Neurocentre Magendie

Les publications

IF du Neurocentre

666 publications

* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en Juillet 2017

02/03/2018 | Sci Rep   IF 4.3
Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.
Szelechowski M, Amoedo N, Obre E, Leger C, Allard L, Bonneu M, Claverol S, Lacombe D, Oliet S, Chevallier S, Le Masson G, Rossignol R

Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients' skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.

Tobacco use leads to 6 million deaths every year due to severe long-lasting diseases. The main component of tobacco, nicotine, is recognized as one of the most addictive drugs, making smoking cessation difficult, even when 70 percent of smokers wish to do so. Clinical and preclinical studies have demonstrated consistently that nicotine seeking is a complex behavior involving various psychopharmacological mechanisms. Evidence supports that the population of smokers is heterogeneous, particularly as regards the breadth of motives that determine the urge to smoke. Here, we review converging psychological, genetic and neurobiological data from clinical and preclinical studies supporting that the mechanisms controlling nicotine seeking may vary from individual to individual. It appears timely that basic neuroscience integrates this heterogeneity to refine our understanding of the neurobiology of nicotine seeking, as tremendous progress has been made in modeling the various psychopharmacological mechanisms driving nicotine seeking in rodents. For a better understanding of the mechanisms that drive nicotine seeking, we emphasize the need for individual-based research strategies in which nicotine seeking, and eventually treatment efficacy, are determined while taking into account individual variations in the mechanisms of nicotine seeking.

30/01/2018 | Neuroimage   IF 5.8
Deciphering the microstructure of hippocampal subfields with in vivo DTI and NODDI: Applications to experimental multiple sclerosis.
Crombe A, Planche V, Raffard G, Bourel J, Dubourdieu N, Panatier A, Fukutomi H, Dousset V, Oliet S, Hiba B, Tourdias T

The hippocampus contains distinct populations of neurons organized into separate anatomical subfields and layers with differential vulnerability to pathological mechanisms. The ability of in vivo neuroimaging to pinpoint regional vulnerability is especially important for better understanding of hippocampal pathology at the early stage of neurodegenerative disorders and for monitoring future therapeutic strategies. This is the case for instance in multiple sclerosis whose neurodegenerative component can affect the hippocampus from the early stage. We challenged the capacity of two models, i.e. the classical diffusion tensor imaging (DTI) model and the neurite orientation dispersion and density imaging (NODDI) model, to compute quantitative diffusion MRI that could capture microstructural alterations in the individual hippocampal layers of experimental-autoimmune encephalomyelitis (EAE) mice, the animal model of multiple sclerosis. To achieve this, the hippocampal anatomy of a healthy mouse brain was first explored ex vivo with high resolution DTI and NODDI. Then, 18 EAE mice and 18 control mice were explored 20 days after immunization with in vivo diffusion MRI prior to sacrifice for the histological quantification of neurites and glial markers in each hippocampal layer. Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) maps were computed from the DTI model while the orientation dispersion index (ODI), the neurite density index (NDI) and the volume fraction of isotropic diffusivity (isoVF) maps were computed from the NODDI model. We first showed in control mice that color-coded FA and ODI maps can delineate three main hippocampal layers. The quantification of FA, AD, RD, MD, ODI, NDI and isoVF presented differences within these 3 layers, especially within the molecular layer of the dentate gyrus which displayed a specific signature based on a combination of AD (or MD), ODI and NDI. Then, the comparison between EAE and control mice showed a decrease of AD (p=0.036) and of MD (p=0.033) selectively within the molecular layer of EAE mice while NODDI indices did not present any difference between EAE and control mice in any layer. Histological analyses confirmed the differential vulnerability of the molecular layer of EAE mice that exhibited decreased dendritic length and decreased dendritic complexity together with activated microglia. Dendritic length and intersections within the molecular layer were independent contributors to the observed decrease of AD (R(2)=0.37 and R(2)=0.40, p<0.0001) and MD (R(2)=0.41 and R(2)=0.42, p<0.0001). We therefore identified that NODDI maps can help to highlight the internal microanatomy of the hippocampus but NODDI still presents limitations in grey matter as it failed to capture selective dendritic alterations occurring at early stages of a neurodegenerative disease such as multiple sclerosis, whereas DTI maps were significantly altered.

24/01/2018 | Neuron   IF 14
Prefrontal-Periaqueductal Gray-Projecting Neurons Mediate Context Fear Discrimination.
Rozeske RR, Jercog D, Karalis N, Chaudun F, Khoder S, Girard D, Winke N, Herry C

Survival critically depends on selecting appropriate defensive or exploratory behaviors and is strongly influenced by the surrounding environment. Contextual discrimination is a fundamental process that is thought to depend on the prefrontal cortex to integrate sensory information from the environment and regulate adaptive responses to threat during uncertainty. However, the precise prefrontal circuits necessary for discriminating a previously threatening context from a neutral context remain unknown. Using a combination of single-unit recordings and optogenetic manipulations, we identified a neuronal subpopulation in the dorsal medial prefrontal cortex (dmPFC) that projects to the lateral and ventrolateral periaqueductal gray (l/vlPAG) and is selectively activated during contextual fear discrimination. Moreover, optogenetic activation and inhibition of this neuronal population promoted contextual fear discrimination and generalization, respectively. Our results identify a subpopulation of dmPFC-l/vlPAG-projecting neurons that control switching between different emotional states during contextual discrimination.

23/01/2018 | Cell Rep   IF 8.3
Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala.
Beyeler A, Chang CJ, Silvestre M, Leveque C, Namburi P, Wildes CP, Tye KM

The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc), medial aspect of the central amygdala (CeM), and ventral hippocampus (vHPC). Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits underlying valence assignment could reveal fundamental principles about emotional processing.

24/11/2017 | cell cycle
Regulation of RNA polymerase III transcription during transformation of human IMR90 fibroblasts with defined genetic elements.
Durrieu-Gaillard S, Dumay-Odelot H, Boldina G, Tourasse NJ, Allard D, Andre F, Macari F, Choquet A, Lagarde P, Drutel G, Leste-Lasserre T, Petitet M, Lesluyes T, Lartigue-Faustin L, Dupuy JW, Chibon F, Roeder RG, Joubert D, Vagner S, Teichmann M

RNA polymerase (Pol) III transcribes small untranslated RNAs that are essential for cellular homeostasis and growth. Its activity is regulated by inactivation of tumor suppressor proteins and overexpression of the oncogene c-MYC, but the concerted action of these tumor-promoting factors on Pol III transcription has not yet been assessed. In order to comprehensively analyse the regulation of Pol III transcription during tumorigenesis we employ a model system that relies on the expression of five genetic elements to achieve cellular transformation. Expression of these elements in six distinct transformation intermediate cell lines leads to the inactivation of TP53, RB1, and protein phosphatase 2A, as well as the activation of RAS and the protection of telomeres by TERT, thereby conducting to full tumoral transformation of IMR90 fibroblasts. Transformation is accompanied by moderately enhanced levels of a subset of Pol III-transcribed RNAs (7SK; MRP; H1). In addition, mRNA and/or protein levels of several Pol III subunits and transcription factors are upregulated, including increased protein levels of TFIIIB and TFIIIC subunits, of SNAPC1 and of Pol III subunits. Strikingly, the expression of POLR3G and of SNAPC1 is strongly enhanced during transformation in this cellular transformation model. Collectively, our data indicate that increased expression of several components of the Pol III transcription system accompanied by a 2-fold increase in steady state levels of a subset of Pol III RNAs is sufficient for sustaining tumor formation.

22/11/2017 | Psychopharmacology (Berl)   IF 3.3
Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice.
Bretin S, Krazem A, Henkous N, Froger-Colleaux C, Mocaer E, Louis C, Perdaems N, Marighetto A, Beracochea D

Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer's disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction.

20/11/2017 | hepatology   IF 13.2
New insights into diagnosis and therapeutic options for proliferative hepatoblastoma.
Hooks KB, Audoux J, Fazli H, Lesjean S, Ernault T, Senant ND, Leste-Lasserre T, Hagedorn M, Rousseau B, Danet C, Branchereau S, Brugieres L, Taque S, Guettier C, Fabre M, Rullier A, Buendia MA, Commes T, Grosset CF, Raymond AA

Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70-80% of patients. However, some important challenges remain in diagnosing high risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of hepatoblastoma tumors have been described, namely C1 and C2; C2 being the subgroup with the poorest prognosis, a more advanced tumor stage and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed but it has not been transferred into clinical routine. To address these issues we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A and C2B, identifiable by a concise four-gene signature: HSD17B6, ITGA6, TOP2A and VIM, with TOP2A being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by RT-qPCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in Fanconi Anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, an FDA-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway associated double-strand DNA repair and significantly impedes HB growth in vivo. In conclusion, the highly proliferating C2A subtype is characterized by TOP2A gene up-regulation and FA pathway activation and HB therapeutic arsenal could include Bortezomib for the treatment of patients with the most aggressive tumors. This article is protected by copyright. All rights reserved.

01/11/2017 | J Clin Invest   IF 12.8
Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages.
Ruiz de Azua I, Mancini G, Srivastava RK, Rey AA, Cardinal P, Tedesco L, Zingaretti CM, Sassmann A, Quarta C, Schwitter C, Conrad A, Wettschureck N, Vemuri VK, Makriyannis A, Hartwig J, Mendez-Lago M, Bindila L, Monory K, Giordano A, Cinti S, Marsicano G, Offermanns S, Nisoli E, Pagotto U, Cota D, Lutz B

Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.

11/2017 | Nat Neurosci   IF 17.8
Synapse-specific astrocyte gating of amygdala-related behavior.
Martin-Fernandez M, Jamison S, Robin LM, Zhao Z, Martin ED, Aguilar J, Benneyworth MA, Marsicano G, Araque A

The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A1 adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A2A receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.