Psychoneuroendocrinology

Interleukin-17A (IL-17A) has been implicated in stress- and pain-related inflammation, yet evidence for acute IL-17A stress response in humans remains scarce. This study examined whether the Maastricht Acute Stress Test (MAST) induces changes in circulating IL-17A and how IL-17A dynamics relate to cortisol and subjective stress/pain. Forty-six healthy adults (mean age: 30.50, SD = 12.86 years; 54% female) completed the standardized MAST. Serum IL-17A and cortisol were assessed repeatedly across baseline and recovery. Stress- and pain-related ratings (VAS) and trait questionnaires (e.g., chronic stress, psychological distress, resilience) were completed. There was a significant increase over time in IL-17A and cortisol following the MAST, with an 36 % increase of IL-17A level measured at 105 min post-stressor and cortisol peaking at 10 min post-stressor. IL-17A indices (baseline and AUCi) showed no meaningful associations with cortisol, subjective stress/pain, or psychological traits, whereas cortisol response (AUCi) correlated positively with perceived acute stress and pain. Overall, the MAST produced clear IL-17A and cortisol responses that appeared dissociable in healthy individuals. Future studies should include broader inflammatory panels and clinical or high-stress samples to clarify conditions under which IL-17A covaries with HPA-axis activity and subjective experience.

The cortisol awakening response (CAR) marks the transition from rest to wake phase by a sharp increase in cortisol levels upon awakening in the morning. This increase may assist in cognitive and behavioral awakening, but its function is not fully understood yet. In this pilot study we aimed to provide first data on the influence of immune system activity on the CAR. Thereby, a within-subject analysis approach was applied to avoid confounding by between-subject bias and improve inference of the results. Three healthy subjects collected their overnight urine for analysis of neopterin (Th1 immune activation marker) and sampled saliva at 0, 30, and 45 minutes after awakening in the morning for cortisol determination and CAR estimation. Additionally, subjects wore an EEG-headband overnight for objective determination of the awakening timepoint. Random-effects models were computed to estimate the effect of overnight neopterin on the CAR. There was a significant positive effect of overnight neopterin levels on the CAR, indicating that overnight Th1 immune activation may predict the dynamic increase of cortisol in the morning, with higher immune levels leading to a stronger CAR. These results provide first evidence for the immunological awakening hypothesis and a potential role of the CAR in the maintenance of circadian immune rhythms, but given the small number of participants, findings should be interpreted as exploratory.

Emerging evidence suggests that saliva cell-free mitochondrial DNA (cf-mtDNA) increases in response to psychosocial and physical stress. Here, we quantified saliva cf-mtDNA changes in response to acute physical and cognitive stressors as well as identifying potential predictors of these responses, while also exploring the potential modulatory effects of transcranial infrared laser stimulation (TILS). In a crossover design, a total of 47 participants (53% female, ages 18-30) underwent up to three experimental sessions, including an exercise stress task and two cognitive stress tasks. Repeated saliva samples were collected for cf-mtDNA and cell-free nuclear DNA (cf-nDNA) quantification, alongside continuous measurement of heart rate, oxygen consumption, and blood pressure. Our results show that average cf-mtDNA levels increased by 90% after baseline during exercise experiments, and in cognitive stress experiments peaked 160% above average baseline levels during the stress task. Inter-individual differences in response trajectories were associated with differences in factors such as fitness, sleep quality, and stress perception. Notably, participants with higher cf-mtDNA elevations during the exercise experiment reported fewer recent stressful incidents, drank alcohol less frequently, had higher maximum VO2 during exercise, and had lower BMI. More dynamic responses to cognitive stress were observed in participants with poorer sleep quality and greater blood pressure reactivity. These findings provide a foundation for larger studies by highlighting the dynamic behavior of saliva cf-mtDNA following physical and cognitive stressors, and by suggesting potential drivers of individual differences in saliva cf-mtDNA stress reactivity.

Social bonds are fundamental to health and well-being, and their disruption through partner separation is associated with significant physiological and psychological consequences. The kappa opioid receptor (KOR) system has been proposed as a key modulator of oxytocin (OT) release during partner separation, with prolonged separation hypothesized to trigger KOR downregulation in the paraventricular nucleus of the hypothalamus that disinhibits OT release over time (Bales & Rogers, 2022). However, this model has been difficult to assess non-invasively in primates. The present study used positron emission tomography (PET) with the KOR-selective radiotracer [11C]GR103545 to examine KOR availability in vivo across brain regions implicated in social bonding and separation distress in 16 pair-bonded titi monkeys using a within-subject two-week separation paradigm. Plasma OT, cerebrospinal fluid OT, and plasma cortisol were collected at each scan as complementary indices of peripheral and central OT signaling and physiological stress. We hypothesized that long-term separation would downregulate KORs in the hypothalamus and pituitary, indexed by reduced non-displaceable binding potential (BPND), consistent with the Bales and Rogers model, and increase plasma OT consistent with KOR downregulation disinhibiting OT release. Partner separation significantly elevated plasma cortisol in both sexes, confirming the physiological stress of the manipulation. A significant Condition x Sex interaction was observed for plasma OT, reflecting a crossover pattern in which males, who had significantly higher plasma OT than females at baseline, showed a significant decrease during separation while females showed a non-significant increase, though the sex difference during separation did not reach significance. KOR availability was significantly reduced in the nucleus accumbens during separation, with a non-significant trend toward reduction in the anterior cingulate cortex, while no significant condition effects were observed in the remaining a priori chosen regions. No significant sex effects or Condition x Sex interactions were observed in any a priori chosen PET region. Together, these findings provide the first in vivo neuroimaging evidence of KOR system engagement during partner separation in a pair-bonded primate species, and reveal a sex-dependent OT response to separation that extends and adds nuance to the Bales and Rogers (2022) framework.

Previous research suggests that women and men may differ in moral decision-making involving instrumental harm. However, prior findings have yielded inconsistent explanations for these differences, suggesting effects of gender expression, empathy, action tendencies, and biological causes, such as differences in gonadal hormone levels. Yet, no data exists on the effects of endogenous estradiol and progesterone on moral decision-making, while the effects of testosterone are inconsistent. Our study aimed to close this research gap. A sample of 137 cis individuals (73 women, 64 men) completed a moral dilemma task based on the Consequences, Norms, Inaction (CNI) model either in the morning or evening. Relevant personality traits, including agreement with instrumental harm, impartial beneficence, empathy, and gender expression, were assessed via self-report. Blood samples were analyzed for estradiol, progesterone, testosterone, and cortisol. Contrary to prior literature, no behavioral differences between women and men were observed in moral decision-making. However, self-reported agreement with instrumental harm positively predicted sensitivity to consequences and negatively predicted adherence to moral norms in the whole sample. Estradiol concentration positively predicted sensitivity to consequences in the morning women group, and general inaction tendency in the morning men group. Overall, these findings highlight the joint influence of biological and personality factors on moral choices and hint towards subtle sex/gender differences.

Although female rats are typically less aggressive than male rats, lactating females will vigorously defend their nests and pups against an intruder. Much attention has been directed at the consequences of this aggression on the intruder and less on the consequences for the mother and her subsequent interactions with her pups. Here, we exposed resident Sprague-Dawley dams to the resident-intruder paradigm twice daily for five consecutive days, beginning when the dam's (RES) pups were 7 days old, to assess social stress effects on maternal behavior and neurobiology. Controls were dams that had time-matched (TMC) separation from their pups but were not exposed to intruders, and naive moms which were never separated nor exposed to an intruder (CTL). We assessed the dam's subsequent behavior and interactions with her pups on Day 1 and Day 5, and Fos expression after Day 5 in select regions of the prefrontal cortex, amygdala, hypothalamus and periaqueductal gray of the midbrain. In separate cohorts, after pups were weaned, the dams underwent restraint stress and plasma corticosterone assayed. PCA analysis of the dam's behaviors identified three components: normal self-focused behaviors; nurturing behaviors and rough non-nurturing behaviors. Relative to CTL, RES dams exhibited more disrupted behaviors towards their pups, including, rough transport, stepping on pups, and flinging/tossing pups around the cage. In contrast, TMC Dams showed some, but fewer changes relative to CTL, suggesting that separation from pups alone does not account for all disrupted behavior in RES dams. The bulk of these behavioral effects occurred in the first 5-10 min after reunion with the pups and were seen on both the first and fifth day of testing. Of the brain regions examined, the prefrontal cortex was activated by both the defeat/intruder stress (RES) and separation stress (TMC), whereas the dorsal PAG was activated specifically by the defeat/intruder stress. The medial and basolateral amygdala exhibited differential neuronal activity between the RES defeat/intruder-exposed dams and the other two groups. The RES moms exhibited an insufficient adrenocortical response to acute restraint stress. The results suggest that amygdala-dPAG activity is important for dissociating disrupted maternal care in RES (due to defense of the nest against an intruder) from simple pup separation, both of which activate the mPFC. The experience of repeatedly defending the nest may induce subsequent disruptions in HPA responses. The amygdala-dPAG pathway may regulate aspects of stress and emotional regulation exhibited by mothers who defend their offspring against intruders.

Psychosocial distress is associated with adverse perinatal outcomes, yet its biological correlates remain incompletely understood. We evaluated associations of prenatal psychosocial distress with allopregnanolone (ALLO) and related steroids, and assessed race/ethnicity as a potential effect modifier, using data from 237 participants from the Healthy Start Study. We selected participants based on high distress (Edinburgh Perinatal Depression Scale [EPDS] >=13 or EPDS-3A >=7; n = 57) or low distress (EPDS <4 and EPDS-3A <2; n = 180). We quantified ALLO, progesterone, pregnanolone, cortisol, and cortisone in maternal serum using HPLC-MS/MS at two timepoints in pregnancy for each participant, (median ~17 and ~27 weeks gestation; range: 10-34 weeks). We modeled the relationship between high vs. low prenatal distress with repeated measures of the steroid hormones using linear mixed-effects models. We found that ALLO was 20.6% lower (95% CI: -30.9%, -8.7%) in high-distress individuals after adjusting for maternal age, fetal sex, smoking and gestational age at blood draw, with no evidence of effect modification by race/ethnicity. However, this association attenuated after additional adjustment for sociodemographic characteristics. Several ALLO-related ratios were lower with high distress, but only ALLO-to-progesterone remained significant across models. These findings suggest that associations between psychosocial distress and circulating ALLO concentrations during pregnancy are influenced by social and structural factors, with the exception of the ALLO-to-progesterone ratio, which may capture aspects of neurosteroid metabolism more closely linked to prenatal psychosocial distress.

Major depressive disorder (MDD) is a severe psychiatric disorder that affects more than 350 million people worldwide, yet its biomolecular mechanisms are incompletely understood, and clinically applicable markers remain elusive. To shed new light on the underlying pathophysiology of MDD across multiple research disciplines, we first used a biochemical fingerprinting approach with human hair (the first 3 cm cut from the scalp) to identify changes in the total set of detectable metabolites and lipids (metabolipidomics) using quadrupole time-of-flight mass spectrometry (qToF-MS). In this study, we focused on endocannabinoid (ECB)-related lipid compounds and identified 7 candidate markers that differed between depressed and non-depressed female participants. Two phosphatidylinositols, namely PI 24:0 and PI 37:4, showed dose-dependent associations with the severity of depressive symptoms. Finally, to bridge hair findings with previously reported results in blood, we tested associations between changes in identified ECB-related compounds and parameters of mitochondrial respiratory activity in peripheral blood mononuclear cells. We found 17 significant associations, with the strongest effects for the lipids PI 24:0, MGDG-O 16:3, PG 12:0, and PI 37:4. Our approach not only identified novel associations between endocannabinoid (ECB)-related lipid dysregulation and impaired mitochondrial energy metabolism in MDD but also revealed ECB-related lipids as a possible surrogate marker of impaired bioenergetic metabolism in MDD, at least in immune cells. More research is needed to replicate these findings, ideally by testing reversibility in longitudinal intervention studies and by including both sexes in larger cohorts.

Background Depressive disorders are among the most common mental disorders, often emerging in adolescence. Despite advances in biological psychiatry, research on early psychopathology remains scarce. Given the heterogeneity and comorbidity of depressive disorders, identifying biologically informed phenotypes could enhance diagnostic accuracy and personalized treatment approaches. Methods This study utilized baseline and 6-month follow-up plasma samples (n=47) and clinical data (n=103) of adolescent outpatients with depression (DD, aged 14-19) from the Finnish SMART study and healthy control samples (HC, n=53, aged 15-16) from the Finnish PANIC study. Fasting plasma samples were analyzed using untargeted liquid chromatography-tandem mass spectrometry for proteomics. Data analyses included dimensionality reduction, regression models, correlation analysis, functional enrichment, and factor analysis of mixed data with k-means clustering, including 72 symptom-related items, lifestyle, and socioeconomic scales. Results Among 756 proteins detected in DD and HC, 308 proteins showed notable, significant (adjusted p<0.01 and Log2FC [&ge;]|1|) alterations in depression. These proteins were enriched in stress-response pathways, including complement and coagulation cascades, energy metabolism, the proteasome complex, and growth factor signaling. Additionally, extracellular matrix proteins were altered. Clinical phenotypes were mostly distinguished by symptom severity, bullying victimization and other trauma-related experiences, social relationships, and medication. Improvement in mood over the 6-month follow-up was associated with shifts in proteins involved in extracellular matrix, cytoplasmic vesicles, and complement and coagulation cascades. Conclusions Together, adolescent depression displays shared plasma proteomic signatures across its clinical phenotypes, and systemic immune dysfunction, oxidative stress, and extracellular matrix are potential targets for biologically informed interventions in depression.

IntroductionEnvironmental factors are increasingly implicated in the etiology of autism spectrum disorder (ASD). Polybrominated diphenyl ethers (PBDEs) are anthropogenic toxicants added as flame retardants to consumer products that have become ubiquitous environmental contaminants and disrupt thyroid hormone (TH) and neuroendocrine systems. We have previously shown that developmental PBDE exposure produces ASD-like traits with involvement of oxytocin (OXT)-thyroid hormone signaling. Limosilactobacillus reuteri (LR), a widely used probiotic bacterium, has been shown to improve social functioning and increase TH and OXT levels in murine models. Therefore, we tested the hypothesis that LR supplementation (LR) prevents PBDE-induced deficits in socioemotional behavior with concomitant modulation of TH signaling genes on hypothalamic OXT neurons. MethodsC57BL/6N mouse offspring were exposed to a commercial penta-mixture of PBDE congeners, DE-71, at an environmentally realistic concentration, 0.1 mg/kg/d (DE-71), or to corn oil vehicle (VEH/CON) via their mothers during gestation and lactation. Offspring received supplementation with LR ATCC PTA 6475 (107-108 CFU/mL, po) indirectly via the dam or continuation directly through adulthood. Unsupplemented controls were given saline. ResultsFecal microbiome analysis in offspring confirmed colonization of LR at postnatal day (P) 40 and depletion by P104. LR treatment increased plasma total thyroxine in DE-71 and plasma OXT in VEH/CON dams. In DE-71 offspring of both sexes, LR normalized deficient scores on social novelty preference and emotional recognition in adult females and males and deficient long-term social recognition memory (SRM) in adult DE-71 females; DE-71 males were normal. Reduced olfactory dishabituation between two social odors may partly explain the compromised socioemotional behavior produced by DE-71 in an LR-dependent manner. Multiplex RNA in situ hybridization performed on immunoreactive OXT-ergic neurons in the paraventricular hypothalamic nucleus (PVH) revealed significant upregulation of TH transporter monocarboxylate transporter 8 (Mct8) and downregulation of iodothyronine deiodinase 3 (Dio3) in DE-71 relative to VEH/CON females. This toxicant-induced reprogramming was prevented by probiotic treatment. DE-71 males expressed reduction in Mct8 and Dio3 transcripts on OXT-ergic neurons with minimal LR protection. In the female supraoptic nucleus (SON), Mct8 and Dio3 were downregulated by DE-71 and normalized in DE-71+LR; there were no group effects on transcript levels in male SON. Results of fecal 16S rRNA sequencing indicated reduced -diversity and altered {beta}-diversity in the gut bacterial community of female but not male DE-71 exposed offspring; most changes were correctable by LR. Alterations in taxa-level abundance caused by DE-71 and reversed by LR were observed in both sexes. These involved Bifidobacterium, Coprococcus, Desulfovibrio, Oscillospira, and Peptococcaceae in females and Desulfovibrionaceae, Rikenella, and Turicibacter in males. Exposed dams showed no detriment in - and {beta}-diversity while showing reduced abundance of several Firmicutes and Proteobacteria taxa that could be rescued by LR. The relative abundance of Lactobacillus was upregulated in DE-71 males and DE-71+LR males and dams. ConclusionsThese results indicate that developmental probiotic supplementation effectively mitigated organohalogen-induced ASD-like deficits in socioemotional behavior and partially corrected dysbiosis of gut bacterial communities in exposed offspring of both sexes. Concomitantly, PBDEs altered the expression of TH regulatory genes Mct8 and Dio3 in PVH OXT neurons in a sex-dependent manner, suggesting that TH regulation of OXT neuroendocrine cells may modulate the emergence of toxicant-induced ASD-relevant behavior. While LR reinstated normal behavioral outcomes in PBDE-exposed offspring of both sexes, coincident normalization of hypothalamic TH signaling transcripts occurred more broadly in females, indicating the existence of unique parallel processes influencing the preventive effects of LR on ASD-relevant behavioral deficits in both sexes.

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.

Combined oral contraceptives (OCs), containing synthetic estrogen and a progestin such as levonorgestrel (LVNG), are widely used, and up to 10% of users experience adverse mood states and increased depression risk. It is well-established that OCs modulate the hypothalamic-pituitary-adrenal (HPA) axis and blunt the cortisol responses to acute stress. This interaction with stress regulatory pathways is one mechanism by which OCs might impact mood. Here, we used a mouse model of OC exposure (ethinyl estradiol (EE) + LVNG) to investigate how OCs affect regulation of the diurnal CORT cycle and stress-related signaling in the dorsal and ventral hippocampus and paraventricular nucleus of the hypothalamus (PVN). We found that EE+LVNG did not alter basal corticosterone (CORT) levels, but impaired glucocorticoid receptor (GR) - mediated negative feedback in the dexamethasone suppression test. Molecular analyses revealed distinct, region-specific effects. In the dorsal hippocampus, EE+LVNG enhanced glucocorticoid receptor (GR)-dependent gene signaling and prolonged Fkbp5 induction. In the ventral hippocampus, EE+LVNG enhanced mineralocorticoid receptor (MR)-dependent signaling and reduced stress-induced corticotropin-releasing factor expression. In the PVN, EE+LVNG reduced MR expression and modulated MR-dependent signaling. Together, these findings demonstrate that chronic OC exposure disrupts GR- and MR-dependent regulation across stress-related brain regions and impairs glucocorticoid feedback, providing potential mechanisms by which OCs blunt stress responsivity, modify long-term HPA-axis function, and increase susceptibility or resilience to stress and depression.

Family environments may contribute to childrens long-term health through biological processes, including epigenetic regulation such as DNA methylation (DNAm). However, most studies in this area focus on Euro-American populations while also rarely including fathering data. The current study investigated childrens blood DNAm associations with positive (father caregiving) and negative (parental conflict) family dynamics in a smaller-scale subsistence society living in the Congo Basin rainforest. We measured DNAm from dried blood spots of 54 children (mean age=8.48 years) and conducted three epigenome-wide association studies aimed at discovering differential co-methylated regions (CMRs) associated with family dynamics. Via path models, we investigated the health implications and shared contribution of family factors of the identified CMRs. Differential DNAm associated with family dynamics was localized to genes related to stress, immunology, development, and aging, thus possibly linking to childrens physical health and were simultaneously connected to other family factors such as number of siblings. Our findings suggested similarities in biological embedding of family factors across socio-ecologically diverse contexts.

Air pollution exposure has been associated with increased risk of developing mental health problems. It is possible that individuals at high genetic risk for psychopathology may be more vulnerable to these effects; however, this question remains to be investigated. We leveraged longitudinal data from n=10,620 participants from the Adolescent Brain Cognitive Development Study to first investigate sex-stratified associations of particulate matter (PM2.) exposure and genetic risk with mental health trajectories across 9-16 years including internalizing symptoms and psychotic like experiences (PLEs). Additionally, we tested whether genetic risk for schizophrenia (PRS-SCZ) and major depressive disorder (PRS-MDD) exacerbate the association with PM2. exposure and change in symptoms over time. PM2. exposure was associated with lower decreases in PLEs over time in females (p-FDR=0.005), with no effects on internalising symptom trajectories in either sex. Genetic influences were sex-specific, with higher PRS-SCZ and PRS-MDD linked to greater increases in internalising symptoms in females (p-FDR=0.009; p-FDR=0.022) and higher PRS-MDD associated with greater decreases in PLEs in males (p-FDR=0.001). In females we also observed an interaction between PM2. and PRS-MDD on PLEs trajectories (p-FDR=0.048) such that those with high genetic risk and high PM2.5 exposure demonstrated increases in PLEs over time. Our results suggest that PM2. exposure and polygenic risk for depression jointly shape mental health during adolescence. This underscores the potential of interventions aimed at lowering air pollution during sensitive periods of neurodevelopment in improving adolescent mental health.

Prenatal alcohol exposure (PAE) is a major cause of neurodevelopmental disorders, yet most children are diagnosed late or misdiagnosed. Neuroplacentology suggest that placental factors released into maternal and/or umbilical cord blood contribute to fetal brain development. Consistently, a preclinical inter-organ transcriptomic database revealed that PAE disrupts the expression ratio of angiogenic and inflammatory factors suggesting an angio-inflammatory response. This study aimed i) to assay, by multiplex immunoassay, angiogenic and inflammatory factors in maternal and umbilical cord blood from alcohol-consuming women and ii) to perform a maternofetal analysis according to neonatal sex. Afterwards, dysregulated factors from mothers who gave birth to females or males were submitted to STRING and ShinyGO analyses. Results showed that PAE differently altered the distribution profiles of dysregulated angiogenic and inflammatory factors in maternal and umbilical cord blood. Moreover, sex-specific differences were observed, with 36% of dysregulated proteins specific to males, 48% to females, and 16% common to both. STRING analysis revealed robust functional protein-protein interactions linking together inflammatory and angiogenic clusters while the ShinyGO analysis identified enriched pathways related to vascular shear stress. These findings provide the first maternofetal analysis of combined angiogenic and inflammatory factors from alcohol-consuming mothers.

Voluntary physical activity is a highly motivated behavior with important implications for physical and mental health, yet the neural and endocrine mechanisms underlying motivation to exercise remain poorly understood. In contrast, motivation for sugar/palatable foods, drugs, and sex has been extensively characterized using operant paradigms. Here, we describe a novel progressive ratio operant task to measure motivation to run, independent of running ability. Using female Long Evans rats, which exhibit robust voluntary running behavior, we validated this paradigm by applying a manipulation well known to enhance the motivation to run: calorie restriction. Calorie-restricted animals exhibited increased operant responding to gain access to a running wheel, thus demonstrating heightened motivation for exercise. More specifically, calorie-restricted rats completed more ratios, reached a higher breakpoint in the progressive ratio task, ran more, and spent more time in the operant chamber. We did not observe any effects of calorie restriction on the estrous cycle or steroids (e.g. corticosterone, testosterone) in the blood or brain. Importantly, our task dissociates the motivational drive for physical activity from the ability to perform the physical activity itself, providing a new paradigm for studying the neural and endocrine mechanisms that regulate exercise motivation.

Cortisol, our stress hormone, exerts widespread influence on neural activity. However, its influence on the aperiodic component of the electroencephalography power spectrum remains to be investigated. Given individual differences in the capacity to cope with stress and adversity, it also remains unclear whether trait resilience moderates this relationship. Hence, the present study examined whether individual differences in trait resilience moderates the association between resting cortisol and aperiodic activity. Participants (N=145) completed various self-report questionnaires (e.g., trait resilience). Electroencephalography was recorded over a 20-minute baseline period, followed by salivary cortisol collection. The results revealed a significant moderating effect of trait resilience in the occipital scalp region. Specifically, higher cortisol concentration was associated with flatter 1/f slopes amongst individuals with low trait resilience, whereas this association was reversed amongst those with high trait resilience. Overall, our findings highlight the role of individual differences in trait resilience in shaping hypothalamic-pituitary-adrenal axis-related neural dynamics.

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.

RationaleThe -opioid receptor (MOR) is widely expressed across tissues and plays crucial roles in pain and stress responses, social behaviour, and immune regulation. Recent evidence indicates seasonal variation in in vivo MOR signalling; for example, short photoperiods are associated with reduced central MOR availability, increased MOR expression in brown adipose tissue (BAT), and strengthened brain-BAT interactions. However, despite this coupling with photoperiod, it remains unclear whether static daylength and dynamically changing photoperiods exert distinct effects, as adaptation to photoperiod transitions may itself induce stress-related modulation of the MOR system. Elucidating how seasonal, stress-related adaptations influence MOR signalling is essential for advancing our understanding of seasonal fluctuations in mood and stress regulation. MethodsWe compared rats housed under seasonal photoperiod cycling with those maintained under constant photoperiod conditions, using ex vivo radioligand binding to directly assess MOR density in central and peripheral tissues. ResultsRats exposed to seasonal photoperiod cycling showed markedly reduced inter-individual variability in MOR density in both the brain (including the cerebellum and striatum) and peripheral tissues (adrenal glands), whereas no tissues exhibited substantially increased variability. ConclusionsThese findings demonstrate that seasonal photoperiod cycling stabilizes MOR dynamics at the population level, suggesting stress-related synchronization of MOR signalling. The findings deepen our understanding of seasonal effects on endogenous MOR signalling, and further underscore the role of seasonal light variation in modulating mood-related processes.

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.