Psychoneuroendocrinology

The prevalence of neurodevelopmental disorders (NDDs) has increased dramatically, with growing evidence linking prenatal maternal stress exposure to NDDs. Across diverse maternal stressors, immune dysregulation emerges as a common feature, suggesting that fetal microglia may detect changes in the intrauterine environment and influence neurodevelopment. Accordingly, we utilized a mouse model of prenatal maternal cold stress to investigate the impact of maternal stress during pregnancy on fetal microglia morphology, cellular interactions, and phagocytic behaviors. Pregnant mice were exposed to cold stress from embryonic day 11.5 (E11.5) to E15.5 and fetal hypothalamic tissue was assessed from both male and female embryos. By adapting the morphology analysis toolset MicrogliaMorphology to assess fetal microglia, we demonstrate regional differences in microglial morphology in the fetal hypothalamus at baseline, with hypothalamic nuclei such as the paraventricular nucleus (PVN) containing fewer rod-like microglia compared to the broader hypothalamus. Interestingly, prenatal maternal cold stress induced a male-specific shift in microglial morphology from ameboid to ramified within the E15.5 PVN. Male embryos also displayed increased microglial-arginine vasopressin (AVP) neuronal interactions and microglial phagocytosis within the E15.5 PVN, but these changes were unique to microglia with a ramified morphology and were not observed when microglia with an ameboid or rod-like morphology were assessed. Using pHrodo bioparticles and flow cytometry, we further illustrate that prenatal maternal cold stress drives increased phagocytic activity in the E15.5 hypothalamus of male embryos, but not females. Together, these data demonstrate that prenatal maternal cold stress alters microglia morphology and drives morphology-dependent microglial interactions and phagocytic behaviors in male embryos which are unique to the hypothalamic PVN--a nuclei critical for social behaviors. Our findings also suggest that specific hypothalamic nuclei such as the PVN may be more sensitive to prenatal maternal stress, which has the potential to provide a cellular basis underlying the sex differences in microglia-dependent social deficits that were previously reported for this model.

Anxiety and maladaptive fear remain difficult to treat, and despite initial promising findings, evidence regarding the anxiolytic and translational potential of oxytocin (OT) remains inconsistent. In a preregistered, randomized, double-blind, placebo-controlled, parallel-group pharmaco-fMRI study in 67 healthy men, we tested whether intranasal OT reduces post-exposure subjective fear during prolonged naturalistic viewing a horror movie comprising independently defined low-, medium-, and high-fear segments. OT reduced subjective fear following naturalistic threat exposure after accounting for pre-exposure baseline ratings. Neuroimaging analyses revealed that OT attenuated recruitment of the dorsolateral prefrontal cortex particularly during higher fear, and enhanced coupling of this region with the bilateral amygdala. At the large-scale network level, OT increased communication between frontoparietal/default-mode control networks and subcortical/limbic networks during high fear indicating more integrative fear regulation. A whole-brain fear neuromarker (CAFE) further confirmed intensity-dependent OT effects. Together, these findings indicate that OT modulates post-exposure fear experience and fear-related neural dynamics in ecologically valid contexts.

Antiestrogenic therapy is widely used in the treatment of hormone receptor positive breast cancer and alters estrogen signaling through different mechanisms, which may affect brain regions sensitive to estrogenic modulation. However, its early effects on brain architecture remain poorly understood. In this study, we examined whether the initiation of antiestrogenic therapy (tamoxifen or letrozole) is associated with short-term changes in brain structure and psychological symptoms, and whether these changes differ between the two treatment types. For now, data from twenty women with breast cancer and twenty healthy controls undergoing MRI scanning and psychological assessments at baseline (t1) and again approximately 2 to 3 weeks later (t2) were used. Patients started antiestrogen therapy immediately after the first assessment. Structural analyses included whole-brain cortical thickness and gyrification, as well as region of interest measures of hippocampal and amygdala volume. Changes in psychological parameters were also assessed, and hormone levels were measured but are not reported here. No robust time-by-group effects were observed for total brain volume, cortical thickness, gyrification, or hippocampal and amygdala volume after correction for multiple comparisons. An exploratory within-patient analysis identified a localized increase in cortical thickness in the right anterior insula/inferior frontal operculum; however, the corresponding time-by-group interaction was not significant. Somatic depressive symptom scores showed a significant time by group interaction, with scores increasing in the breast cancer group but remaining stable in healthy controls. Across time points, women with breast cancer also reported higher overall depressive symptoms and state anxiety and lower positive affect than healthy controls. Exploratory associations between changes in brain structure and psychological symptoms were observed at uncorrected thresholds but did not survive correction for multiple comparisons. In this interim sample, no robust group-level macrostructural brain changes were detected over the first 2 to 3 weeks following initiation of antiestrogen therapy. However, this does not exclude the possibility of early structural effects, which may be subtle or heterogeneous and therefore difficult to detect in the current sample. Somatic depressive symptoms increased in the BC group relative to healthy controls during this early treatment period, while exploratory neural findings suggested potential localized changes and individual difference associations that warrant cautious interpretation and require confirmation in larger samples. Recruitment is ongoing toward the prospectively defined final sample.

Background: Emerging evidence suggests that alterations in the gut microbiome may contribute to mental health outcomes through the gut-brain axis. However, older adults with post-traumatic stress disorder (PTSD) remain underrepresented in microbiome research. This pilot study investigated associations between PTSD symptoms, dietary fibre intake, cognitive function, and gut microbiome functional capacity in adults aged 50 years and older. Methods: Participants with PTSD symptoms and trauma-exposed controls (TEC) completed validated assessments of mental health, trauma exposure, and dietary fibre intake. A subset of participants provided stool samples for microbiome analysis and undertook cognitive function assessment. Quantitative PCR was used to assess phylum-level taxonomy and butyrate-producing bacterial pathways (terminal butyrate generating enzyme), with abundances normalised to the 16S rRNA gene. Results: Participants with PTSD demonstrated significantly greater mental health symptom burden and poorer performance on cognitive tasks related to executive function, working memory, and learning. Dietary fibre intake did not differ significantly between PTSD and TEC groups and no significant differences in overall microbial composition were identified at the phylum level. In contrast, differences were more apparent when assessing functional microbiome pathways, with butyrate kinase abundance significantly lower in PTSD participants than TEC participants. When stratified by fibre intake, a greater butyrogenic capacity was observed in the High fibre TEC participants compared to the Low fibre TEC participants, while little difference was observed in the PTSD fibre-stratified groups. Substantial inter-individual variation was also evident across both taxonomic and functional measures. Conclusions: These findings suggest that functional characteristics of the gut microbiome may provide greater insight into PTSD-related biological processes than broad taxonomic measures alone. Dietary fibre intake may be associated with greater butyrate-producing capacity in trauma-exposed older adults without PTSD symptoms, although this relationship appeared less evident among older adults living with PTSD symptoms. These findings support further investigation of microbiome function, diet, and cognition within the gut-brain axis. Larger studies incorporating metagenomic and metabolomic approaches are warranted.

Black carbon (BC), a combustion-derived component of fine particulate matter, has been linked to depressive symptoms, but controlled experimental evidence remains limited. We established a controlled BC inhalation model combined with chronic restraint stress (CRS) to determine whether inhaled BC alone induces depressive-like behavior and whether concurrent stress enhances behavioral and molecular vulnerability. Male C57BL/6J mice were assigned to Control, CRS, BC, or BC+CRS groups and exposed for 21 consecutive days, followed by behavioral testing and molecular analyses of plasma-depleted whole blood and stress-related brain regions. BC exposure alone induced depressive-like behavior, and the combined BC+CRS condition showed the most pronounced phenotype. These findings indicate that inhaled BC is sufficient to influence stress-relevant behavior and may heighten vulnerability under chronic stress. At the molecular level, BC shifted peripheral responses toward a stress- and inflammation-associated state with reduced plasticity-related signaling, whereas CRS preferentially engaged glucocorticoid-responsive regulation. Combined BC+CRS exposure further altered plasticity- and transcription-related regulatory programs in blood and stress-related brain regions, with prominent changes in the nucleus accumbens. These condition-dependent molecular patterns suggest that BC engages blood-brain stress-related pathways in a context- and region-specific manner. Together, these findings identify inhaled BC as a neurobehaviorally relevant environmental hazard.

In mammals, sex differences in the brain arise from genetic and hormonal factors, including organizational effects of perinatal testosterone. Epigenetic mechanisms including DNA methylation and demethylation have emerged as critical mediators of brain masculinization; specifically, their regulatory enzymes are upregulated in neonatal mice during the critical period of sexual differentiation, with their inhibition abolishing sex-specific cellular phenotypes. Here, we assessed sex differences in gene expression of the DNA demethylation machinery (Tet1, Tet2, Tet3, Gadd45a, Gadd45b and Tdg) during and after the critical period, and examined how these differences relate to the oxytocinergic system. mRNA expression was measured in the prefrontal cortex (PFC), preoptic area (POA) and paraventricular nucleus of the hypothalamus (PVN) at postnatal day (P) 7 and P18. At P7, males showed higher expression of all six genes than females in PFC, with no differences in POA or PVN; by P18, no regional differences remained. Oxytocin (OXT) immunoreactivity was surveyed across periventricular nucleus (Pe), anteroventral periventricular nucleus (AVPe), POA, PVN and supraoptic nucleus (SON). OXT was undetectable in the POA, AVPe and Pe at P7, and no sex differences were found in PVN or SON at either age, or in AVPe at P18. At P18, females showed higher OXT-immunoreactivity in the Pe and POA, than males. For Oxtr, qPCR revealed higher mRNA expression in the PFC of males at P7, with no other regional differences and none remaining at P18. Together, these findings suggest that sex differences in oxytocinergic regions arise from sex-specific epigenetic regulation during the critical period, and that perinatal testosterone may program DNA methylation dynamics underlying sex-specific gene expression in the developing brain. Our results support a model in which testosterone-dependent epigenetic mechanisms contribute to the sexual differentiation of neuroendocrine circuits, linking hormonal signals to long-term brain organization.

Background: The October 7, 2023 attack in southern Israel was one of the deadliest terror attacks in modern history, with 1,182 fatalities, more than 4,000 wounded individuals, and 251 hostages. The Nova music festival, an all-night outdoor rave near the Gaza border, suffered the highest number of civilian casualties, with more than 370 festival attendees killed. Survivors were exposed to prolonged life-threatening trauma with similar characteristics and within a narrow time window. Many survivors also reported being under the acute influence of psychoactive substances during the attack and the following hours. This tragic combination of civilian mass trauma and naturalistic pharmacological exposure created a rare opportunity to study trauma processing prospectively. Objective: This paper describes the rationale, design, and methodology of the Nova Protocol, a multimodal longitudinal observational study of survivors of the October 7, 2023 Nova festival attack and a sociocultural comparison group. Methods: The protocol spans from the first weeks to approximately 24 months post-trauma and includes three major assessment time points. It integrates repeated online clinical assessments, prolonged wearable-sensor monitoring, ecological assessments, saliva-based endocrine and inflammatory markers, structural and functional MRI, cardiac interoception paradigms, online and in-scanner reinforcement-learning tasks, and semi-structured qualitative interviews. Primary outcomes are PTSD symptom severity (PCL-5) and general psychological distress (K6), supplemented by a rich battery of secondary measures. Conclusion: The Nova Protocol provides an unusually rich longitudinal framework for characterizing psychological, behavioral, physiological, inflammatory, neural, interoceptive, and subjective mechanisms that shape clinical trajectories after civilian mass trauma. Because psychoactive substance exposure was naturalistic and self-selected, findings will be interpreted as mechanistic and prognostic associations rather than causal effects. The protocol is expected to inform early risk detection and scalable post-disaster monitoring and intervention strategies, as well as unique insights into how psychoactive substances impact trauma processing.

Objectives: Menopausal symptoms are heterogeneous and commonly assessed by questionnaires. We explored serum two-dimensional gel electrophoresis (2-DE) protein spots associated with menopausal symptom burden. Methods: This exploratory cross-sectional study included 27 women aged 45-55 years. A total of 550 matched serum 2-DE spots were quantified. A frequency-adjusted symptom burden score was calculated as the sum of severity x frequency products across 10 symptoms. Spots were screened using Spearman rank correlation with Benjamini-Hochberg false discovery rate (FDR) adjustment, followed by qualitative image review. Spots #285 and #636 were prioritized for vasomotor and psychological domain analyses. Results: The median age was 51.0 years; 13 participants were menstruating and 14 were amenorrheic. The median overall symptom burden score was 45.0 (interquartile range, 6.5-58.5) and was inversely correlated with spots #285 and #636. Spot #285 was inversely correlated with vasomotor symptom score, including inverse correlations in both menstrual-status groups. Spot #636 was inversely correlated with psychological symptom score overall, with a stronger descriptive correlation among menstruating participants. Neither candidate remained significant after FDR adjustment. Conclusions: Spots #285 and #636 are hypothesis-generating candidates requiring molecular identification, analytical validation, multiplicity-aware confirmation, and independent replication.

Chronic stress is a major risk factor for psychiatric disorders such as depression and anxiety, yet the biological basis of individual differences in stress susceptibility and resilience remains poorly understood. Here, we examined physiological, behavioral, and medial prefrontal cortex (mPFC) transcriptomic responses to chronic restraint stress (CRS) in male BALB/c and C57BL/6J mice. After 21 days of CRS, BALB/c mice exhibited greater stress-related changes than C57BL/6J mice, including greater body weight loss, elevated serum corticosterone, reduced serum antioxidant capacity, and more pronounced depression-like behaviors. RNA sequencing showed largely strain-specific transcriptional changes in the mPFC. Strain x stress interaction analysis, followed by canonical pathway analysis using Ingenuity Pathway Analysis (IPA), identified strain-dependent molecular signatures. The most prominent differences involved extracellular matrix (ECM) organization and remodeling and neuroinflammatory signaling pathways, with greater predicted activation in BALB/c mice. IPA upstream regulator analysis further predicted multiple candidate regulators associated with these pathways, including TGF-{beta}/SMAD, C4a/C4b, and MAPK14. Among genes associated with these pathways, several ECM-related genes were preferentially upregulated in BALB/c mice, whereas activity-dependent immediate early genes were preferentially downregulated in C57BL/6J mice. These findings suggest that the strain-dependent mPFC transcriptional programs identified here may contribute to differential stress susceptibility and resilience.

Dominance hierarchies are a fundamental aspect of social organization, enabling animals to minimize aggression and optimize access to resources. Previous studies have highlighted the energetic and physiological demands of dominant status, as well as the behavioral flexibility required of subordinates to navigate these hierarchies. Despite advancements in automated behavior tracking, limitations persist in tracking fine-scale, real-time interactions within complex social environments. Here, we developed and validated a novel RFID-based system to continuously monitor dominance hierarchies in group-housed male mice over 10 days. This system enabled unbiased behavioral inference across light phases and revealed spatial and temporal patterns of dominance behavior undetectable through traditional live-scored methods. Automated tracking accurately identified alpha individuals and consistently inferred linear hierarchies across cohorts, with greater precision for higher-ranked individuals. Behavioral metrics, such as transition frequencies and proximity to food zones, were consistent with dominance driven activity. Hormonal analyses revealed that higher-ranked mice exhibited increased leptin and peptide YY, consistent with heightened activity and satiety signaling, while lower C-peptide levels reflected greater metabolic demands of dominance. Furthermore, dominance rank was associated with differences in light-dark activity, which were in turn related to circulating hormone profiles. This study demonstrates the utility of automated RFID tracking in capturing dominance hierarchies with temporal and spatial granularity, while revealing links between social rank, metabolic regulation, and activity patterns advancing our understanding of social behavior dynamics.

Background Childhood adversity is linked to psychopathology risk and dysregulated stress reactivity; however, unified underlying neural mechanisms are unclear. A central visceral network, including the bed nucleus of the stria terminalis (BNST), amygdala and subgenual anterior cingulate cortex (sgACC), is implicated in affective processes and proximally controls stress reactivity. We examined relationships among childhood adversity, stressor-evoked neural activity/connectivity and affective and cardiovascular outcomes. Methods Participants were adults (n=97, mean age=27.32, SD=4.02, 57 females) uniformly distributed across physical abuse severity. Childhood adversity was assessed by threat (abuse or traumatic events) and socioeconomic deprivation (SED). Participants performed an fMRI stress task with cardiovascular recordings. Linear/curvilinear regressions were performed with threat and deprivation together as predictors of stressor-evoked activity/connectivity. Neural variables showing significant adversity associations were examined as predictors of affective symptoms/diagnoses or cardiovascular responses. Results Threat and SED displayed opposing curvilinear relationships with stressor-evoked amygdala and sgACC activity, respectively: at low and high adversity, amygdala reactivity was greater, whereas sgACC reactivity was blunted. Greater SED was associated with weaker BNST-sgACC connectivity. Blunted amygdala reactivity and lower sgACC reactivity were associated with greater post-traumatic stress symptoms. Affective diagnoses peaked at near-zero BNST-sgACC connectivity. Greater amygdala reactivity was associated with blunted diastolic blood pressure reactivity and recovery. Conclusions The curvilinear relationships suggest adversity-related vulnerability thresholds. Blunted amygdala, lower sgACC reactivity and weaker BNST-sgACC connectivity may confer affective risk, whereas heightened amygdala reactivity may confer cardiovascular risk. Our findings support a central visceral network pathway by which childhood adversity may contribute to affective and cardiovascular health.

Background: Posttraumatic stress disorder (PTSD) has been associated with advanced biological age in DNA methylation data, but results have been inconsistent. This study evaluated PTSD in association with epigenetic age in the largest cohort to date (by about 20 fold). Methods: Participants were 45,091 US Veterans (92.76% male) enrolled in the VA Million Veteran Program, with VA electronic health record (EHR), self-report PTSD severity (n = 22,835), and DNA methylation and genotype data. PTSD diagnoses predated the blood draw for obtaining DNA by > = one year. Results: PTSD diagnosis, severity, and duration were associated with age-adjusted metrics of epigenetic age (age residuals) per the Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE epigenetic age algorithms after multiple testing adjustment. The strongest and most robust effect (to additional covariates) was evident for PTSD severity in association with GrimAge residuals (B = .029, adjusted-p = 2.48e-53, up to 2 years advanced age). The relationships between PTSD severity and GrimAge and PhenoAge residuals were stronger among younger vs. older Veterans. In stratified analyses, all PTSD variables were associated with all epigenetic age residuals in the European ancestry subgroup (n = 27,578), but significant associations only emerged for GrimAge and DunedinPACE in the African ancestry participants (n = 11,690). Conclusions: PTSD was associated with advanced epigenetic aging in the largest study to date to evaluate this question. Effects were generally small in magnitude, though meaningful when considering the personal and healthcare system impact of advanced aging in the large population of VA users with PTSD.

Animals experience stressors in a variety of contexts that result in activation of neuroendocrine and cellular stress responses. Release of stress hormones can disrupt or restore redox homeostasis, and the resulting changes in oxidative states, physiology and behavior vary by an individuals stress coping style. However, oxidative stress can also directly modulate neuroendocrine stress signaling. To what extent individual differences in brain antioxidant levels alter behavioral stress levels is not well understood. The present study investigated how N-acetylcysteine amide (NACA), an antioxidant and glutamate-modulating compound, regulates stress behavior across zebrafish (Danio rerio) with different stress coping styles (proactive, reactive). Following 24-hour exposure to NACA or control conditions, we quantified individual and composite stress behaviors using a Light-Dark Test (LDT). As expected, both proactive fish and NACA-treated fish showed significantly lower stress behaviors compared to reactive and control animals, respectively. Notably, stress-reducing effects of NACA were only seen in those with a reactive stress coping style. Overall, our data suggest that antioxidant mechanisms (e.g., glutathione system) may be key in facilitating the distinct behavioral and physiological responses to stressors that characterize alternative stress coping styles. The results underscore how individual differences in stress coping style and redox state can influence behavioral responses to stress.

Autoimmune diseases have shown biased proportion in female population, existing clinical investigations of sex hormones in autoimmune populations have been relatively limited in terms of patient size and types of hormones investigated. In this study, we examined the relationship of sexual hormones and autoimmune antibodies in a large cohort of US women. This retrospective study sample included a total of 15319 female subjects medical information that were collected between December 2015 to May 2019 and tested in the Vibrant America Clinical Laboratory. The present serum sample was limited to female participants who had ever menstruated at the time of blood collection and completed the testing of the autoimmune antibodies and sex hormones. We focused on a total of 13 clinically significant autoantibodies including antinuclear antibody (ANA), 11 anti-extractable nuclear antigens (anti-ENAs), anti-cyclic citrullinated peptide 3 (anti-CCP3), and 11 female sex hormones. First, the prevalence of serological autoantibodies in a large set of adult female subjects divided by the menopause age was investigated. Next, the levels of sex hormones were compared in the seropositive autoimmune subjects and seronegative controls across the pre- and post-menopausal female groups. The presented study involving a large cohort of females showed no statistically different levels of sex hormones in seropositive autoimmune subjects and matched controls except for DHEA-s.

Background: Acute cortisol responses to psychosocial stress vary substantially across individuals, yet how this variability is reflected in post-stress resting-state functional connectivity (rsFC) remains unclear. Although prior work has linked stress-related endocrine responses to brain connectivity, studies have been limited by small samples, region-of-interest approaches, or a sole focus on group-level analyses. Here, we investigated whether acute cortisol increase is associated with, and can be predicted from, whole-brain post-stress rsFC. Methods: We analyzed 339 healthy participants from two ScanSTRESS datasets using complementary inferential and predictive approaches. First, we used the Network-Based Statistic (NBS) to identify connected rsFC networks associated with acute cortisol increase, controlling for age, site, and sex/hormonal status. Second, we predicted participants' acute cortisol increase from their connectivity patterns using NBS-Predict and Connectome-Based Predictive Modeling (CPM). Together, we examined the cortisol-rsFC relationship at the population and individual levels. Results: Greater cortisol responses were associated with lower post-stress rsFC within a significant distributed network comprising 258 connections among 78 regions, centered on thalamic nuclei and pallidal regions and extending to default-mode, limbic, orbitofrontal, and cerebellar regions. Sex-stratified analyses revealed a significant negative association only in females, but formal sex-difference contrasts were not significant. NBS-Predict and CPM yielded modest but significant out-of-sample prediction, with predictive networks converging on subcortical and posterior cingulate regions. Conclusions: Post-stress rsFC carries convergent inferential and predictive information about individual HPA-axis reactivity. Stronger cortisol responses were characterized by reduced connectivity within a distributed subcortical-cingulate network, supporting a network-level perspective on neural-endocrine coupling following acute stress.

Understanding the neurobiological systems that regulate alcohol cue-induced craving is of utmost importance for the development of novel intervention strategies for alcohol use disorders (AUDs). However, although a human experimenter is required to conduct alcohol self-administration studies in the lab, the cues associated with the experimenter are seldom if ever factored into the experimental design. Thus, although we have learned much to date about alcohol cue-induced behavior and neurobiology, and in particular about discrete cues presented many times throughout a single daily alcohol self-administration session, we know relatively little about how responses to alcohol availability cues might predict subsequent alcohol consumption. For the current experiment, mice were exposed daily to auditory cues that preceded 2 hours of alcohol or water access using drinking-in-the-dark (DID) methods. An additional control group experienced cues but were not otherwise manipulated. Importantly, cues were initiated remotely from outside the animal facility, avoiding the experimenter being the first cue predicting ethanol availability. Head direction, location in the home cage, and movement velocity were the primary variables on interest. Surprisingly, during the cue period, there were no significant differences between groups in any of these measures, despite meaningful alterations over days. However, we observed many significant correlations between behaviors and drinking variables. First, we observed significant positive associations between ambulatory velocity during cues and subsequent total alcohol (R2=0.14; p<0.0001) and total water (R2=0.12; p=0.0002) consumption, but only in females. We also observed a significant positive relationship (R2=0.25; p<0.0001) between the amount of time oriented toward the sipper port during the auditory cues and the average rate of subsequent alcohol consumption (i.e. front-loading), but only in females. In males, head direction was found to be positively associated with subsequent total water consumption (R2=-0.21; p<0.0001), but not alcohol (R2=-0.01; p=0.2267). We also observed a significant negative relationship (R2=-0.15; p<0.0001) between proximity to the sipper during the cue period and subsequent total 2-hour alcohol intake in males. Although these associations were modest in strength, they suggest potential sex-specific behavioral predictors of alcohol consumption that are regulated by different neural dynamics.

Importance The menopausal transition has been associated with an increased risk of depression, although findings are inconsistent. While most research has focused on menopausal stage, some studies suggest that later age at menopause may be associated with lower depression risk. Objective To examine the association between age at menopause and depression risk during perimenopause and early postmenopause using multivariable regression and genetic approaches. Design Prospective cohort study using data from the mothers of the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort that recruited pregnant women in 1991-1992. Setting UK community-based cohort study. Participants Up to 3,307 women with repeated measures of depressive symptoms across the perimenopausal and postmenopausal periods and data on observed or genetically predicted age at menopause. Exposure Observed age at menopause, a polygenic risk score (PRS) for age at menopause, and genetically predicted age at menopause. Main Outcome(s) and Measure(s) Depressive symptoms during the perimenopausal and early postmenopausal periods were assessed using the Edinburgh Postnatal Depression Scale (EPDS), with depression defined as a score >= 13. Results Effect estimates across multivariable regression and genetic analyses were small and directionally consistent with lower odds of depression with older age at menopause, although most confidence intervals included the null. In analyses using observed age at menopause, there was little evidence of an association with depression during perimenopause (Odds ratio (OR) per year increase in age at menopause 0.98, 95%CI 0.89-1.08) or postmenopause (OR 1.00, 95%CI 0.89-1.13). Results were similar when using a PRS as a genetic proxy for age at menopause during perimenopause (OR per standard deviation (SD) increase in PRS 0.98, 95%CI 0.89-1.09) but suggested lower odds of depression during postmenopause (OR 0.92, 95%CI 0.86-0.99). Mendelian randomization analyses did not support a causal effect (OR per year increase 1.00, 95%CI 0.89-1.13 for perimenopause, and OR 0.97, 95%CI 0.86-1.09 for postmenopause). Conclusions and Relevance Age at menopause is unlikely to be a major driver of midlife depression risk. However, consistent effect directions across approaches suggest a small association may exist, but further research in larger samples is needed to confirm this.

Psilocybin acutely alters neurotrophic, neurochemical, and immune markers, but the relationships between these responses and circulating microRNAs (miRNAs), i.e. non-coding RNAs that regulate post-transcriptional gene expression, remain unclear. In a randomized, double-blind, placebo-controlled study of 62 healthy adults who received psilocybin (0.17 mg/kg) or placebo, we previously demonstrated that let-7g-5p and miR-150-5p were transiently differentially expressed 360 minutes after psilocybin administration. Here, we examined whether changes in these miRNAs were associated with concurrent neurotrophic, inflammatory, pharmacokinetic, and glutamatergic measures. Expression changes from baseline to 360 min and 7 days were analysed using linear regression against changes in BDNF, TNF-, IL-6, C-reactive protein, cortisol, medial prefrontal cortex glutamate/total creatine, and psilocin concentrations. Psilocybin increased let-7g-5p and decreased miR-150-5p expression. Changes in let-7g-5p were positively associated with psilocin concentrations, suggesting sensitivity to inter-individual pharmacokinetic variability, whereas miR-150-5p showed no concentration-dependent association. In both groups, miRNA changes were negatively related to baseline expression: lower baseline let-7g-5p predicted larger increases, whereas higher baseline miR-150-5p predicted larger decreases. BDNF changes were associated with both miRNAs under placebo but not psilocybin, consistent with reduced between-subject variability and a flattened BDNF-miRNA relationship following treatment. Medial prefrontal glutamate was negatively associated with miR-150-5p change under psilocybin. No associations were found with immune biomarkers. Together, these findings support the predicted involvement of let-7g-5p and miR-150-5p in neuroplasticity and their potential as accessible blood-based biomarkers of individual neurobiological responsiveness to psilocybin and other psychedelics.

Background Oral contraceptive (OC) use, particularly during adolescence, may increase depression risk in some individuals, but it remains unclear who is susceptible to mood-related side effects and who is not. We aimed to detect single nucleotide polymorphisms (SNPs) and genes that moderate the effect of OC use on depression in young adulthood using data from the UK Biobank. Methods N=202,243 participants were followed from birth to age 23.29 (SD: 2.58) years. We used Cox models for counting processes to test the association between OC use and incident depression in young adulthood, and conducted a genome-wide-by-drug-interaction study (GWDIS) of SNP by OC use interactions alongside a standard genome-wide association study (GWAS) on incident depression in young adulthood. Results Over half of all participants (57.5%) initiated OC and 1.0% received a depression diagnosis during follow up. OC initiators had a 20% higher hazard of incident depression than non-initiators (HR=1.20, 95% CI=1.04-1.37). No SNPs reached genome-wide significance in the GWDIS, though eight showed suggestive interaction signals (p<1e-5). At the gene level, FSIP1 (p=5.90e-5) and EHBP1 (p=6.47e-5) showed suggestive signals, but none passed the genome-wide threshold. No SNPs reached genome-wide significance in the GWAS. Conclusions We did not find evidence for genetic variants that moderate the association between OC initiation and depression. If such effects exist, they are likely to be small and polygenic, suggesting there is currently no solid basis for using genetic data for individualised contraception counselling concerning mood-based side effects.

Sleep is proposed to have a beneficial effect on the consolidation of memories and gist abstraction in adults. For children, gist abstraction is of special relevance to transform new information from social and emotional contexts into stable representations. This study investigated the effect of sleep on emotional and social recognition and gist abstraction on N=34 typically developing children assessed in a sleep and a wake condition. In an emotional memory task, reward-associated stimuli were presented, while a social memory task used face-stimuli to implement social acceptance or rejection from peers. Both paradigms relied on a hidden rule to be abstracted. In general, children were able to remember emotional and social stimuli and to abstract gist information. With respect to sleep, we found a beneficial effect of sleep on the recognition of emotional stimuli but no sleep-dependent enhancement for either social recognition or emotional or social gist abstraction. Overall, our results indicate, that sleep-dependent recognition might depend on the type of memory task. Furthermore, nighttime sleep as compared to daytime wakefulness has no differential influence on gist abstraction in children as assessed in our paradigms, contrasting previous results found in adults.