Psychoneuroendocrinology

The present study analyzes the impact of naturalistic stress and emotions on saliva cell-free mitochondrial DNA (cf-mtDNA) in daily life across two independent cohorts with different temporal resolutions. Study 1 examined the interaction between daily stress and major depressive disorder (MDD) on cf-mtDNA in young adults (n= 18, 8 MDD, 10 controls) across four days. For individuals with MDD, stress exposure was associated with a 68% reduction in cf-mtDNA. A higher number or greater severity of stressors also reduced cf-mtDNA by 24 to 27%. Study 2 extended this framework by implementing a finer temporal resolution, measuring saliva and affective states every hour, up to 20 times per day for 2 days (n = 25). Negative emotions, including stress and frustration, were associated with reductions in cf-mtDNA of 15%, whereas positive emotions, such as happiness and calm, predicted increases of up to 28%. The strength and direction of the effects were person- and context-dependent. These findings suggest that cf-mtDNA does not exhibit a uniform stress response in daily life. Instead, it reflects dynamic signaling shaped by timing, emotional context, and diagnostic status. Accordingly, cf-mtDNA should be conceptualized as a dynamic biobehavioral signal rather than a static indicator of between-person differences.

IntroductionAdolescence is a sensitive developmental period during which chronic stress can induce lasting adaptations in corticolimbic circuits involved in stress regulation, cognition, and emotional behavior. We examined the long-term behavioral, endocrine, and molecular consequences of adolescent chronic variable stress (CVS) in male and female rats, focusing on the infralimbic cortex (IL) and basolateral amygdala (BLA) MethodsSprague Dawley rats of both sexes were exposed to CVS during late adolescence and evaluated in adulthood after an extensive recovery period. Behavioral testing included cued fear conditioning and extinction recall, delayed spatial win-shift, novel object recognition, Morris water maze, three-chamber social behavior, and passive avoidance. HPA-axis reactivity to acute restraint was assessed. Targeted qPCR was used to measure stress-related gene expression in the IL and BLA immediately after stress or after a 5-week recovery period ResultsAdolescent CVS did not cause generalized cognitive impairment, but instead produced selective, sex-specific effects. Females had reduced HPA responses to acute stress and mild deficits in delayed spatial win-shift performance, together with long-term IL changes in genes related to adrenergic signaling, plasticity, and GABA clearance. Males showed enhanced Morris water maze probe retention, weaker novel object discrimination, altered passive avoidance with marked inter-individual variability, and enhanced social preference. At the molecular level, males exhibited long-term upregulation of Fkbp5 in IL and downregulation of PACAP, 1D adrenergic receptor, and proenkephalin in BLA, whereas females showed delayed PACAP upregulation in BLA DiscussionAdolescent CVS induces persistent, sex- and region-specific recalibration of corticolimbic function, supporting distinct patterns of vulnerability and resilience, rather than uniform stress pathology.

Despite their prevalence, the pathophysiology of depression and anxiety remains poorly understood. Although adversity is a known risk factor, the mechanisms and biological contexts through which it contributes to mood disorder symptoms remain unclear. Immune and mitochondrial adaptations have both been implicated in mood disorders, suggesting the biological embedding of adversity may involve both systems. However, inconsistencies in the literature remain, partly due to reliance on mixed peripheral blood mononuclear cell (PBMC) populations despite substantial variability in mitochondrial biology across immune cell subtypes. We therefore investigated associations between adversity, mood disorder symptoms, immune cell proportions, and immune cell-specific mitochondrial bioenergetics (enzyme activities and respirometry) in participants from the Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study (n=105, age 18-60, 68% female, 35% with mitochondrial disease). Depressive and anxiety symptoms were positively associated with the monocyte-to-lymphocyte ratio, suggesting a shift toward greater innate relative to adaptive immunity. Associations between mood disorder symptoms and immune cell count were stronger in those exposed to greater early life adversity. Mood disorder symptoms were negatively associated with lymphocyte maximal mitochondrial respiratory capacity (MRC). As expected, the associations between mood disorder symptoms and lymphocyte mitochondrial bioenergetics (enzyme-based MRC and respiratory measurements) were stronger and more consistent among individuals exposed to higher lifetime adversity compared to those with lower lifetime adversity. Overall, these results suggest a complex interplay between adversity, immune cell mitochondrial bioenergetics, and mood disorder symptoms, highlighting immune mitochondrial biology as a potential allostatic pathway linking adversity to psychiatric disorders.

Importance: The menopausal transition is associated with an increased risk of depression. Prior depression is a well-established risk factor, but studies do not distinguish between prior reproductive and non-reproductive depression. Objective: To compare the associations of reproductive (i.e., premenstrual mood disorder and perinatal depression) and non-reproductive (i.e., not related to hormonal transitions) histories of depression with depressive symptoms during the menopausal transition. Design: Cross-sectional analysis of questionnaire data from the Multidisciplinary Menopausal Outpatient Care Project (MOPP) collected between February 2023 and October 2025. Setting: Menopause outpatient clinics Amsterdam, the Netherlands, including a specialized multidisciplinary menopause clinic. Participants: In total 364 individuals were approached; 244 enrolled at baseline. After exclusions for age <40 (n=3), premature ovarian insufficiency (n=2), premenopausal status (n=1), age >58 with final menstruation >10 years earlier (n=12), bipolar disorder (n=5), and missing survey data (n=41), 180 participants were included. Exposures: Premenstrual mood disorder measured with Premenstrual Symptom Screening Tool, perinatal depression with Edinburgh Postnatal Depression Scale Lifetime version, and reported prior non-reproductive depression in medical records. Main outcome and measures: Depressive symptom severity measured with Inventory of Depressive Symptomatology-Self Rated. We used univariable and multivariable linear regressions; multivariable models accounted for overlap between exposures. Results: Among 180 participants (median age 51; 61% perimenopausal and 39% postmenopausal), premenstrual mood disorder showed the strongest association with depressive symptom severity (B = 9.0, 95% CI 5.1-12.9, p < 0.001), followed by perinatal depression (B = 7.8, 95% CI 3.4-12.1, p < 0.001) and prior non-reproductive depression (B = 4.7, 95% CI 0.7-8.7, p = 0.021). In multivariable analysis, only premenstrual mood disorder (B = 7.2, 95% CI 2.4-12.1, p = 0.0037) and perinatal depression (B = 5.7, 95% CI 1.2-10.1, p = 0.013) remained associated with depressive symptom severity. Conclusions and Relevance: Prior reproductive depression, but not prior non-reproductive depression, was associated with greater depressive symptom severity during the menopausal transition. A history of premenstrual mood disorder and/or perinatal depression may therefore help identify individuals at increased vulnerability to depressive symptoms during this period. Future studies should replicate these findings in population-based samples.

Background: Individuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH. Methods: This secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications. Results: A total of 3,934 participants (mean (M) {+/-} standard deviation (SD) age=27.6{+/-}5.6 years) met inclusion criteria with a mean follow-up interval of 3.2{+/-}0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: {beta}=0.06, p<0.01; decreasing severity: {beta}=0.05, p=0.02; increasing severity: {beta}=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24). Discussion: The longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.

The menopausal transition represents a major neuroendocrine shift marked by declining estradiol and progesterone, rising follicle-stimulating hormone, and increased vulnerability to cognitive and affective symptoms. Despite extensive evidence of hormone-related neural changes, few biomarkers directly index hormone-sensitive neuronal adaptations in vivo. Neuron-enriched extracellular vesicles (nEVs) isolated from blood provide a minimally invasive window into central nervous system (CNS) biology by carrying microRNAs (miRNAs) linked to neuronal regulatory processes. This pilot study tested whether L1 cell adhesion molecule (L1CAM)-positive nEV miRNA profiles differ between early (STRAW stage -2; n = 22) and late (STRAW stage -1; n = 24) perimenopause. A pooled discovery screen of 179 miRNAs identified 10 candidates with substantial fold-change differences between groups; these were then quantified at the individual level using qPCR. Linear mixed-effects models showed a significant main effect of STRAW stage, with late perimenopause associated with higher {Delta}Cq values (lower overall expression) across the miRNA panel. The miRNA x STRAW stage interaction was not significant, indicating a coordinated shift across the measured miRNAs rather than miRNA-specific regulation. No evidence of an association between nEV miRNA expression and current estradiol levels or menopausal symptom severity was observed. Bioinformatic analysis of predicted mRNA targets identified significant enrichment of the gonadotropin-releasing hormone (GnRH) receptor pathway, along with related growth factor, immune, and intracellular signaling pathways, with preferential expression in brain-relevant tissues. These findings are consistent with stage-related differences in hormone-sensitive neuronal regulatory processes across the transition.

Polycystic ovary syndrome (PCOS) is characterized by reproductive and metabolic disturbances and is associated with increased symptoms of anxiety and depression. Circulating adiponectin, an insulin-sensitizing adipokine, is reduced in women with PCOS, and low adiponectin has been linked to impaired mental health, particularly in females. We investigated whether low serum adiponectin is associated with impaired mental health in women with PCOS and whether adiponectin deficiency exacerbates anxiety-like behaviour in a PCOS-like mouse model. Serum adiponectin was measured in women with (n=179) and without PCOS (n=228), stratified by body mass index (BMI). Health-related quality of life was assessed using the SF-36, generating physical and mental component scores. In parallel, the prenatal androgenization (PNA) PCOS-like mouse model was combined with adiponectin-deficient mice (APNhet) to assess the impact of reduced adiponectin on anxiety-like behaviour with and without prenatal androgen exposure. Women with PCOS had lower total and high molecular weight adiponectin levels compared with controls. Adiponectin positively correlated with mental component scores in women with BMI <30, but not in those with obesity. Free testosterone was inversely correlated with adiponectin. In mice, PNA induced anxiety-like behaviour, however, reduced adiponectin did not exacerbate this phenotype. Although APNhet PNA mice showed 65% lower serum adiponectin levels and reproductive dysfunction, they displayed improved metabolic function. Unlike women with PCOS, adult PNA mice were not hyperandrogenic. These findings suggest that adiponectin is associated with mental health in non-obese women, but reduced adiponectin alone does not induce anxiety-like behaviour in the absence of hyperandrogenism. The differing patterns observed across BMI categories, as well as between the human cohort and experimental data, underscore the complexity of the mechanisms underlying mental health disturbances in PCOS.

We assessed whether pigs provide consolation, referring to targeted affiliation that attenuates a partners stress, under experimental conditions that manipulated exposure to stressed partners. Using a within-subject design, 74 pigs were tested in three contexts: a helping task in which group members could observe and help a trapped focal pig to return to the group, a direct-reunion, in which group members were naive to the experience of a separated focal pig until reunion, and an undisturbed control. We measured affiliative and non-affiliative interactions, anxiety behaviours and changes in salivary cortisol. Only the helping context satisfied most consolation criteria: there were selective increases in unidirectional affiliative contacts from the observer to the focal pig, non-affiliative interactions remained at baseline, and focal pigs showed fewer anxiety behaviours. In contrast, direct-reunions triggered increases in affiliative and non-affiliative interactions and higher anxiety. Cortisol increased during both direct-reunions and helping, but its level was not linked to affiliation. Results add to growing evidence for consolation behaviour in pigs and suggest best practices for reintegrating pigs into groups. Graded reintroductions that allow observers to assess the emotional state of targets may promote social buffering, whereas abrupt regrouping may trigger more generalized arousal or personal distress.

Cannabis (marijuana) is the most widely used recreational drug in the USA accounting for about 62 million users in 2024. Among cannabis users, 26% are of prime reproductive age (18-25 years). Delta-9 tetrahydrocannabinol (THC) is the principal psychoactive component of cannabis and has been detected in human seminal fluids. Although abundant evidence indicates adverse effects of THC exposure on spermatogenesis in different species, acute effects of THC on postejaculatory sperm including fertilization potential and subsequent carryover effects on embryo development are largely unknown. The present study was designed to provide missing information on structural and mechanistic effects of THC exposure to postejaculatory sperm function by evaluating sperm indices often overlooked or masked during clinical evaluation. A bovine embryo continuum model was employed to determine effects of THC on sperm structure, kinematics, bioenergetics, and binding mechanisms. Effects of THC on the sperm genomic and epigenomic landscape were determined, complemented by paternal carry over effects on embryo development as a human translational model to elucidate paternal effects on future development, and to mirror sperm exposure during transport within the female reproductive tract. Cryopreserved bovine sperm from three bulls were independently exposed to physiologically relevant concentrations of THC (0 and 32nM, n = 2 individual replicates/bull) for 24 h under non-capacitating conditions at 25{degrees}C followed by quantification of sperm kinematics at 37{degrees}C. Samples of THC-exposed sperm and vehicle-control (0.1% DMSO) were collected in replicate following immediate addition of THC (0 h) and again at 24 h. DNA damage, acrosome integrity, bioenergetics, changes to DNA methylation and embryo development were quantified. Data were analyzed by logistic regression with a generalized linear mixed effect model. Computer-assisted sperm assessment revealed a reduction in progressive motility of THC-exposed sperm after 24 h while other parameters were not affected. Acrosome integrity as determined by flowcytometric analysis with FITC-PSA was severely compromised in THC-exposed sperm (P [&le;] 0.05), despite no detectable difference in capacitation status using merocyanine staining. Similarly, DNA integrity as determined by TUNEL assay was significantly impaired after 24 h of THC exposure (P [&le;] 0.05). Mechanistic effects of THC were explored through characterization of the transmembrane G-protein coupled cannabinoid 1 receptor (CB1). CB1 is expressed in the post-acrosomal region and its abundance decreased as compared to unexposed sperm. Alterations to the methylation landscape of sperm were then determined after 24 h of THC exposure through whole-genome Enzymatic Methyl Sequencing. PCA analysis indicated that sperm from different males formed distinct clusters, implying individual differences among bulls, while the effects of THC exposure produced tighter clusters. Paternal carryover effects on embryos derived by in vitro fertilization from THC exposed sperm had reduced 2-cell cleavage, 8-16 cell morula development, and reduced blastocyst development compared to unexposed sperm (46% vs. 33%). In conclusion, post-ejaculatory mammalian sperm exposure to THC compromises acrosome integrity, induces DNA damage, changes the sperm methylome, and reduces developmental potential. Collectively, these data implicate new considerations for recreational and clinical use of cannabis that impact cellular and molecular mechanisms important for sperm function with detrimental consequences for gamete interaction and embryo development.

To attract mating partners, female mammals communicate their reproductive status through one or multiple sensory modalities, providing redundant or complementary information. Chimpanzees (Pan troglodytes) are an excellent model for studying multimodal communication. Exaggerated sexual swellings of females serve as a visual proxy for ovulation but increased male mating interest during maximum swelling suggests that olfactory cues may pinpoint fertility more accurately than the swelling alone. Here, we combined gas chromatography-mass spectrometry, hormonal analyses, and bioassays to examine (1) whether chemical composition of female anogenital odours changes during the fertile period, and (2) whether males are able to detect these changes. Our results suggest that, in addition to prominent olfactory changes associated with swelling stages, chemical cues provide complementary information regarding the timing of the fertile window. These changes, however, are minor compared to those related to swelling stages. Male behavioural responsiveness in bioassays was too low to draw conclusions regarding their ability to detect these subtle shifts when presented with a chemical cue only. Overall, our findings support the existence of a multimodal fertility cue in chimpanzees, wherein visual signals are complemented by subtle olfactory changes indicating the timing of the fertile period.

Pregnancy is accompanied by structural brain remodeling in networks supporting socio-emotional processing and cognitive control. However, it remains unclear whether and how modifiable preconception environments shape individual variability in pregnancy-related brain remodeling, and whether such environment-shaped brain features relate to subsequent maternal and offspring mental health. Here we leverage the Singaporean S-PRESTO preconception cohort, with brain structural MRI acquired before conception (PCV; n = 194) and at 3 months postpartum (PNV; n = 61). Age-related gray matter volume (GMV) trajectories were modeled based on PCV data to derive longitudinal region-wise deviation scores, accounting for normative age trends. Pregnancy-related GMV reductions were found in default mode, frontoparietal control, salience, and limbic networks, as well as hippocampus and caudate. We then identified a multivariate pattern linking preconception lifestyle, sociodemographic, psychological, and social-support variables to GMV within these pregnancy-vulnerable brain regions using partial least squares approach. Specifically, higher preconception brain GMV was associated with more advantaged socioeconomic status, healthier diet, better sleep, non-smoking, stronger social support, and higher conscientiousness/lower neuroticism. This environment-associated brain pattern relates to better maternal executive function, lower depression, anxiety, stress and more favorable metabolic health. Importantly, the same brain resilience pattern also predicted lower postpartum anxiety and fewer offspring internalizing symptoms at age four. Together, these findings implicate modifiable preconception environments in shaping brain structural resilience to pregnancy-related remodelling and highlight preconception as a potential window to promote maternal brain health and positive intergenerational mental health outcomes.

BackgroundMaternal oxycodone (oxy) exposure can disrupt placental function and fetal neurodevelopment, but the molecular mechanisms remain unclear. We investigated whether prenatal oxy exposure activates inflammation and stress response pathways in the placenta and fetal brain, and if maternal melatonin supplementation attenuates these effects. MethodsFemale Sprague-Dawley rats received either saline or oxy via oral gavage for 15 days before mating (10-15mg/kg/day dose escalation) and throughout pregnancy (15mg/kg/day). From gestational day (GD) 12.5, half of the dams received melatonin (10mg/kg/day). On GD 19.5, placental and fetal brain tissues were collected. Changes in expression of markers of oxidative stress, antioxidant defense signaling, inflammation, ER stress, and apoptosis were assessed by western blotting. Data were analyzed by two-way ANOVA with Tukeys post hoc test. ResultsNeither oxy exposure nor melatonin treatment increased markers of oxidative stress or antioxidant defenses in the placenta and fetal brain. Oxy exposure increased placental IL-1{beta} expression but did not alter expression of the other inflammatory markers examined. Oxy increased phosphorylation of eIF2 and increased the phospho-eIF2:eIF2 ratio in the placentas of male fetuses, and fetal brains of both sexes. CHOP expression was increased in the placentas and brains of female, but not male fetuses after oxy exposure. Oxy exposure increased levels of cleaved caspase-3 and cleaved caspase-9 in the fetal brain, but not the placenta; melatonin treatment attenuated the oxy-induced increase in cleaved caspase-9, but not cleaved caspase-3. ConclusionPrenatal oxy exposure induced a modest inflammatory response in the placenta and activated the integrated stress response and intrinsic apoptotic signaling in the fetal brain. Maternal melatonin supplementation partially mitigated the oxy-induced upregulation of caspase-9 but did not prevent stress signaling in either tissue. These findings demonstrate the presence of sex-specific placental and fetal brain responses to prenatal oxy exposure but suggest that melatonin may not provide complete protection against oxy-induced neurodevelopmental impairment.

Background Emerging evidence highlights the gut-brain axis as a key pathway linking diet and anxiety, yet the key determinants remain unclear. Most studies have focused on single components of diet and rarely integrate long- and short-term intake. Furthermore, prior gut-brain work has focused on microbiome composition, while functional features remain underexplored. In this study, we investigated associations between long- and short-term dietary intake, gut microbiome composition and functions, and anxiety in a subclinical cohort of 46 females (18-24 years) from the United Kingdom. Results Long-term diet quality was assessed using the Healthy Eating Index (HEI-2020) derived from a food frequency questionnaire, stratifying participants into lower and higher diet quality clusters. Short-term dietary intake was assessed via 24-hour recalls. Shotgun metagenomics of stool samples was used to assess differences in alpha and beta diversity indices, species abundances, and bacterial pathways putatively metabolizing gut-brain-axis-relevant molecules. Anxiety was measured using the State-Trait Anxiety Inventory (state subscale STAI-s). Regression models identified diet quality (HEI cluster) as the primary dietary feature of anxiety variation. The presence of Ruminococcus gnavus and Flavonifractor plautii and the abundances of Bilophila wadsworthia and Bacteroides thetaiotaomicron were positively associated with anxiety. The presence of Feacalibacterium prausnitzii and greater abundances of butyrate, propionate, and GABA synthesis pathways were inversely associated with anxiety. Non-linear models revealed a U-shaped relationship between inositol synthesis and STAI-s. Finally, we found that habitual diet quality may modulate anxiety-related responses to short-term dietary variation. Conclusions These findings reveal widespread links between long-term diet quality, microbiota composition and function, and anxiety symptoms. These results point towards several promising targets for prebiotic, probiotic, postbiotic, and dietary interventions aimed at reducing anxiety.

BackgroundHormonal transition phases represent windows of increased neuroplasticity across the female lifespan. In this study, we aim to investigate the brain anatomical architecture of hormonal transition phases by directly comparing menarche, as a period of rising levels of steroid hormones, and menopause, as a time of declining levels. MethodsWe fit linear models on cross-sectional and linear mixed-effect models on longitudinal magnetic resonance imaging (MRI) datasets, to explore the effects of menarche onset (ABCD study data, Ncross-sectional=1274, Nlongitudinal=611) and transition into menopause (UK Biobank data, Ncross-sectional=1614, Nlongitudinal=212) on 66 cortical and 135 subcortical brain volumes, and to identify brain structures with opposing but regional overlapping effects in both periods. Models were adjusted for age and corrected for multiple comparison (P <.05; FDR-corrected). ResultsCross-sectionally, using a between-subject design, 83 brain volumes showed effects of menarche-onset and 17 volumes showed effects of menopause-transition. Of these, seven brain volumes were significantly affected by both transitional periods, showing opposing directional volume changes. Longitudinally, using a within-subject design, 56 brain volumes exhibited menarche effects, of which 46 replicated cross-sectionally. No menopause effect survived correction for multiple comparison, likely due to limited longitudinal sample size. ConclusionOur findings confirm regionally overlapping brain structural alteration between the two hormonal phases - menarche and menopause - showing the hypothesized opposite effect directions. Additionally, our results show the robustness of menarche effects, which converged across cross-sectional and longitudinal study designs. Taken together, our results contribute to a better understanding of hormone related neuroplasticity, emphasizing the importance of not only understanding individual phases, but understanding the overarching patterns across the female reproductive lifespan.

Purpose: To evaluate the efficacy and safety of oral L-ergothioneine (EGT) in improving ovarian reserve and clinical symptoms in women with diminished ovarian reserve (DOR). As a proof-ofconcept study, we explored correlations between hormonal shifts and symptom amelioration. Methods: This single-center, open-label trial enrolled 40 women (aged 35-45 years) with DOR (baseline AMH: 1.0-3.0 ng/mL) and menstrual disorders. Participants received oral EGT (120 mg/day) for three consecutive menstrual cycles. The primary outcome was the change in serum AMH. Secondary outcomes included sex hormones (FSH, E2), antral follicle count, and validated clinical questionnaires (modified Kupperman Index [KI], PSQI, SF-36, and Menstrual Symptom Score). Results: Thirty-six participants completed the intervention without product-related adverse events. EGT significantly improved core ovarian markers: mean AMH increased from 1.79 {+/-} 0.71 to 2.47 {+/-} 1.52 ng/mL (p = 0.029). Concurrently, basal FSH decreased (8.22 {+/-} 2.93 to 7.05 {+/-} 2.47 mIU/mL, p = 0.032) and E2 increased (46.00 {+/-} 22.70 to 63.46 {+/-} 50.10 pg/mL, p = 0.030). Clinical assessments showed progressive reductions in KI (5.42 {+/-} 3.66 to 1.90 {+/-} 2.16, p < 0.0001) and PSQI scores (6.89 {+/-} 1.82 to 5.50 {+/-} 1.40, p < 0.0001), alongside improved menstrual and SF-36 scores (p < 0.001). Subgroup analysis revealed upward AMH trends across both the 35-39 and 40-45 age cohorts. Crucially, endocrine restoration ({Delta}FSH) significantly correlated with improvements in sleep quality ({Delta}PSQI, r = 0.43, p < 0.05) and E2 increases (r = -0.46, p < 0.05), linking hormonal stabilization directly to systemic relief. Conclusion: Oral EGT safely enhances serum AMH and optimizes the FSH/E2 balance in women with DOR, yielding substantial relief from peri-menopausal and sleep disturbances. This pilot proofof- concept study provides the first clinical evidence supporting EGT's systemic benefits in reproductive aging, laying the groundwork for future placebo-controlled trials. Trial Registration: ChiCTR2500104484; Prospectively registered on 2025-06-18. Keywords: L-Ergothioneine, diminished ovarian reserve, anti-Mullerian hormone (AMH), oxidative stress, clinical trial

Polycystic Ovarian Syndrome (PCOS) is a complex endocrine disorder characterised by hyperandrogenism, oligo- or anovulation, and polycystic ovaries. Endocrine dysfunction in PCOS disrupts both hormonal and neurotransmitter balance, contributing to the psychological distress frequently reported by affected individuals. Although hormonal imbalances have been associated with memory impairments, their specific contribution to cognitive dysfunction in PCOS remains incompletely understood. In this study, we investigated the impact of PCOS on the hippocampus, a brain region critical for memory formation and highly sensitive to sex steroid modulation. A dehydroepiandrosterone (DHEA)-induced PCOS mouse model was employed to assess anxiety-like behaviour, locomotion, and memory. In the open field test (OFT), DHEA-treated mice spent significantly less time in the central zones and travelled a shorter total distance compared with controls, indicating increased anxiety-like behaviour. DHEA treatment also resulted in significantly impaired performance in both the object location test (OLT) and novel object recognition test (NORT), as reflected by a reduced discrimination index. Analysis of hippocampal immediate early gene expression using qRT-PCR revealed altered transcription of memory-related markers, including downregulation of Npas4 and Grin2a, and upregulation of Grin1, Arc, Egr1, and Egr2. Collectively, these findings suggest that elevated androgen levels induce anxiety- and depression-like behaviours and impair cognitive function, including spatial, recognition, and motor learning abilities, in PCOS. Our results further indicate that disrupted cortex-hippocampus communication may underlie these cognitive deficits, underscoring the importance of evaluating memory and cognitive health in women with PCOS to support brain health and overall well-being.

Women filmed for pornography report extensive abuse and serious health consequences, yet pathways into pornography remain under-examined. Using an embedded qualitative mixed-methods approach, we explored factors shaping these pathways in Sweden. Twenty-five adults (23 women) who had been filmed for pornography completed questionnaires and participated in teller-focused interviews. Informed by a socio-ecological framework, our reflexive thematic analysis generated the global theme Primed for exploitation, comprising three themes: Imprints of early violence, No one has my back: Relational and institutional betrayals, and Compounding structural vulnerabilities. Our findings reveal how childhood abuse and violence, relational and institutional betrayals, material precarity, and a pornified cultural landscape converge to shape pathways into pornography. To prevent and disrupt these pathways, early identification of sexual abuse, timely access to trauma-informed care that avoids individualizing and pathologizing the consequences of violence, and practical support that addresses material precarity are critical. From a socio-ecological perspective, framing entry into pornography as a simple matter of "choice" is fundamentally flawed: it individualizes deeply social processes and obscures the profound impact of cumulative violence, repeated relational and institutional betrayals, and intersecting structural constraints.

Post-traumatic stress disorder (PTSD) has been linked to various alterations within the immune system, yet the metabolic programming of immune cells remains unexplored. In the current cross-sectional study, we interrogated immunometabolic function by applying cell-specific metabolic flow cytometry, serum biomarker profiling, and targeted gene expression analysis in peripheral blood mononuclear cells from patients with PTSD (N=34) compared with healthy controls (N=32). PTSD was associated with higher glycolysis- and oxidative pentose phosphate pathway-related markers across adaptive and innate immune cell subsets, as well as elevated circulating interleukin-6. Expression of inflammatory- and stress-related genes was largely comparable between groups. Together, these data provide preliminary evidence for immunometabolic alterations in PTSD at both cellular and systemic levels. These results could contribute to understanding potential pathophysiological mechanisms and support further investigation of immunometabolism in PTSD.

Chronic psychosocial stress (CPS) is associated with adverse brain and mental health outcomes. Effects on the cerebral microvasculature have been proposed as an underlying mechanism, although this remains to be established. Here, we examined the association between CPS and an early marker of microvascular dysfunction, magnetic resonance imaging (MRI)-visible perivascular spaces (PVS). Analyses were conducted in two cohorts of healthy young adults (N = 61; ages 18-43 years; 88% male) using high-resolution 3T MRI and an automated PVS quantification pipeline. CPS was assessed using the Perceived Stress Scale (PSS-10). We applied a two-step meta-analytic framework and controlled for known allostatic factors impacting PVS, including age, body mass index and mean arterial pressure. In accordance with our hypothesis, individuals with higher CPS had significantly higher fractional PVS volumes in the centrum semiovale (CSO), in particular in the frontal and occipital lobes (pFDR < .05). No such effect was found in the basal ganglia, or in the CSO subdivision, parietal, and temporal lobes (pFDR > .09). Our findings indicate that CPS may contribute to subtle, centrum semiovale specific microvascular alterations even in healthy young adults. Future multimodal research including inflammatory marker and blood-brain barrier measures may help to elucidate mechanistic pathways.

Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.