Psychoneuroendocrinology

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.

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.

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.

Impaired seminal redox balance is a main factor that contributes to male fertility disorders and reduced sperm survival during storage. Although several methods are available to measure antioxidant and reactive oxygen species (ROS) levels, their cost and complexity limit their use in routine sperm analysis. Recently, assessment of oxidation-reduction potential (ORP) has emerged as a convenient and comprehensive method for evaluating seminal redox status. While the implications of seminal ORP in humans have been extensively explored, its use in other species is limited. In this study, we explored the relationship between boar seminal ORP and sperm quality and its dynamics during liquid preservation. We found that the ORP of the porcine ejaculate was lower than that of the seminal plasma, while both parameters were correlated with the total antioxidant capacity (TAC) of seminal plasma. Sperm concentration and seminal pH influenced the seminal ORP, with lower values observed in ejaculates with higher sperm concentration and pH. Notably, a more oxidative seminal environment (characterized by high ORP or low TAC) was correlated with high mitochondrial activity and sperm velocity in fresh samples, which might be explained by increased ROS production by sperm mitochondria. Our results also show that seminal ORP increased during three days of liquid storage, while the ORP of the extender did not change significantly during the same period. Our findings advance our understanding of the implications of redox status in porcine sperm biology and pave the way for the broader application of ORP measurement in animal andrology. HighlightsO_LIThe ejaculates oxidation-reduction potential is lower than that of seminal plasma C_LIO_LISeminal oxidation-reduction potential is correlated with total antioxidant capacity C_LIO_LISeminal redox status is influenced by sperm concentration and semen pH C_LIO_LIAn oxidative seminal environment is correlated with high sperm metabolism C_LIO_LISeminal oxidation-reduction potential increases during 3 days of liquid storage C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/726780v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@18fd914org.highwire.dtl.DTLVardef@f4f179org.highwire.dtl.DTLVardef@1195e32org.highwire.dtl.DTLVardef@7760ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

Separate research has evaluated trajectories of posttraumatic stress symptoms (PTSS) and obsessive-compulsive symptoms (OCS), but no study has evaluated OCS trajectories following trauma exposure nor combined PTSS/OCS trajectories. The present study evaluated combined PTSS/OCS trajectories among 585 survivors of Hurricane Helene, spanning three waves of data collection over 12 months. A 3-class solution was supported, including resilient (i.e., consistently low PTSS and OCS), chronic (i.e., elevated PTSS and OCS with gradual reduction over time), and moderate-yet-diverging (i.e., moderate elevations in PTSS and OCS with gradually declining PTSS and persistent and increasing OCS over time) classes. This study shows both overlap and differentiation in symptom trajectories from earlier research, with the moderate-yet-diverging trajectory suggesting unique OCS pathways distinct from PTSS.

Young people with major depressive disorder (MDD) exhibit altered thermoregulation, which has also been linked to vigilance and sustained attention. However, whether peripheral skin temperature is associated with cognitive vulnerability around sleep onset is unknown. We examined the relationship between the distal-proximal skin temperature gradient (DPG) and vigilance in 38 young people with MDD (20.1{+/-}3.7 years, 65.9% female) using an in-laboratory protocol spanning 4h before, to 2h after, habitual sleep time. Participants were classified into DPGwarm and DPGcold subgroups based on being above or below median DPG before sleep onset. Linear mixed models adjusted for age and sex examined psychomotor vigilance task performance across timepoints. The DPGwarm subgroup (n=19) showed significantly worse performance than DPGcold (n=19) across the evening for mean reaction time (RT), reciprocal reaction time, number of lapses, and fastest 10% of RT (all p[&le;]0.003). Significant GroupxTime interactions were observed for mean RT (F(3,90.4)=5.00, p=0.003) and lapses (F(3,93.6)=6.73, p<0.001), with DPGwarm participants showing progressively worse performance approaching sleep onset. At 2h post-habitual sleep onset, DPGwarm participants exhibited slower RT ({Delta}=129ms, p<0.001) and nearly four times more lapses (14.9 vs 4.1, p<0.001). Performance decrements were not accompanied by differences in melatonin timing, subjective sleepiness or mood, suggesting DPG may index cognitive vulnerability independently. Of note, younger age was associated with greater vigilance decrements. These findings demonstrate that elevated peripheral skin temperature before sleep onset is associated with reduced vigilance in young people with MDD, and may therefore have potential utility as a non-invasive thermoregulatory biomarker of cognitive vulnerability.

Background: Aberrations in neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways are implicated in major depressive disorder (MDD). First-episode simple dysmood disorder (FE-SDMD) without metabolic syndrome offers a unique model to investigate early lipid alterations underlying NIMETOX pathophysiology. Methods: Plasma samples were collected from 88 university students (44 FE-SDMD, 44 healthy controls). Participants underwent comprehensive psychiatric and psychological assessments, including adverse childhood experiences (ACEs), negative life events (NLEs), depression, anxiety, suicidal behaviors, and insomnia. Untargeted lipid profiling was performed using LC-QTOF-MS, while indices of oxidative and nitrosative stress (ONS) and lecithin-cholesterol acyltransferase (LCAT) activity were assessed. Data was analyzed using machine learning approaches with recursive feature elimination and cross-validation. Results: FE-SDMD was characterized by increased ceramides (CER), diacylglycerides (DAG), triacylglycerides (TG), sphingomyelins (SM), bis-monoacylglycerol phosphates (BMP), cholestone, and fatty-acyl amino acids (FAAA). DAG, CER, and BMP were the strongest predictors of depression severity and physiosomatic symptoms, whereas cholestone, CER, and SM predicted suicidal behaviors. These lipid modules, together with lowered LCAT and increased ONS, explained substantial variance in depression severity (46.4%), physiosomatic symptoms (42.4%), cognitive-affective symptoms (37.9%), suicidal behaviors (30.1%), insomnia (32%), and anxiety (19.5%). ACEs and NLEs were strongly associated with CER (p<0.001), DAG (p<0.01), and cholestone (p<0.01). Conclusion: Early-stage MDD is characterized by distinct lipid dysregulations linked to psychosocial stress exposure, oxidative and nitrosative stress, and an indicant of impaired reverse cholesterol transport. These lipid modules may serve as early biomarkers and therapeutic targets in vulnerable populations.

The persistence of a left-handed minority of slightly over 10% of the population is enigmatic because it is associated with stigma, increased psychopathology, and cognitive deficits. In a community sample of 9,352 individuals (age range 8-21 years) with neurobehavioral assessments, left-handers (N=1,281, 673 male) indeed showed greater psychopathology and performed more poorly than right-handers (N=8,076, 3,839 male) on tests of executive function, memory, complex cognition, and social cognition, while excelling in motor speed. Furthermore, the variance was higher and within-individual variability (WIV) - the extent to which scores in the different domains varied within individuals - was higher in left-handers. Since low WIV indicates even distribution of abilities while high WIV reflects specialization in circumscribed areas, the finding indicates that left-handers are "neurocognitive specialists". This combination of behavioral traits could confer resilience against natural selection pressures and help explain preponderance of left-handers in highly specialized professions requiring specific talents. Our findings encourage more research on left-handers, who are currently excluded from multiple brain behavior studies.

Learning in adulthood is embedded in everyday social life, in which periods of psychosocial stress alternate with recovery. The autonomic nervous system regulates how the body responds to environmental demands, yet individuals differ markedly in this regulation. It remains unknown whether such individual differences in bodily regulation modulate the ability to learn probabilistic patterns from sensory input. Here, we investigated statistical learning of probabilistic patterns in speech streams in a six-hour experiment incorporating psychosocial stress and recovery to approximate everyday conditions. Sixty-five adults were exposed to novel speech streams in high- and low-stress contexts, with learning assessed immediately after exposure and following a rest period. Heart rate variability was recorded throughout the experiment to capture individual differences in autonomic reactivity to stress and recovery. From these measures, we constructed composite proxies of sympathetic (SNS) and parasympathetic (PNS) nervous system reactivity. Individuals with congruent SNS-PNS reactivity--either jointly high or jointly low--showed superior statistical learning outcomes across stress contexts. SNS reactivity preferentially supported encoding, whereas PNS reactivity supported consolidation. Moreover, the effect of SNS activation during speech exposure on statistical learning depended on individuals SNS reactivity profiles. These findings demonstrate that individual differences in bodily regulation are tightly linked to the ability to learn statistical dependencies in stressful environments. Overall, the findings highlight the essential role of brain-body-environment interactions in statistical learning.

Background: Androgen deficiency in males is associated with reduced motivation, fatigue, and decreased goal-directed behavior, yet the neural mechanisms underlying these changes remain poorly understood. Dopamine signaling within the nucleus accumbens (NAc) plays a central role in regulating effort-based decision making. Here, we tested the hypothesis that loss of testicular hormones alters mesoaccumbal dopamine function to increase sensitivity to effort-related costs. Methods: Male mice underwent orchiectomy (ORX) either before puberty onset or in adulthood. Effort-based decision making was assessed using a progressive ratio 1 closed economy (PR1-CE) task. Dopamine-related function was assessed using systemic haloperidol administration and high-performance liquid chromatography to measure dopamine and metabolites, while whole-cell recordings were used to assess intrinsic excitability of NAc spiny projection neurons (SPNs). Results: ORX increased sensitivity to effort costs, reflected by a shift toward energy-efficient responding while maintaining overall food intake. These behavioral changes were accompanied by reduced responsiveness to haloperidol. Postpubertal ORX increased dopamine content and reduced metabolite-to-dopamine ratios in the NAc, consistent with reduced dopamine turnover, whereas prepubertal ORX did not affect dopamine measures. Prepubertal ORX selectively reduced excitability of NAc core D1R+ SPNs, while postpubertal ORX increased excitability across both D1R+ and D1R- populations. Conclusions: Androgen depletion increases effort cost sensitivity and is associated with alterations in mesoaccumbal circuit function. Although behavioral effects were similar following pre- or postpubertal ORX, distinct neurochemical and cellular adaptations were observed, suggesting developmental timing influences neural adaptations to androgen depletion. These findings provide insight into neural mechanisms linking androgen deficiency to motivational deficits.

Background: Physical activity is a well-established modifiable risk factor for depression and anxiety. However, whether vigorous intermittent lifestyle physical activity (VILPA), defined as short, sporadic bouts embedded in daily life, confers mental health benefits remains unclear. We aimed to examine the associations of accelerometer-measured VILPA with risks of incident depression and anxiety among non-exercising adults. Methods: This prospective cohort study included 19,962 non-exercising adults (mean age 62.3 years) from the UK Biobank, free of depression and anxiety at baseline (2013-2015), with 7-day wrist-worn accelerometry data. Cox proportional hazards models and restricted cubic splines were used to examine associations between average daily duration of VILPA bouts lasting up to 1 or 2 minutes and these outcomes. Findings: Over an average follow-up of 7.8 years, 469 participants developed depression and 536 developed anxiety. Approximately 94.6% of participants engaged in VILPA bouts lasting up to 1 minute. Daily VILPA duration exhibited L-shaped associations with both depression and anxiety. Compared with participants who accumulated no VILPA, the whole-sample median daily VILPA duration for bouts lasting up to 1 minute, 4.1 minutes, was associated with a hazard ratio of 0.70 (95% confidence interval [CI]: 0.56-0.88) for depression and 0.79 (95% CI: 0.64-0.97) for anxiety. Findings were similar for VILPA bouts lasting up to 2 minutes. Interpretation: Among non-exercisers, even small amounts of VILPA were associated with substantially lower risks of depression and anxiety, highlighting the potential of high-intensity incidental physical activity as a feasible strategy for preventing depression and anxiety, particularly among individuals unable or unwilling to engage in structured exercise.

Background: Sleep debt and irregular sleep patterns are highly prevalent amongst adolescents. However, whether the absence of these sleep behaviours protects against subsequent depression remains unclear. Here, we examined the association of sleep debt, weekend catch-up sleep (WCS), and social jetlag (SJL) in adolescence with depression in young adulthood and identified underlying biopsychosocial mechanisms. Methods: Secondary data analyses were conducted using the Avon Longitudinal Study of Parents and Children. Bedtimes and wake-up times on school days and weekends (i.e., sleep duration) and sleep need were self-reported at 15 years. This was used to generate sleep debt (sleep need minus school day sleep duration), WCS (weekend sleep duration minus school day sleep duration), and SJL (absolute difference in the midpoint of sleep times between school days and weekends). Depression was assessed at 24 years with the Clinical Interview Schedule-Revised. Common mental health symptoms, biological, and school-related factors at 17 years were the mediators. Results: Logistic regression analyses revealed that greater WCS (adjusted odds ratio [AOR]=0.90; 95% CI=0.84-0.97; p=0.004) and lower sleep debt (AOR=1.10; 95% confidence interval [CI]=1.03-1.18; p=0.005) at age 15 reduced the likelihood of depression at 24 years. Irritability at 17 years partially mediated the relationship between sleep debt and depression (bias-corrected estimate=0.003; 95% CI=0.002-0.004; p<0.001). Conclusions: Adolescents who experience less sleep debt (i.e., less discrepancies between their actual sleep and their perceived sleep need) and those who extend their sleep duration on weekends are at reduced risk for depression in young adulthood. These findings underscore the need for greater opportunities for adolescents to obtain more hours of sleep to protect them against later poor mental health outcomes, such as depression. Keywords: Sleep; longitudinal studies; depression; ALSPAC

Affective biases, or shifts in learning and decision-making driven by affective states, are central to human cognition. Translational studies in rodents have shown that pharmacological and stress manipulations alter reward valuation, but how positive social signals shape these processes remains poorly understood. Here, we adapted the Affective Bias Test (ABT), a translational rodent assay of affective biases in depression and antidepressant therapy, to ask whether positive social signals influence reward valuation in orangutans (Pongo spp.). We first validated the task by manipulating reward magnitude during learning and found that participants showed a significant preference for substrates previously associated with higher reward value, confirming sensitivity to reward valuation. We then tested whether play vocalizations influence reward learning by presenting either conspecific play vocalizations or control sounds prior to learning reward-substrate associations, with identical reward values. In subsequent preference tests, orangutans showed a significant choice bias for substrates previously associated with play vocalization recordings. These findings demonstrate that orangutans experience positive affective states when hearing conspecific play vocalizations, as indicated by affective biases in reward valuation and memory.

This study aims to elucidate the association of circadian rhythm disruption with male testosterone levels and reproductive health using integrated epidemiological and experimental evidence. In the UK Biobank (n = 38,562), rest-activity rhythm amplitude was associated with lower serum testosterone levels (-0.21 nmol/L comparing the lowest vs. highest quartiles) and increased risks of orchitis and hydrocele (hazard ratios: 1.23 and 1.14, respectively). These findings were replicated in an occupational study of shift workers in China (n = 118), where shift work was independently associated with decreased testosterone levels ({beta} = -0.301, P = 0.015). In mouse models, circadian disruption induced testicular and epididymal atrophy, spermatogenic disorders, and suppressed circulating testosterone levels, accompanied by downregulation of key steroidogenic proteins. Together, these findings provide converging evidence that circadian rhythm disruption impairs testosterone synthesis, potentially through dysregulation of steroidogenesis, highlighting circadian rhythm as a modifiable environmental determinant of male reproductive health.

Within species, male testosterone is often linked to mating competition and paternal care, suggesting that sex differences in endogenous testosterone values across mammals may covary with broader reproductive strategies. Using a structured literature search, we compiled 63 studies, spanning 31 non-human species and 9 human populations, reporting endogenous, non-experimentally manipulated testosterone values for both adult males and females within the same population and context. From these studies, we calculated male-to-female testosterone ratios, and analysed these data using Bayesian phylogenetic multilevel models. We tested whether testosterone dimorphism was associated with paternal care and sexual size dimorphism while accounting for sampling matrix, assay method, breeding context, and wild versus captive setting. Across non-human mammals, neither paternal care nor sexual size dimorphism (indexing competition) showed a clear association with testosterone ratios, and the same pattern emerged in the primate-only subset. By contrast, sampling matrix was consistently associated with testosterone dimorphism across all analyses, with lower male-to-female ratios in non-blood than in blood-based measures. In primates, testosterone ratios were also lower in captive than in wild populations, although this pattern was not clearly supported in the broader non-human dataset. In the human-only analysis, testosterone ratios did not clearly differ between industrialized and small-scale societies, whereas the matrix effect remained evident. Overall, our results suggest that sampling matrix is a major source of variation even for ratio-based measures, highlighting the need for caution when inferring between-species endocrine differences from studies using different substrates. More broadly, directly comparable, non-experimentally manipulated testosterone data for both sexes remain rare across mammals, limiting comparative inference.

Preterm birth is associated with alterations in early caregiver-infant regulation, with potential consequences for socio-emotional and physiological development. However, the mechanisms through which early interactional experience shapes these processes remain unclear. Here, we tested whether a structured dyadic intervention could modify co-regulatory dynamics across physiological, behavioral, and relational levels. Fifty-four 7-month-old preterm infants and their parents were assigned to either a shared book reading intervention (n = 22) or an active control condition based on a shared building activity (n = 32) and compared with 39 full-term infants. The intervention consisted of an 8-week program of shared book reading, designed to structure parent-infant interaction. Physiological synchrony was assessed at the dyadic level, alongside infants autonomic regulation and cardiovascular signal complexity. Behavioral engagement and parental attachment representations were also evaluated. Results showed that mother-infant physiological synchrony emerged selectively within the interactional context trained by the intervention and only in the intervention group. This context-specific synchrony was accompanied by modulation of vagal activity and increased cardiovascular complexity in preterm infants, consistent with enhanced flexibility of autonomic control. At the behavioral and relational levels, intervention infants showed increased initiating joint attention, while parents reported higher secure attachment. These findings support a model of experience-dependent early synchrony, in which repeated dyadic interaction through shared book reading shapes the coupling between interpersonal coordination and individual physiological regulation. By linking synchrony, autonomic flexibility, and social engagement, this study identifies a mechanism through which early caregiving experience can organize developmental trajectories following prematurity.

Alterations in rodent self-grooming have been used to model various facets of neuropsychiatric illness. In the context of affective behavior, increases in grooming have been proposed as a sign of stress. This is because grooming has been observed to increase in close temporal proximity to stressful events. However, in other situations, stress appears to suppress grooming, complicating the utility of measuring grooming in the study of stress and mental health. Here, we show that this discrepancy can be resolved by considering time and experimental context. We found that in initial response to stress, grooming declined in proportion to stressor intensity. Moreover, stress-related cues and anxiogenic stimuli similarly suppressed grooming. Conversely, optogenetic inhibition of the amygdala in a stress-associated context decreased threat-elicited freezing, consistent with a reduction in stress, and increased grooming. These results indicate that the immediate response to stress is a suppression of grooming. However, when stressed mice were returned to their homecage environment, grooming increased. Similarly, mice increased grooming when they returned to the safe zone in an anxiety assay. Accordingly, rather than being a defensive response to signs of danger, increased grooming seems to reflect a post-stress response that occurs once animals detect the absence of danger. These findings suggest that post-stress grooming could provide a window into the neurobiology of post-stress recuperative processes.

Psychedelic drugs are emerging as potentially efficacious tools for treating psychiatric conditions and probing the neural basis of consciousness. Although drug administration context is widely believed to shape psychedelic effects, it remains unclear whether it can independently generate placebo and nocebo effects resembling psychedelic experiences and side effects. In a pre-registered experiment, 78 non-clinical participants inhaled inert medical air under placebo and control conditions while completing a time perception task and a resting-state period. In the placebo condition, the gas was presented as nitrous oxide, whereas in the control, it was correctly identified. Placebo administration increased altered states of consciousness, ego dissolution, dissociation, and side effects, but did not significantly impact time perception. Predictive modelling indicated that placebo-induced psychedelic effects were predicted by trait responsiveness to verbal suggestion and absorption. These findings demonstrate that context alone can induce psychedelic effects, with implications for its causal role in psychedelic action.