Scalable CIGS Solar Cells Employing a New Device Design of Nontoxic Buffer Layer and Microgrid Electrode.

The efficiency of copper indium gallium selenide (CIGS) solar cells that use transparent conductive oxide (TCO) as the top electrode decreases significantly as the device area increases owing to the poor electrical properties of TCO. Therefore, high-efficiency, large-area CIGS solar cells require the development of a novel top electrode with high transmittance and conductivity. In this study, a microgrid/TCO hybrid electrode is designed to minimize the optical and resistive losses that may occur in the top electrode of a CIGS solar cell. In addition, the buffer layer of the CIGS solar cells is changed from the conventional CdS buffer to a dry-processed wide-band gap ZnMgO (ZMO) buffer, resulting in increased device efficiency by minimizing parasitic absorption in the short-wavelength region. By optimizing the combination of ZMO buffer and the microgrid/TCO hybrid electrode, a device efficiency of up to 20.5% (with antireflection layers) is achieved over a small device area of 5 mm × 5 mm (total area). Moreover, CIGS solar cells with an increased device area of up to 20 mm × 70 mm (total area) exhibit an efficiency of up to 19.7% (with antireflection layers) when a microgrid/TCO hybrid electrode is applied. Thus, this study demonstrates the potential for high-efficiency, large-area CIGS solar cells with novel microgrid electrodes.

Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy.

We previously reported altered neuronal Ca 2+ dynamics in the motor cortex of 12-month-old JNPL3 tauopathy mice during quiet wakefulness or forced running, with a tau antibody treatment significantly restoring the neuronal Ca 2+ activity profile and decreasing pathological tau in these mice 1 . Whether neuronal functional deficits occur at an early stage of tauopathy and if tau antibody treatment is effective in younger tauopathy mice needed further investigation. In addition, neuronal network activity and neuronal firing patterns have not been well studied in behaving tauopathy models. In this study, we first performed in vivo two-photon Ca 2+ imaging in JNPL3 mice in their early stage of tauopathy at 6 months of age, compared to 12 month old mice and age-matched wild-type controls to evaluate neuronal functional deficits. At the animal level, frequency of neuronal Ca 2+ transients decreased only in 6 month old tauopathy mice compared to controls, and only when animals were running on a treadmill. The amplitude of neuronal transients decreased in tauopathy mice compared to controls under resting and running conditions in both age groups. Total neuronal activity decreased only in 6 month old tauopathy mice compared to controls under resting and running conditions. Within either tauopathy or wild-type group, only total activity decreased in older wild-type animals. The tauopathy mice at different ages did not differ in neuronal Ca 2+ transient frequency, amplitude or total activity. In summary, neuronal function did significantly attenuate at an early age in tauopathy mice compared to controls but interestingly did not deteriorate between 6 and 12 months of age. A more detailed populational analysis of the pattern of Ca 2+ activity at the neuronal level in the 6 month old cohort confirmed neuronal hypoactivity in layer 2/3 of primary motor cortex, compared to wild-type controls, when animals were either resting or running on a treadmill. Despite reduced activity, neuronal Ca 2+ profiles exhibited enhanced synchrony and dysregulated responses to running stimulus. Further ex vivo electrophysiological recordings revealed reduction of spontaneous excitatory synaptic transmission onto and in pyramidal neurons and enhanced excitability of inhibitory neurons in motor cortex, which were likely responsible for altered neuronal network activity in this region. Lastly, tau antibody treatment reduced pathological tau and gliosis partially restored the neuronal Ca 2+ activity deficits but failed to rescue altered network changes. Taken together, substantial neuronal and network dysfunction occurred in the early stage of tauopathy that was partially alleviated with acute tau antibody treatment, which highlights the importance of functional assessment when evaluating the therapeutic potential of tau antibodies. Highlights: Layer 2/3 motor cortical neurons exhibited hypofunction in awake and behaving mice at the early stage of tauopathy.Altered neuronal network activity disrupted local circuitry engagement in tauopathy mice during treadmill running.Layer 2/3 motor cortical neurons in tauopathy mice exhibited enhanced neuronal excitability and altered excitatory synaptic transmissions.Acute tau antibody treatment reduced pathological tau and gliosis, and partially restored neuronal hypofunction profiles but not network dysfunction.

HRAS-Mutant Cardiomyocyte Model of Multifocal Atrial Tachycardia.

BACKGROUND: Germline HRAS gain-of-function pathogenic variants cause Costello syndrome (CS). During early childhood, 50% of patients develop multifocal atrial tachycardia, a treatment-resistant tachyarrhythmia of unknown pathogenesis. This study investigated how overactive HRAS activity triggers arrhythmogenesis in atrial-like cardiomyocytes (ACMs) derived from human-induced pluripotent stem cells bearing CS-associated HRAS variants. METHODS: HRAS Gly12 mutations were introduced into a human-induced pluripotent stem cells-ACM reporter line. Human-induced pluripotent stem cells were generated from patients with CS exhibiting tachyarrhythmia. Calcium transients and action potentials were assessed in induced pluripotent stem cell-derived ACMs. Automated patch clamping assessed funny currents. HCN inhibitors targeted pacemaker-like activity in mutant ACMs. Transcriptomic data were analyzed via differential gene expression and gene ontology. Immunoblotting evaluated protein expression associated with calcium handling and pacemaker-nodal expression. RESULTS: ACMs harboring HRAS variants displayed higher beating rates compared with healthy controls. The hyperpolarization activated cyclic nucleotide gated potassium channel inhibitor ivabradine and the Nav1.5 blocker flecainide significantly decreased beating rates in mutant ACMs, whereas voltage-gated calcium channel 1.2 blocker verapamil attenuated their irregularity. Electrophysiological assessment revealed an increased number of pacemaker-like cells with elevated funny current densities among mutant ACMs. Mutant ACMs demonstrated elevated gene expression (ie, ISL1, TBX3, TBX18) related to intracellular calcium homeostasis, heart rate, RAS signaling, and induction of pacemaker-nodal-like transcriptional programming. Immunoblotting confirmed increased protein levels for genes of interest and suppressed MAPK (mitogen-activated protein kinase) activity in mutant ACMs. CONCLUSIONS: CS-associated gain-of-function HRASG12 mutations in induced pluripotent stem cells-derived ACMs trigger transcriptional changes associated with enhanced automaticity and arrhythmic activity consistent with multifocal atrial tachycardia. This is the first human-induced pluripotent stem cell model establishing the mechanistic basis for multifocal atrial tachycardia in CS.

Sex difference in the effect of environmental enrichment on food restriction-induced persistence of cocaine conditioned place preference and mechanistic underpinnings.

Psychosocial and environmental factors, including loss of natural reward, contribute to the risk of drug abuse. Reward loss has been modeled in animals by removal from social or sexual contact, transfer from enriched to impoverished housing, or restriction of food. We previously showed that food restriction increases the unconditioned rewarding effects of abused drugs and the conditioned incentive effects of drug-paired environments. Mechanistic studies provided evidence of decreased basal dopamine (DA) transmission, adaptive upregulation of signaling downstream of D1 DA receptor stimulation, synaptic upscaling and incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in medium spiny neurons (MSNs) of nucleus accumbens (NAc). These findings align with the still evolving 'reward deficiency' hypothesis of drug abuse. The present study tested whether a compound natural reward that is known to increase DA utilization, environmental enrichment, would prevent the persistent expression of cocaine conditioned place preference (CPP) otherwise observed in food restricted rats, along with the mechanistic underpinnings. Because nearly all prior investigations of both food restriction and environmental enrichment effects on cocaine CPP were conducted in male rodents, both sexes were included in the present study. Results indicate that environmental enrichment curtailed the persistence of CPP expression, decreased signaling downstream of the D1R, and decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (EPSCs) in NAc MSNs of food restricted male, but not female, rats. The failure of environmental enrichment to significantly decrease food restriction-induced synaptic insertion of CP-AMPARs, and how this may accord with previous pharmacological findings that blockade of CP-AMPARs reverses behavioral effects of food restriction is discussed. In addition, it is speculated that estrous cycle-dependent fluctuations in DA release, receptor density and MSN excitability may obscure the effect of increased DA signaling during environmental enrichment, thereby interfering with development of the cellular and behavioral effects that enrichment produced in males.

Clinical features of COVID-19 among patients with end-stage renal disease on hemodialysis in the context of high vaccination coverage during the omicron surge period: a retrospective cohort study.

BACKGROUND: We determined the clinical presentation and outcomes of the Omicron variant of severe acute respiratory syndrome coronavirus 2 infection in hemodialysis patients and identified the risk factors for severe coronavirus disease (COVID-19) and mortality in the context of high vaccination coverage. METHODS: This was a retrospective cohort study involving hemodialysis patients who were vaccinated against COVID-19 during March-September 2022, when the Omicron variant was predominant, and the COVID-19 vaccination rate was high. The proportion of people with severe COVID-19 or mortality was evaluated using univariate logistic regression. RESULTS: Eighty-three (78.3%) patients had asymptomatic/mild symptoms, 10 (9.4%) had moderate symptoms, and 13 (12.3%) had severe symptoms. Six (5.7%) patients required intensive care admission, two (1.9%) required mechanical ventilation, and one (0.9%) was kept on high-flow nasal cannula. Of the five (4.7%) mortality cases, one was directly attributed to COVID-19 and four to pre-existing comorbidities. Risk factors for both severe COVID-19 and mortality were advanced age; number of comorbidities; cardiovascular diseases; increased levels of aspartate transaminase, lactate dehydrogenase, blood urea nitrogen/creatinine ratio, brain natriuretic peptide, and red cell distribution; and decreased levels of hematocrit and albumin. Moreover, the number of COVID-19 vaccinations wasa protective factor against both severe disease and mortality. CONCLUSIONS: Clinical features of hemodialysis patients during the Omicron surge with high COVID-19 vaccination coverage were significant for low mortality. The risk features for severe COVID-19 or mortality were similar to those in the pre-Omicron period in the context of low vaccination coverage.

Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines.

Transactivating response region DNA binding protein 43 (TDP-43) pathology is prevalent in dementia, but the cell type-specific effects of TDP-43 pathology are not clear, and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimer's disease or frontotemporal dementia have aberrant TDP-43 accumulation in hippocampal astrocytes. In mouse models, induction of widespread or hippocampus-targeted accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines, and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43 dysregulation, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43-linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions.

Atom-Scale Chemistry in Chalcopyrite-Based Photovoltaic Materials Visualized by Atom Probe Tomography.

Chalcopyrite-based materials for photovoltaic devices tend to exhibit complex structural imperfections originating from their polycrystalline nature; nevertheless, properly controlled devices are surprisingly irrelevant to them in terms of resulting device performances. The present work uses atom probe tomography to characterize co-evaporated high-quality Cu(In,Ga)Se2 (CIGS) films on flexible polyimide substrates either with or without doping with Na or doping with Na followed by K via a post-deposition treatment. The intent is to elucidate the unique characteristics of the grain boundaries (GBs) in CIGS, in particular the correlations/anti-correlations between matrix elements and the alkali dopants. Various compositional fluctuations are identified at GBs irrespective of the presence of alkali elements. However, [Cu-poor and Se/In,Ga-rich] GBs are significantly more common than [Cu-rich and Se/In,Ga-poor] ones. In addition, the anti-correlations between Cu and the other matrix elements are found to show not only regular trends among themselves but also the association with the degree of alkali segregation at GBs. The Na and K concentrations exhibited a correlation at the GBs but not in the intragrain regions. Density functional theory calculations are used to explain the compositional fluctuations and alkali segregation at the GBs. Our experimental and theoretical findings not only reveal the benign or beneficial characteristics of the GBs of CIGS but also provide a fundamental understanding of the GB chemistry in CIGS-based materials.

Bidirectional control of infant rat social behavior via dopaminergic innervation of the basolateral amygdala.

Social interaction deficits seen in psychiatric disorders emerge in early-life and are most closely linked to aberrant neural circuit function. Due to technical limitations, we have limited understanding of how typical versus pathological social behavior circuits develop. Using a suite of invasive procedures in awake, behaving infant rats, including optogenetics, microdialysis, and microinfusions, we dissected the circuits controlling the gradual increase in social behavior deficits following two complementary procedures-naturalistic harsh maternal care and repeated shock alone or with an anesthetized mother. Whether the mother was the source of the adversity (naturalistic Scarcity-Adversity) or merely present during the adversity (repeated shock with mom), both conditions elevated basolateral amygdala (BLA) dopamine, which was necessary and sufficient in initiating social behavior pathology. This did not occur when pups experienced adversity alone. These data highlight the unique impact of social adversity as causal in producing mesolimbic dopamine circuit dysfunction and aberrant social behavior.

Insights into High-Efficiency Ag-Alloyed CZTSSe Solar Cells Fabricated through Aqueous Spray Deposition.

Kesterite Cu2ZnSnSe4 (CZTSe), Cu2ZnSn(S,Se)4 (CZTSSe), and Cu2ZnSnS4 (CZTS) solar cells show considerably lower open-circuit voltages than their theoretical values. The large open-circuit voltage deficiency (Vocdef) hinders the improvement of the power conversion efficiency (PCE) and the development of the pathway to mass production of kesterite solar cells. The main reason behind the Vocdef is considered to be the low formation energy of Cu/Zn disorders and their highly distributed defect complexes. To diminish the Cu/Zn disorder, we substituted Ag with a relatively large atomic radius into the host CZTSSe as (AgxCu1-x)2ZnSn(S,Se)4 (ACZTSSe) and investigated its beneficial effect in a systematic way. The ACZTSSe absorbers were all fabricated using aqueous spray pyrolysis in ambient air. The device performance was found to increase up to the optimum Ag substitution and decrease after the optimum Ag substitution. Admittance spectroscopy revealed that the optimal substitution of Ag reduced the Cu-/Zn-related defects, that is, charge recombination centers, which further mitigates the band tailing issue and enhances the PCE of the solar cell, and higher Ag substitution induced the generation of deeper defects, which decreases the PCE back. At the optimum Ag content of Ag/(Ag + Cu) = ∼9%, the ACZTSSe solar cell with the highest PCE of 11.83% was obtained, where both the interface recombination and bulk recombination were found to be minimized.

Publisher Correction: Innate and plastic mechanisms for maternal behaviour in auditory cortex.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Innate and plastic mechanisms for maternal behaviour in auditory cortex.

Infant cries evoke powerful responses in parents1-4. Whether parental animals are intrinsically sensitive to neonatal vocalizations, or instead learn about vocal cues for parenting responses is unclear. In mice, pup-naive virgin females do not recognize the meaning of pup distress calls, but retrieve isolated pups to the nest after having been co-housed with a mother and litter5-9. Distress calls are variable, and require co-caring virgin mice to generalize across calls for reliable retrieval10,11. Here we show that the onset of maternal behaviour in mice results from interactions between intrinsic mechanisms and experience-dependent plasticity in the auditory cortex. In maternal females, calls with inter-syllable intervals (ISIs) from 75 to 375 milliseconds elicited pup retrieval, and cortical responses were generalized across these ISIs. By contrast, naive virgins were neuronally and behaviourally sensitized to the most common ('prototypical') ISIs. Inhibitory and excitatory neural responses were initially mismatched in the cortex of naive mice, with untuned inhibition and overly narrow excitation. During co-housing experiments, excitatory responses broadened to represent a wider range of ISIs, whereas inhibitory tuning sharpened to form a perceptual boundary. We presented synthetic calls during co-housing and observed that neurobehavioural responses adjusted to match these statistics, a process that required cortical activity and the hypothalamic oxytocin system. Neuroplastic mechanisms therefore build on an intrinsic sensitivity in the mouse auditory cortex, and enable rapid plasticity for reliable parenting behaviour.

Optimal CdS Buffer Thickness to Form High-Quality CdS/Cu(In,Ga)Se2 Junctions in Solar Cells without Plasma Damage and Shunt Paths.

CdS has been known to be one of the best junction partners for Cu(In,Ga)Se2 (CIGS) in CIGS solar cells. However, the use of thick CdS buffer decreases the short-circuit current density of CIGS solar cells. There are two obstacles that limit the use of ultrathin CdS. The first is plasma damage to CIGS during the preparation of transparent conducting windows and the second is a low shunt resistance due to the direct contact between the window and CIGS via pinholes in the thin CdS buffer. In other words, to avoid plasma damage and shunt paths, we may have to use a CdS buffer that is thicker than necessary to form a high-quality CdS/CIGS junction. This work aims to determine how thin the CdS buffer can be employed without sacrificing device performance while also eliminating the above two obstacles. We investigate the effect of CdS thickness on the performance of CIGS solar cells with silver nanowire-based window layers, which can eliminate both obstacles. An approximately 13 nm thick CdS buffer allows us to achieve high short-circuit current density and fill factor values. To attain an even high open-circuit voltage, an additional CdS buffer with a thickness of 13 nm is needed. The data from this study imply that an approximately 26 nm thick CdS buffer is sufficient to form a high-quality CdS/CIGS junction.

Broadband Entrainment of Striatal Low-Threshold Spike Interneurons.

Striatal interneurons and spiny projection (SP) neurons are differentially tuned to spectral components of their input. Previous studies showed that spike responses of somatostatin/NPY-expressing low threshold spike (LTS) interneurons have broad frequency tuning, setting these cells apart from other striatal GABAergic interneurons and SP neurons. We investigated the mechanism of LTS interneuron spiking resonance and its relationship to non-spiking membrane impedance resonance, finding that abolition of impedance resonance did not alter spiking resonance. Because LTS interneurons are pacemakers whose rhythmic firing is perturbed by synaptic input, we tested the hypothesis that their spiking resonance arises from their phase resetting properties. Phase resetting curves (PRCs) were measured in LTS interneurons and SP neurons and used to make phase-oscillator models of both cell types. The models reproduced the broad tuning of LTS interneurons, and the differences from SP neurons. The spectral components of the PRC predicted each cell's sensitivity to corresponding input frequencies. LTS interneuron PRCs contain larger high-frequency components than SP neuron PRCs, providing enhanced responses to input frequencies above the cells' average firing rates. Thus, LTS cells can be entrained by input oscillations to which SP neurons are less responsive. These findings suggest that feedforward inhibition by LTS interneurons may regulate SP neurons' entrainment by oscillatory afferents.

Posterior amygdala regulates sexual and aggressive behaviors in male mice.

Sexual and aggressive behaviors are fundamental to animal survival and reproduction. The medial preoptic nucleus (MPN) and ventrolateral part of the ventromedial hypothalamus (VMHvl) are essential regions for male sexual and aggressive behaviors, respectively. While key inhibitory inputs to the VMHvl and MPN have been identified, the extrahypothalamic excitatory inputs essential for social behaviors remain elusive. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the posterior amygdala (PA) as a main source of excitatory inputs to the hypothalamus and key mediators for mating and fighting in male mice. We find two largely distinct PA subpopulations that differ in connectivity, gene expression, in vivo responses and social behavior relevance. MPN-projecting PAEsr1+ cells are activated during mating and are necessary and sufficient for male sexual behaviors, while VMHvl-projecting PAEsr1+ cells are excited during intermale aggression and promote attacks. These findings place the PA as a key node in both male aggression and reproduction circuits.

Fabrication of Robust Nanoscale Contact between a Silver Nanowire Electrode and CdS Buffer Layer in Cu(In,Ga)Se2 Thin-film Solar Cells.

Silver nanowire transparent electrodes have been employed as window layers for Cu(In,Ga)Se2 thin-film solar cells. Bare silver nanowire electrodes normally result in very poor cell performance. Embedding or sandwiching silver nanowires using moderately conductive transparent materials, such as indium tin oxide or zinc oxide, can improve cell performance. However, the solution-processed matrix layers can cause a significant number of interfacial defects between transparent electrodes and the CdS buffer, which can eventually result in low cell performance. This manuscript describes how to fabricate robust electrical contact between a silver nanowire electrode and the underlying CdS buffer layer in a Cu(In,Ga)Se2 solar cell, enabling high cell performance using matrix-free silver nanowire transparent electrodes. The matrix-free silver nanowire electrode fabricated by our method proves that the charge-carrier collection capability of silver nanowire electrode-based cells is as good as that of standard cells with sputtered ZnO:Al/i-ZnO as long as the silver nanowires and CdS have high-quality electrical contact. The high-quality electrical contact was achieved by depositing an additional CdS layer as thin as 10 nm onto the silver nanowire surface.

A Hypothalamic Midbrain Pathway Essential for Driving Maternal Behaviors.

Maternal behaviors are essential for the survival of the young. Previous studies implicated the medial preoptic area (MPOA) as an important region for maternal behaviors, but details of the maternal circuit remain incompletely understood. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the MPOA as key mediators of pup approach and retrieval. Reversible inactivation of MPOAEsr1+ cells impairs those behaviors, whereas optogenetic activation induces immediate pup retrieval. In vivo recordings demonstrate preferential activation of MPOAEsr1+ cells during maternal behaviors and changes in MPOA cell responses across reproductive states. Furthermore, channelrhodopsin-assisted circuit mapping reveals a strong inhibitory projection from MPOAEsr1+ cells to ventral tegmental area (VTA) non-dopaminergic cells. Pathway-specific manipulations reveal that this projection is essential for driving pup approach and retrieval and that VTA dopaminergic cells are reliably activated during those behaviors. Altogether, this study provides new insight into the neural circuit that generates maternal behaviors.

Cell-type-specific resonances shape the responses of striatal neurons to synaptic input.

Neurons respond to synaptic inputs in cell-type-specific ways. Each neuron type may thus respond uniquely to shared patterns of synaptic input. We applied statistically identical barrages of artificial synaptic inputs to four striatal cell types to assess differences in their responses to a realistic input pattern. Each interneuron type fired in phase with a specific input-frequency component. The fast-spiking interneuron fired in relation to the gamma-band (and higher) frequencies, the low-threshold spike interneuron to the beta-band frequencies, and the cholinergic neurons to the delta-band frequencies. Low-threshold spiking and cholinergic interneurons showed input impedance resonances at frequencies matching their spiking resonances. Fast-spiking interneurons showed resonance of input impedance but at lower than gamma frequencies. The spiny projection neuron's frequency preference did not have a fixed frequency but instead tracked its own firing rate. Spiny cells showed no input impedance resonance. Striatal interneurons are each tuned to a specific frequency band corresponding to the major frequency components of local field potentials. Their influence in the circuit may fluctuate along with the contribution of that frequency band to the input. In contrast, spiny neurons may tune to any of the frequency bands by a change in firing rate.

Genetic analysis of the neurosteroid deoxycorticosterone and its relation to alcohol phenotypes: identification of QTLs and downstream gene regulation.

BACKGROUND: Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3α,5α)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence. METHODOLOGY/PRINCIPAL FINDINGS: To systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)×DBA/2J (D2) (BXD) mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p<0.0001) with a heritability of ∼0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p<0.0001) with heritability of ∼0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels across BXD strains were further shown to be co-regulated with networks of genes linked to neuronal, immune, and endocrine function. DOC levels and its responses to dexamethasone were associated with several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories. CONCLUSIONS/SIGNIFICANCE: Both basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. DOC levels were also strongly correlated with networks of genes associated with neuronal function, innate immune pathways, and steroid metabolism, likely linked to behavioral phenotypes.

Differential effects of ethanol on serum GABAergic 3alpha,5alpha/3alpha,5beta neuroactive steroids in mice, rats, cynomolgus monkeys, and humans.

BACKGROUND: Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone-derived neuroactive steroids (3alpha,5alpha)-3-hydroxypregnan-20-one (3alpha,5alpha-THP) and (3alpha,5alpha)-3,21-dihydroxypregnan-20-one (3alpha,5alpha-THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3alpha,5alpha- and 3alpha,5beta-reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography-mass spectrometry. METHODS: Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL/6J and DBA/2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g/kg), cynomolgus monkeys received ethanol (1.5 g/kg) intragastrically, and healthy men consumed a beverage containing 0.8 g/kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans. RESULTS: Ethanol administration to rats increased levels of 3alpha,5alpha-THP, 3alpha,5alpha-THDOC, and pregnenolone at the doses of 1.5 g/kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g/kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g/kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL/6J mice exhibited a 27% decrease in serum 3alpha,5alpha-THP levels (p < 0.01), while DBA/2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g/kg) was observed in men. CONCLUSIONS: These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses.