elucidated the effects of anxiety and reward-seeking traits on rat's hierarchy establishment. Furthermore, we were able to modulate the output of a social competition test by optical activations of the mesolimbic dopaminergic system.

EPFL2015