Deficiencies in oxytocin are associated with neurodevelopmental and behavioral disorders, and the oxytocin gene (Oxt) can be regulated by thyroid hormone. We have previously shown that a systemic excess of thyroid hormone during development causes deficits in oxytocin that are associated with major abnormalities in mood-related and social behaviors. To determine whether the disruption in oxytocin physiology is responsible for these aberrant behaviors we targeted thyroid hormone excess to oxytocin neurons using a mouse model of conditional deficiency of the type 3 deiodinase (DIO3), the neuronal enzyme responsible for the clearance of thyroid hormones and the modulation of thyroid hormone action. We observed that mice of both sexes with T3 excess in oxytocin neurons largely recapitulated the oxytocin deficits of systemic thyrotoxicosis, and exhibited reduced neonatal and adult hypothalamic expression of Oxt mRNA, markedly blunted pituitary Oxt expression and lower serum levels of oxytocin. However, these mice did not show any significant abnormality in physical activity levels, depression- and anxiety-like behaviors, aggression, sociability or maternal behavior. We conclude that T3 excess in mouse oxytocin neurons is sufficient to cause significant oxytocin deficits, but insufficient per se to cause detectable abnormalities in behavioral profiles. Our results suggest that the profound behavioral syndrome previously observed in mice with systemic developmental thyrotoxicosis likely involves other brain neural circuits affected by developmental T3 excess that remain to be identified.

Allostatic load (AL), a composite of biological measures, is frequently used to capture the physiological burden of chronic stress and is associated with cognitive decline. Black Americans are more likely to develop Alzheimer's disease and related dementias than White Americans, but racial disparities in the AL-cognition relationship have been under explored. Additionally, AL is not consistently measured in literature. The aim of this research was to examine racial variation of the AL-cognition relationship using various AL scoring methods. Data were from the 2006-2016 waves of the Health and Retirement Study, and the sample included 29,809 person-waves of White adults and 7612 person-waves of Black adults. Cognitive function was measured using a modified Telephone Interview for Cognitive Status (mTICS). AL calculation methods included quartile, z-score, and clinical cut-offs. Each measure defined biomarker levels as either high risk or low risk. For 'one-tailed' measures, higher values indicated higher risk for all biomarkers except HDL, for which lower values indicated higher risk. For quartile and z-scores, additional two-tailed measures were calculated which define risk at both unusually low and high biomarker levels. Mixed models were run examining both within-person and between-person change in allostatic load measures in relation to cognitive function. Two-tailed measures more strongly predicted cognitive function both within- and between-persons than traditional quartile or clinical cut-offs, particularly in the Black sample. Findings suggest that nonlinear relationships should be given greater consideration when examining AL, particularly in diverse populations of older adults.

Pain is felt and expressed through a complex interaction of biological, psychological, and social factors. While hormonal factors have been linked with pain in humans, these factors are underexplored. In this study, daily-diary data from the publicly available Texas Longitudinal Study of Adolescent Stress Resilience and Health dataset was used to examine the longitudinal relationship between a series of stress and sex hormones with self-reported headache, backache, stomachache. Latent growth modeling within a generalized structural equation modelling framework was used. A total of 735 students from 9th grade high school contributed self-reported daily diary on their mental and physical health alongside saliva samples up to 10 days. Analyses included available diary observations with complete data for each model with analytic sample size ranging from 440 to 530 participants. The hormones cortisol, testosterone, estradiol, progesterone, and DHEA-S were all examined as independent variables. In the adjusted models that did not control for sex, higher testosterone was associated with a decrease in the likelihood of having backache (β = -.24, p < .001), headaches β = -.20, p < .001) and stomachache (β = -.19, p < .001). Cortisol was positively associated with a higher likelihood of backache (β =.16, p = .034). In a stratified analysis based on pubertal status, testosterone remained negatively associated with the likelihood of having a headache, backache, and stomachache for participants in late/post puberty. The current study provides evidence that variations in hormonal levels depend on pubertal status when impacting pain.

Adolescence begins with puberty and involves dynamic hormonal, neural, and social changes. The early-pubertal testosterone surge, particularly in boys, may shape the amygdala, which regulates emotion and behavior. However, it remains unclear how testosterone- and amygdala-related correlates of psychobehavioral problems differ across early adolescence. Using data from the Tokyo Teen Cohort and its neuroscience extension, we examined associations among salivary testosterone, amygdala volumes, and parent-rated Child Behavior Checklist (CBCL) scores at approximately ages 10-11 and 12-13. Participants were 106 boys in wave 1 and 98 boys in wave 2, with 69 contributing complete biological measures at both waves. Wave-specific Poisson models of CBCL internalizing and externalizing scores were adjusted for age, Tanner stage, and intracranial volume. In wave 1, higher testosterone was associated with lower internalizing and externalizing scores (exp(β)= 0.64 and 0.66, both adjusted P < 0.001). In wave 2, testosterone was not significantly related to CBCL scores, whereas smaller right amygdala volume was associated with higher internalizing problems (exp(β)= 0.71, adjusted P < 0.001). Exploratory analyses suggested that testosterone moderated the wave-2 right amygdala-internalizing association, and that smaller right amygdala volume and lower testosterone at wave 1 were both prospectively associated with higher wave-2 internalizing problems (n = 104), associations that persisted after adjustment for wave-1 Internalizing score. These findings suggest age-dependent differences in endocrine and neural correlates of psychobehavioral problems and highlight the importance of developmental timing and hormone-brain interplay.

Burnout is highly prevalent in high-demand healthcare professions, with medical students and trainees already at increased risk. The pathophysiological processes associated with burnout remain insufficiently understood as previous research is mostly limited to cross-sectional studies focusing on specific biological correlates. This study aims to investigate a wide range of biological correlates associated with burnout symptoms by exploring cortisol, cortisone, and multiple inflammatory markers in medical students and physicians-in-training. A three-year open cohort study was carried out in medical students and physicians-in-training. Burnout symptoms were assessed using the Maslach Burnout Inventory. The cortisol and cortisone awakening response were measured simultaneously in saliva samples via liquid chromatography-tandem mass spectrometry, while inflammatory markers were measured in blood samples. Linear mixed-effects models were used to investigate changes of biological correlates in burnout symptoms. In total, 154 participants were included, contributing 241 measurements. The analysis indicated no significant associations between burnout symptoms and cortisol or cortisone awakening responses. Higher burnout symptoms were associated with a lower inflammatory index, and associations between inflammatory markers and HPA-axis measures were observed. Our results suggest associations between burnout symptoms and inflammatory markers, as well as between inflammatory markers and HPA-axis measures. Long-term follow-up studies with repeated assessments are needed to further investigate the biological correlates of burnout and its relationship with neuroendocrine-immune processes.

Posttraumatic stress disorder (PTSD) is a chronic psychiatric disorder associated with functional impairment and health burden. Evidence highlights the role of large-scale neural network disruptions, within and between the Default Mode Network (DMN) and Salience Network (SN), in PTSD pathophysiology, and early alterations in these networks may serve as biomarkers for predicting PTSD symptom trajectories and guiding early interventions. This longitudinal mega-analysis integrated resting-state functional connectivity (rsFC) data from two trauma-exposed cohorts (Tel Aviv and Toledo), collected within the first month posttrauma. Seed-based rsFC analyses focused on DMN regions (hippocampus, ventromedial prefrontal cortex [vmPFC], posterior cingulate cortex) and SN regions (amygdala, insula, dorsal anterior cingulate cortex [dACC]). PTSD symptoms were assessed at 12- to 14-month follow-up using the Clinician-Administered PTSD Scale (CAPS-5) and PTSD Checklist (PCL-5). Early posttrauma reductions in within-DMN connectivity, particularly between the hippocampus and rostral ACC/vmPFC, mPFC, and inferior parietal lobe, were associated with greater PTSD symptom severity at annual follow-up. Decreased connectivity between the DMN and visual cortex (calcarine) was also linked to more severe symptoms. Decreased DMN-SN connectivity, specifically between the amygdala and rostral ACC/vmPFC, was linked to more severe symptoms at follow-up, adding to a complex picture of the relationship between networks. Early disruptions in within-DMN connectivity emerged as the most consistent neural correlate of later PTSD symptom severity. These findings underscore a central role of within-DMN dysfunction in PTSD pathophysiology, reflecting deficits in context processing governed by hippocampus-mPFC circuitry. Identifying these early neural markers may guide targeted interventions to prevent chronic PTSD.

Native Americans (NAs) experience disproportionate exposure to chronic sociocultural stressors that may shape physiological stress systems and contribute to health disparities. Yet, little research has examined acute stress reactivity, stress recovery, and their predictors in NAs. The present study investigated the independent and joint effects of sex and socioeconomic position (SEP) on sympathetic-adrenomedullary (SAM), hypothalamic-pituitary-adrenal (HPA), and negative affective responses to the Trier Social Stress Test (TSST) in 120 healthy NA adults (74 women). SEP was assessed using objective (household income) and subjective (subjective social status) indicators. SAM (skin conductance level, heart rate, blood pressure), HPA (cortisol), and negative affect were measured during baseline, stress, and recovery. Men displayed robust stress responding across all measures, whereas women showed robust SAM and affective responses but blunted cortisol reactivity. Exploratory analyses suggested this difference was not likely explained by hormonal contraceptive use. Lower income was associated with heart rate blunting in both sexes and cortisol blunting among men. By contrast, cortisol blunting was consistent across the income gradient among women. Lower income was associated with poorer cortisol recovery in both sexes. Subjective social status was unrelated to stress outcomes. These findings suggest that sex and SEP jointly shape stress physiology among NAs and support an intersectionality-informed understanding of stress-system functioning. Future research is needed to further understand how sociocultural and structural stressors become biologically embedded in NA populations and contribute to stress-related health disparities, but to also identify sources of resilience.

Insomnia is characterized by a state of hyperarousal, sometimes seen as increases in hypothalamic-pituitary-adrenal (HPA) axis activity (e.g., greater cortisol secretion). The evidence for the association between insomnia symptoms and HPA-axis functioning, however, is surprisingly mixed. Moreover, few studies have investigated whether insomnia is related to differences in cortisol responses to acute stressors. We used an in-lab, cross-sectional design to collect insomnia symptoms and salivary cortisol stress data from 295 young adults. Mixed effects models were used to examine whether differences in insomnia symptom severity were associated with cortisol reactivity to a psychosocial stressor. The study findings supported that greater insomnia symptoms were associated with a significantly more blunted cortisol stress response. Gender and hormonal contraceptive use were also associated with more blunted cortisol slopes, but the link between insomnia symptoms and cortisol stress reactivity remained significant even when controlling for gender and contraceptive use. These data add additional support to growing evidence that insomnia symptom severity is associated with alterations in HPA-axis functioning in response to acute laboratory challenges.

Animal studies suggest that osteocalcin (OCN) may play an important role in the early steps of parasympathetic nervous system withdrawal to initiate the autonomic nervous system (ANS) component of the fight-or-flight response to stress. However, the OCN response to stress has not yet been well-characterized in humans. This study examined reactivity of OCN, measured in saliva, in response to acute social stress in healthy African Americans, and considered associations of OCN reactivity with well-established biomarkers associated with stress-reactivity of the autonomic, endocrine, and immune systems. Participants were 60 healthy African Americans (20 men, 40 women; Mage = 27.33 years) who completed a modified Trier Social Stress Test (TSST). Saliva collected before, during, and after the TSST was assayed for OCN, cortisol, alpha-amylase (sAA), and interleukin-6 (IL-6). Salivary OCN (sOCN) exhibited strong reactivity, including a 19% increase for the full sample, and a 58% increase from pre- to post-stressor levels among men. We also observed muted recovery of sOCN in response to the TSST, but only among men. Among men, individual differences in sOCN stress reactivity and recovery were significantly predicted by sAA reactivity and recovery (β = .51, p = .021; β = .45, p = .026, respectively), but not with task-related change in cortisol or IL-6. Findings suggest OCN may be a specific early-phase and ANS-related component of the multisystem acute stress response in humans. Results further highlight possible sex differences and raise awareness that OCN dysregulation may be implicated in stress-related health disparities.