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Targeting the oxytocin (OXT) peptide system has emerged as a promising new approach for the treatment of alcohol use disorder (AUD). However, further advancements in this development depend on properly modeling various complex social aspects of AUD and its treatment. Here we examined behavioral and molecular underpinnings of OXT receptor (OXTR) agonism in prairie voles, a rodent species with demonstrated translational validity for neurobiological mechanisms regulating social affiliations. To further improve translational validity of these studies, we examined effects of intranasal (IN) OXT administration in male and female prairie voles socially housed in the presence of untreated cagemates. IN OXT selectively inhibited alcohol drinking in male, but not female, animals. Further, we confirmed that exogenously administered OXT penetrates the prairie vole brain and showed that Receptor for Advanced Glycation End-products assists this penetration after IN, but not intraperitoneal (IP), OXT administration. Finally, we demonstrated that IP administration of LIT-001, a small-molecule OXTR agonist, inhibits alcohol intake in male, but not female, prairie voles socially housed in the presence of untreated cagemates. Taken together, results of this study support the promise of selectively targeting OXTR for individualized treatment of AUD.

Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen occurred via rapid signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking. Thus, this study demonstrates a rapid, nongenomic signaling mechanism for ovarian-derived estrogen in the brain controlling behavior in gonadally intact females. Early alcohol drinking confers greater risk for alcohol use disorder in women than men. Here authors show that ovarian-derived estrogen rapidly drives binge alcohol drinking via signaling with membrane-associated estrogen receptors in the extended amygdala.

Immunoassays have been the preferred method for steroid hormone analysis for more than 50 years. Automated immunoassays (AIAs) offer high throughput, rapid data turnaround, and low cost for measuring steroid hormone concentrations. The application of liquid chromatography–tandem mass spectrometry (LC-MS/MS) for steroid quantification provides greater specificity and selectivity for individual steroids, the ability to simultaneously analyze multiple steroids, and high throughput and automation. We compared AIA and LC-MS/MS for analysis of 17beta-estradiol (E2) and progesterone (P4) over the course of several menstrual cycles in 12 rhesus macaques (Macaca mulatta). Serum samples were collected every 4 days across four menstrual cycles from each monkey. AIAs were performed on a Roche cobas e411 analyzer. LC-MS/MS analysis was performed on a Shimadzu-Nexera-LCMS-8060 instrument. Scatter plots with Passing–Bablok regression showed excellent agreement between AIA and LC-MS/MS for both E2 and P4. Bland–Altman plots revealed no bias for either method; however, AIA overestimated E2 at concentrations >140 pg/ml and underestimated P4 at concentrations >4 ng/ml compared to LC-MS/MS. A comparison of testosterone concentrations measured by AIA and LC-MS/MS in the same samples was also performed. In contrast to E2 and P4, AIA and LC-MS/MS yielded significantly different results for testosterone concentrations, with AIA consistently underestimating concentrations relative to those obtained by LC-MS/MS. Well-characterized automated immunoassays are an excellent tool for daily monitoring of monkey menstrual cycles or providing single data points requiring fast turnaround. In certain situations where AIAs may provide inaccurate estimations of E2 and P4 concentrations, LC-MS/MS assays are preferable. Well-characterized automated immunoassays are an excellent tool for daily monitoring of monkey menstrual cycles or providing single data points requiring fast turnaround.

Chemosynthetic sediment and planktonic community composition and sizes, aqueous geochemistry and sediment mineralogy were determined in 15 non-photosynthetic hot springs in Yellowstone National Park (YNP). These data were used to evaluate the hypothesis that differences in the availability of dissolved or mineral substrates in the bulk fluids or sediments within springs coincides with ecologically differentiated microbial communities and their populations. Planktonic and sediment-associated communities exhibited differing ecological characteristics including community sizes, evenness and richness. pH and temperature influenced microbial community composition among springs, but within-spring partitioning of taxa into sediment or planktonic communities was widespread, statistically supported (P < 0.05) and could be best explained by the inferred metabolic strategies of the partitioned taxa. Microaerophilic genera of the Aquificales predominated in many of the planktonic communities. In contrast, taxa capable of mineral-based metabolism such as So oxidation/reduction or Fe-oxide reduction predominated in sediment communities. These results indicate that ecological differentiation within thermal spring habitats is common across a range of spring geochemistry and is influenced by the availability of dissolved nutrients and minerals that can be used in metabolism. The presence of minerals, such as elemental sulfur, that can support microbial metabolism promotes the ecological differentiation of sediment- and planktonic-associated microbial populations within Yellowstone National Park hot springs. Graphical Abstract Figure. The presence of minerals, such as elemental sulfur, that can support microbial metabolism promotes the ecological differentiation of sediment- and planktonic-associated microbial populations within Yellowstone National Park hot springs.

The syntheses, spectroscopic characteristics, and electrochemical behavior of 1,1-dimethyl-2,5-diphenyl-3,4-bis( p -methylphenyl)silole and 1,1-dimethyl-2,3,4,5-tetra( p -methylphenyl)silole are reported. The compounds are weakly luminescent in dilute fluid solution but exhibit dramatic aggregation-induced emission (AIE). Absorbance, luminescence, and voltammetric characteristics are compared to 1,1-dimethyl-2,3,4,5-tetraphenylsilole and 1,1-dimethyl-3,4-diphenyl-2,5-bis( p -methylphenyl)silole, allowing a comparison of the effects of the position of the substituents on the silole ring. In addition, HOMO and LUMO energies and band gaps, derived from electrochemical, spectroscopic, and computational data, are reported. Substitution of the weakly electron-donating p -methyl groups on the peripheral aryl groups at the 2- and 5-positions of the silole ring results in slight red shifts in absorption and emission maxima, slight enhancement of luminescence quantum yields, slightly longer luminescence lifetimes, and more anodic oxidation potentials.

Ovarian-derived estrogen is a key modulator of numerous physiological processes via genomic and nongenomic mechanisms, including signaling non-canonically at membrane-associated estrogen receptors in the brain to rapidly regulate neuronal function. However, the mechanisms mediating estrogen regulation of behaviors such as alcohol consumption remain unclear. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen levels, but a causal role for estrogen signaling in driving alcohol drinking in gonadally-intact animals has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance behavior when circulating estrogen was high during the proestrus phase of the estrous cycle than when it was low, contributing to sex differences in these behaviors. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen state occurred via rapid estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking behavior. This study is the first to demonstrate a rapid, nongenomic signaling mechanism for ovarian-derived estrogen signaling in the brain controlling behavior in gonadally intact females, and it establishes a causal role for estrogen in an intact hormonal context for driving alcohol consumption that contributes to known sex differences in this behavior.