• Energy Research

AbstractWith the growth of decentralized/federated analysis approaches in neuroimaging, the opportunities to study brain disorders using data from multiple sites has grown multi-fold. One such initiative is the Neuromark, a fully automated spatially constrained independent component analysis (ICA) that is used to link brain network abnormalities among different datasets, studies, and disorders while leveraging subject-specific networks. In this study, we implement the neuromark pipeline in COINSTAC, an open-source neuroimaging framework for collaborative/decentralized analysis. Decentralized analysis of nearly 2000 resting-state functional magnetic resonance imaging datasets collected at different sites across two cohorts and co-located in different countries was performed to study the resting brain functional network connectivity changes in adolescents who smoke and consume alcohol. Results showed hypoconnectivity across the majority of networks including sensory, default mode, and subcortical domains, more for alcohol than smoking, and decreased low frequency power. These findings suggest that global reduced synchronization is associated with both tobacco and alcohol use. This work demonstrates the utility and incentives associated with large-scale decentralized collaborations spanning multiple sites.

Significance Genetic factors play a major role in the development of human addiction. Identifying these genes and understanding their molecular mechanisms are necessary first steps in the development of targeted therapeutic intervention. Here, we have isolated the gene encoding Ras suppressor 1 (Rsu1) in an unbiased genetic screen for altered ethanol responses in the vinegar fly, Drosophila melanogaster . Our behavioral, genetic, and biochemical experiments show that Rsu1 links signaling from the integrin cell adhesion molecule to the small GTPase Rac1 in adult neurons to regulate actin dynamics and alcohol consumption preference. We also show that variants in human RSU1 associate with altered drinking and brain activation during a reward prediction task, thereby validating the predictive power of our approach.

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 ( RASGRF2 ) gene, encoding a protein that mediates Ca 2+ -dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2 −/− mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2 −/− mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I A potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive–delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

Le trouble de la consommation d'alcool (AUD) est une maladie chronique et mortelle. Le principal obstacle au traitement par AUD est une forte probabilité de rechute à l'abus d'alcool, même après une abstinence prolongée. Les mécanismes moléculaires de la rechute induite par les signaux ne sont pas bien établis, malgré le fait qu'ils peuvent offrir de nouvelles cibles pour le traitement de l'AUD. En utilisant un modèle animal complet d'AUD, des manipulations génétiques à médiation virale et ciblées sur l'amygdale par la technologie CRISPR/Cas9 et l'électrophysiologie ex vivo, nous identifions un mécanisme qui contrôle sélectivement la rechute d'alcool induite par les signaux et la gravité des symptômes d'AUD. Ce mécanisme est basé sur l'activité régulée de la protéine associée au cytosquelette (ARC)/plasticité dépendante de l'Arg3.1 des synapses de l'amygdale. Chez l'homme, nous avons identifié des polymorphismes mononucléotidiques dans le gène ARC et leur méthylation prédisant non seulement la taille de l'amygdale, mais aussi la fréquence de la consommation d'alcool, même au début de la consommation régulière. Cibler l'arc pendant l'exposition à l'alcool peut donc être un nouveau mécanisme sélectif pour la prévention des rechutes. El trastorno por consumo de alcohol (TCA) es una enfermedad crónica y mortal. El principal impedimento de la terapia AUD es una alta probabilidad de recaída en el abuso de alcohol incluso después de una abstinencia prolongada. Los mecanismos moleculares de la recaída inducida por señales no están bien establecidos, a pesar de que pueden ofrecer nuevas dianas para el tratamiento de la AUD. Utilizando un modelo animal integral de AUD, manipulaciones genéticas mediadas por virus y dirigidas a la amígdala mediante tecnología CRISPR/Cas9 y electrofisiología ex vivo, identificamos un mecanismo que controla selectivamente la recaída de alcohol inducida por señales y la gravedad de los síntomas de AUD. Este mecanismo se basa en la actividad regulada de la proteína asociada al citoesqueleto (ARC)/plasticidad dependiente de Arg3.1 de las sinapsis de la amígdala. En humanos, identificamos polimorfismos de un solo nucleótido en el gen ARC y su metilación prediciendo no solo el tamaño de la amígdala, sino también la frecuencia del consumo de alcohol, incluso al inicio del consumo regular. Dirigirse a Arc durante la exposición al alcohol puede ser, por lo tanto, un nuevo mecanismo selectivo para la prevención de recaídas. Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of the AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (Arc)/ARG3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol cue exposure may thus be a selective new mechanism for relapse prevention. Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (arc)/Arg3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol exposure may thus be a selective new mechanism for relapse prevention. اضطراب تعاطي الكحول (AUD) هو مرض مزمن ومميت. العائق الرئيسي لعلاج AUD هو احتمال كبير للانتكاس إلى تعاطي الكحول حتى بعد الامتناع عن ممارسة الجنس لفترات طويلة. الآليات الجزيئية للانتكاس الناجم عن الإشارة ليست راسخة، على الرغم من حقيقة أنها قد تقدم أهدافًا جديدة لعلاج AUD. باستخدام نموذج حيواني شامل من AUD، والتلاعب الجيني بوساطة فيروسية واستهداف اللوزة بواسطة تقنية CRISPR/Cas9 والفسيولوجيا الكهربية خارج الجسم الحي، نحدد آلية تتحكم بشكل انتقائي في انتكاس الكحول الناجم عن الإشارة وشدة أعراض AUD. تعتمد هذه الآلية على البروتين المرتبط بالهياكل الخلوية المنظم للنشاط (ARC )/ اللدونة المعتمدة على Arg3.1 في مشابك اللوزة الدماغية. في البشر، حددنا تعدد أشكال النيوكليوتيدات المفردة في جين القوس وتنبأت مثيلتها ليس فقط بحجم اللوزة، ولكن أيضًا بتكرار تعاطي الكحول، حتى في بداية الاستهلاك المنتظم. وبالتالي، قد يكون استهداف القوس أثناء التعرض للكحول آلية جديدة انتقائية للوقاية من الانتكاس.