• Energy Research
• 2016-2025close
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AbstractEnergy dissipation through interscapular brown adipose tissue (iBAT) thermogenesis is an important contributor to adaptive energy expenditure. However, it remains unresolved how acute and chronic changes in energy availability are detected by the brain to adjust iBAT activity and maintain energy homeostasis. Here we provide evidence that AGRP inhibitory tone to iBAT represents an energy-sparing circuit that integrates environmental food cues and internal signals of energy availability. We establish a role for the nutrient-sensing mTORC1 signaling pathway within AGRP neurons in the detection of environmental food cues and internal signals of energy availability, and in the bi-directional control of iBAT thermogenesis during nutrient deficiency and excess. Collectively, our findings provide insights into how mTORC1 signaling within AGRP neurons surveys energy availability to engage iBAT thermogenesis, and identify AGRP neurons as a neuronal substrate for the coordination of energy intake and adaptive expenditure under varying physiological and environmental contexts.

Human imaging data suggest that the motivational processes associated with alcohol reward are reflected in the patterns of neural activation after alcohol or alcohol-related cues. In animal models of alcohol drinking, however, the changes in brain activation during voluntary alcohol ingestion are poorly known. In order to improve the translational utility of animal models, we examined alcohol-induced functional brain activation in Alko Alcohol (AA) and Marchigian-Sardinian alcohol-preferring (msP) rats that drink voluntarily high levels of alcohol, but exhibit widely different neurochemical and behavioral traits cosegregated with alcohol preference. Brain imaging was performed using manganese-enhanced MRI (MEMRI), which is based on accumulation of Mn2+ ions in activated neurons, allowing the identification of functional neuronal networks recruited during specific behaviors in awake animals during a subsequent imaging session under anesthesia. MEMRI was performed following 4 weeks of voluntary alcohol drinking, using water drinking as the control. Despite similar levels of alcohol drinking, strikingly different alcohol-induced neuronal activity patterns were observed in AA and msP rats. Overall, functional activation in the AA rats was more widespread, involving large cortical areas and subcortical structures, such as the bed nucleus of the stria terminalis, preoptic area, hypothalamus, periaqueductal grey, and substantia nigra. In the msP rats, however, alcohol-related activation was largely confined to prefrontal cortical regions and insular cortex, and olfactory areas. Overlapping areas of activation found in both rat lines included the nucleus accumbens, prelimbic, orbital, and insular cortex. In conclusion, our data reveal strikingly different brain circuits associated with alcohol drinking in two genetically different rat lines and suggest innately different motivational and behavioral processes driving alcohol drinking. These findings have important implications for the use of these lines in translational alcohol research.

AbstractCondensate formation of biopolymer solutions, prominently those of various intrinsically disordered proteins (IDPs), is determined by “sticky” interactions between associating residues, multivalently present along the polymer backbone. Using a ternary mean field “stickers-and-spacers” model, we demonstrate that if sticker association is of the order of a few times the thermal energy, a delicate balance between specific binding and non-specific polymer-solvent interactions gives rise to a particularly rich ternary phase behavior under physiological circumstances. For a generic system represented by a solution comprising multi-associative scaffold and client polymers, the difference in solvent compatibility between the polymers modulates the nature of isothermal liquid-liquid phase separation (LLPS) between associative and segregative. The calculations reveal regimes of dualistic phase behavior, where both types of LLPS occur within the same phase diagram, either associated with the presence of multiple miscibility gaps, or a flip in the slope of the tie-lines belonging to a single coexistence region.

Abstract Naltrexone (NTX), a homologue of the opiate antidote naloxone, is an orally active long-acting mu-opioid receptor (MOP) antagonist used in the treatment of opiate dependence. NTX is also found to relieve craving for alcohol and is one of the few FDA-approved drugs for alcohol use disorder (AUD). Reports that NTX blocks the actions of endogenous opioids released by alcohol are not convincing, suggesting that NTX interferes with alcohol actions by affecting opioid receptors. MOP and kappa-opioid receptor (KOP) are structurally related but functionally different. MOP is mainly located in interneurons activated by enkephalins while KOP is located in longer projections activated by dynorphins. While the actions of NTX on MOP are well established, the interaction with KOP and addiction is not well understood. We used sensitive fluorescence-based methods to study the influence of alcohol on KOP and the interaction between KOP and NTX. Here we report that alcohol interacts with KOP and its environment in the plasma membrane. These interactions are affected by NTX and are exerted both on KOP directly and on the plasma membrane (lipid) structures (“off-target”). The actions of NTX are stereospecific. Selective KOP antagonists, recently in early clinical trials for major depressive disorder, block the receptor but do not show the full action profile of NTX. The therapeutic effect of NTX treatment in AUD may be due to direct actions on KOP and the receptor environment.

El éxito de las perovskitas orgánico-inorgánicas en optoelectrónica está dictado por la compleja interacción entre varios fenómenos microscópicos subyacentes. Se supone que la dinámica estructural de los cationes orgánicos y la subred inorgánica después de la fotoexcitación tienen un efecto directo sobre las propiedades del material, lo que afecta el rendimiento general del dispositivo. Aquí, utilizamos la espectroscopia electrónica bidimensional (2D) detectada por heterodino ultrarrápida para revelar los modos vibracionales de excitación impulsiva de la perovskita de yoduro de plomo de metilamonio (MA), que impulsan la distorsión estructural después de la fotoexcitación. El análisis vibracional de los datos medidos nos permite monitorear el movimiento libracional evolucionado en el tiempo del catión MA junto con las coherencias vibracionales de la sub-red inorgánica. El análisis de ondículas de las coherencias vibratorias observadas revela la generación coherente del movimiento libracional del catión MA dentro de ~300 fs complementado con la evolución coherente del movimiento esquelético inorgánico. Para racionalizar esta constatación, empleamos los sencillos de interacción de configuración (CIS), que respaldan nuestras observaciones experimentales de la generación coherente de movimientos libracionales en el catión MA y resaltan la importancia de la interacción anarmónica entre el catión MA y la subretícula inorgánica. Además, nuestros cálculos teóricos avanzados predicen la transferencia de la coherencia vibratoria fotoinducida del catión MA a la sub-red inorgánica, lo que lleva a la reorganización de la red para formar un estado polarónico con una larga vida útil. Nuestro estudio descubre la interacción del catión orgánico y la subretícula inorgánica durante la formación del polarón, lo que puede conducir a nuevos principios de diseño para la próxima generación de materiales de células solares de perovskita. Le succès des pérovskites organiques-inorganiques en optoélectronique est dicté par l'interaction complexe entre divers phénomènes microscopiques sous-jacents. La dynamique structurelle des cations organiques et le sous-réseau inorganique après photoexcitation sont supposés avoir un effet direct sur les propriétés du matériau, affectant ainsi la performance globale du dispositif. Ici, nous utilisons la spectroscopie électronique bidimensionnelle (2D) à détection hétérodyne ultra-rapide pour révéler les modes vibratoires excités de manière impulsive de la pérovskite d'iodure de plomb de méthylammonium (MA), qui entraînent la distorsion structurelle après photoexcitation. L'analyse vibratoire des données mesurées nous permet de surveiller le mouvement libratoire du cation MA en fonction du temps ainsi que les cohérences vibratoires du sous-réseau inorganique. L'analyse par ondelettes des cohérences vibrationnelles observées révèle la génération cohérente du mouvement librationnel du cation MA dans ∼300 fs complétée par l'évolution cohérente du mouvement squelettique inorganique. Pour rationaliser cette observation, nous avons utilisé les simples d'interaction de configuration (CIS), qui soutiennent nos observations expérimentales de la génération cohérente de mouvements librationnels dans le cation MA et soulignent l'importance de l'interaction anharmonique entre le cation MA et le sous-réseau inorganique. De plus, nos calculs théoriques avancés prédisent le transfert de la cohérence vibrationnelle photoinduite du cation MA au sous-réseau inorganique, conduisant à la réorganisation du réseau pour former un état polaronique avec une longue durée de vie. Notre étude révèle l'interaction du cation organique et du sous-réseau inorganique lors de la formation du polaron, ce qui peut conduire à de nouveaux principes de conception pour la prochaine génération de matériaux de cellules solaires en pérovskite. The success of organic–inorganic perovskites in optoelectronics is dictated by the complex interplay between various underlying microscopic phenomena. The structural dynamics of organic cations and the inorganic sublattice after photoexcitation are hypothesized to have a direct effect on the material properties, thereby affecting the overall device performance. Here, we use ultrafast heterodyne-detected two-dimensional (2D) electronic spectroscopy to reveal impulsively excited vibrational modes of methylammonium (MA) lead iodide perovskite, which drive the structural distortion after photoexcitation. Vibrational analysis of the measured data allows us to monitor the time-evolved librational motion of the MA cation along with the vibrational coherences of the inorganic sublattice. Wavelet analysis of the observed vibrational coherences reveals the coherent generation of the librational motion of the MA cation within ∼300 fs complemented with the coherent evolution of the inorganic skeletal motion. To rationalize this observation, we employed the configuration interaction singles (CIS), which support our experimental observations of the coherent generation of librational motions in the MA cation and highlight the importance of the anharmonic interaction between the MA cation and the inorganic sublattice. Moreover, our advanced theoretical calculations predict the transfer of the photoinduced vibrational coherence from the MA cation to the inorganic sublattice, leading to reorganization of the lattice to form a polaronic state with a long lifetime. Our study uncovers the interplay of the organic cation and inorganic sublattice during formation of the polaron, which may lead to novel design principles for the next generation of perovskite solar cell materials. إن نجاح البيروفسكايت العضوي غير العضوي في الإلكترونيات البصرية يمليه التفاعل المعقد بين الظواهر المجهرية الكامنة المختلفة. من المفترض أن يكون للديناميكيات الهيكلية للكاتيونات العضوية والشبكة الفرعية غير العضوية بعد الاستثارة الضوئية تأثير مباشر على خصائص المادة، مما يؤثر على الأداء العام للجهاز. هنا، نستخدم التحليل الطيفي الإلكتروني ثنائي الأبعاد (2D) المكتشف من قبل هتروداين فائق السرعة للكشف عن الأنماط الاهتزازية المتحمسة للميثيلامونيوم (MA) بيروفسكايت يوديد الرصاص، والتي تدفع التشوه الهيكلي بعد الإثارة الضوئية. يسمح لنا التحليل الاهتزازي للبيانات المقاسة بمراقبة الحركة المكتبية التي تطورت بمرور الوقت لكاتيون MA جنبًا إلى جنب مع التماسك الاهتزازي للشبكة الفرعية غير العضوية. يكشف تحليل الموجات للترابطات الاهتزازية المرصودة عن التوليد المتماسك للحركة المكتبية لكاتيون MA ضمن 300 قدم مكملة بالتطور المتماسك للحركة الهيكلية غير العضوية. لترشيد هذه الملاحظة، استخدمنا فرادى تفاعل التكوين (CIS)، والتي تدعم ملاحظاتنا التجريبية للجيل المتماسك من الحركات المكتبية في كاتيون MA وتسلط الضوء على أهمية التفاعل اللاانسجامي بين كاتيون MA و sublattice غير العضوي. علاوة على ذلك، تتنبأ حساباتنا النظرية المتقدمة بنقل التماسك الاهتزازي المستحث ضوئيًا من كاتيون MA إلى الشبكة الفرعية غير العضوية، مما يؤدي إلى إعادة تنظيم الشبكة لتشكيل حالة قطبية ذات عمر طويل. تكشف دراستنا عن تفاعل الكاتيون العضوي والشبكة الفرعية غير العضوية أثناء تكوين القطبين، مما قد يؤدي إلى مبادئ تصميم جديدة للجيل القادم من مواد الخلايا الشمسية البيروفسكايتية.

Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Δ9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse.