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AbstractAlcohol exposure during pregnancy disrupts fetal development and programs lifelong disease. We have shown, in rats, that alcohol exposure during the periconceptional period (PC:EtOH), causes placental dysfunction and cardiometabolic disease in offspring. The process of metabolising alcohol can cause oxidative stress and damage mitochondrial DNA (mtDNA). It is unknown whether alcohol metabolism in a rat model of PC:EtOH impacts oxidative stress markers and mitochondrial content in maternal and placental tissues. We aimed to determine whether PC:EtOH induced oxidative stress and reduced mtDNA in maternal liver and the placental labyrinth and junctional zone. Sprague–Dawley rats were given an ethanol liquid (12.5% v/v) or control (0%) diet for one oestrous cycle before mating to embryonic day (E) 4. Maternal livers were collected at E5 and E20. Placentas were collected at E20 and separated into the junctional zone and labyrinth zone. PC:EtOH reduced Cyp2e1 mRNA levels and mtDNA in the E5 liver with lower mtDNA persisting to E20, at which time mitochondrial proteins were also decreased. PC:EtOH also reduced mitochondrial content in the E20 junctional zone, although mitochondrial protein levels were unaffected. Superoxide dismutase activity was increased in the placental junctional zone and there was no evidence of oxidative stress. The present study demonstrates that alcohol exposure around conception, reduces mitochondrial content within the maternal liver and the junctional zone of the placenta towards the end of pregnancy. These prolonged deficits may have disrupted metabolic processes required for a healthy pregnancy. The study further supports avoiding alcohol when planning a pregnancy. imageKey points Even when alcohol is consumed only around conception (PC:EtOH), it can have profound impacts on the developing baby. Here, we use our established rat model to investigate if PC:EtOH causes oxidative stress and reduces mitochondrial content in the maternal liver immediately after exposure on embryonic day (E) 5. We also investigate these parameters at the end of pregnancy (E20) in maternal liver and the placenta. PC:EtOH reduced mitochondrial DNA content in the maternal liver by 77% at E5 and by 40% at E20. At E20, expression of proteins that form the electron transport chain were also reduced. The placenta had a more subtle reduction in mitochondrial DNA content, but protein levels of mitochondrial complexes were unchanged. There was no evidence of oxidative stress in the maternal liver or placenta in response to PC:EtOH. The lack of oxidative stress in the placenta may be a result of compensatory increases in antioxidants.

IntroductionBrain dynamics offer a more direct insight into brain function than network structure, providing a profound understanding of dysregulation and control mechanisms within intricate brain systems. This study investigates the dynamics of functional brain networks in major depressive disorder (MDD) patients to decipher the mechanisms underlying brain dysfunction during depression and assess the impact of repetitive transcranial magnetic stimulation (rTMS) intervention.MethodsWe employed energy landscape analysis of functional magnetic resonance imaging (fMRI) data to examine the dynamics of functional brain networks in MDD patients. The analysis focused on key dynamical indicators of the default mode network (DMN), the salience network (SN), and the central execution network (CEN). The effects of rTMS intervention on these networks were also evaluated.ResultsOur findings revealed notable dynamical alterations in the pDMN, the vDMN, and the aSN, suggesting their potential as diagnostic and therapeutic markers. Particularly striking was the altered activity observed in the dDMN in the MDD group, indicative of patterns associated with depressive rumination. Notably, rTMS intervention partially reverses the identified dynamical alterations.DiscussionOur results shed light on the intrinsic dysfunction mechanisms of MDD from a dynamic standpoint and highlight the effects of rTMS intervention. The identified alterations in brain network dynamics provide promising analytical markers for the diagnosis and treatment of MDD. Future studies should further explore the clinical applications of these markers and the comprehensive dynamical effects of rTMS intervention.

Prenatal ethanol exposure (PE) causes Fetal Alcohol Spectrum Disorders (FASD), characterized by cognitive, behavioral, and emotional deficits, including anxiety and depression. PE-induced alteration in the function of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons is thought to be major contributing factor for increased anxiety. However, the precise neuronal circuits involved are unknown. Using electrophysiology, optogenetics, chemogenetics, and behavioral approaches, we find that PE preferentially potentiates medial prefrontal cortex (mPFC) glutamatergic inputs, but not lateral habenula (LHb), to DRN 5-HT neurons projecting to mPFC. Additionally, PE also increases the strength of LHb but not mPFC excitatory inputs to DRN 5-HT neurons projecting to central amygdala (Ce). This input and target selective effect of PE was mediated by a circuit-specific increase in nitric oxide (NO) signaling. Importantly, chemogenetic inhibition of mPFC-DRN neuronal circuit blunted anxiety-like behaviors in PE rats. As such, our results unraveled the DRN neuronal circuitries affected by PE, which gate FASD-induced anxiety-like behaviors.

Previous electrophysiology studies show that acute ethanol inhibits firing of orbitofrontal (OFC) cortex neurons while chronic intermittent ethanol (CIE) exposure increases firing accompanied by enhanced ethanol drinking. The acute ethanol inhibition of OFC neuronal firing is mediated by inhibitory glycine receptors and is reduced by expressing a plasma membrane calcium ATPase (PMCA) in OFC astrocytes. In this study, we tested the effects of astrocyte PMCA on CIE-induced increases in excitability and alcohol consumption and the physical interaction between OFC astrocytes and neurons. CIE increased neuronal firing in male mice as compared to Air controls while PMCA itself increased firing in Air control male mice. In contrast, PMCA reduced CIE-mediated hyperexcitability of firing in females. CIE did not affect OFC astrocyte size in control or PMCA male mice but increased astrocyte size in female mice. Similar to spiking, PMCA and CIE both increased the number of GluA1 containing synapses within the vicinity of virally labeled astrocytes in male mice but had differential effects in females. The astrocytic interaction with GluA1 labeled synapses was not affected by CIE treatment in male or female control mice, but there was a treatment-dependent effect of PMCA in male mice. CIE increased alcohol consumption in control but not PMCA male mice and had no effect on drinking in female mice. Lastly, OFC astrocyte PMCA expression had no effect on behavioral measures of locomotion, anxiety, spontaneous alternation, or spatial memory. These findings reveal important sex-dependent differences in the physiological, structural and behavioral actions of OFC astrocytes.

The endocannabinoid system is involved in multiple drug-related behaviors and the transient increase in endogenous cannabinoids and endocannabinoid-like molecules contributes to healthy adaptation to stress exposure. Oleoylethanolamide (OEA) belongs to the N-acylethanolamines and interacts with the endocannabinoid system. In this study, we investigated the effect of systemic OEA treatment (10 mg/kg), before or after social defeat (SD), on ethanol self-administration (SA). Mice were divided into non-stressed (EXP) and stressed (SD) groups and randomly assigned to a treatment condition (control-CTRL, OEA or 10OEA). The EXP/SD-OEA group of mice received four doses of OEA before each SD encounter, while mice in the EXP/SD-10OEA group received a daily dose for 10 consecutive days following stress exposure. Three weeks after SD, mice were trained to self-administer a 20 % (vol/vol) ethanol solution. Upon extinction, a cue-induced reinstatement test was performed. Our results showed that both OEA treatments effectively prevented the stress-induced increase in ethanol consumption observed in defeated mice. No significant effects of OEA on relapse-like behavior were observed. Additionally, we found that animals exposed to OEA during SD encounters showed reduced nuclear factor kappa B (NF-κB) levels, suggesting an anti-inflammatory effect of OEA, while tumor necrosis factor (TNFα) gene expression decreased in defeated animals. In summary, these findings suggest that exogenously increasing OEA levels counteracts the adverse effects of stress on ethanol drinking while having some impact on inflammatory patterns.

This paper applies the Phase 4 formulation of the Universal Oscillating Energy (UOE) framework to the case of PKS 1830-211. By replacing gravitational curvature with structured Ξ-field gradients, we reinterpret the Einstein ring as a product of oscillatory identity realignment, not spacetime deformation. The model incorporates dual inflow emergence, angle persistence, and collapse-linked lensing, using field simulations and consistent UOE logic as developed in prior work.

This paper introduces a new theoretical framework for understanding mass emergence, gravitational lensing phenomena, and structured cosmic formation, grounded entirely in oscillatory field dynamics. We propose that the universe’s large-scale structures, localized mass concentrations, and field-induced lensing effects arise naturally from structured oscillations of foundational fields — not from gravitational curvature or hypothetical dark matter components. Centered around a trinary field cascade (Ψ→Φ→Ξ\Psi \to \Phi \to \XiΨ→Φ→Ξ), the framework formalizes how potential oscillations (Ψ\PsiΨ) evolve into transformation fields (Φ\PhiΦ), which stabilize into structured identity fields (Ξ\XiΞ) that govern observable mass and lensing effects. A master action is constructed, incorporating finite collapse damping to ensure ultraviolet completeness without traditional renormalization. Eight derived working laws are presented, covering energy–mass emergence, boundary oscillation stability, curvature thresholds, and oscillatory lensing deflection mechanisms. Early-universe structure formation is hypothesized to proceed via a bifurcation cascade, with critical thresholds encoded by the Feigenbaum constant δF\delta_FδF, offering a structured alternative to standard inflationary exit models. Preliminary simulations demonstrate key UOE behaviors, including oscillatory field lensing consistent with observed cluster anomalies and finite loop corrections matching QED precision tests such as the hydrogen Lamb shift. This work establishes a foundational framework for future explorations into oscillatory-driven cosmology, field-structured emergence, and next-generation experimental tests.

Alcohol impairs motor performance, but it remains unclear precisely why this is the case. Here, we examine the effects of alcohol intoxication on conditioned eyeblink responses, a form of classical conditioning dependent on the cerebellum. In experiment 1, the conditioned responses of 18 students before and after alcohol consumption up to 1 ‰ were compared against the performance of 26 non-drinking controls. In experiment 2, 17 students were tested repeatedly at increasing blood alcohol levels up to 1 ‰. The results reveal a gradual decrease in both the percentage and timing of conditioned responses following alcohol consumption, with pronounced impairments emerging at blood alcohol content levels exceeding 0.5 ‰. These findings are consistent with the idea that the motor deficits associated with alcohol consumption are linked to effects on the cerebellum.