Hormones and Behavior

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.

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.

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.

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.

AimThe aim of the present study was to determine whether pharmacological inhibition of aldosterone synthesis during the stress-hyporesponsive period (SHRP) affects behaviour and adrenocortical stress responsiveness later in development and whether these effects differ between males and females. MethodsNewborn Wistar rat pups (males n=40, females n=40) were treated with aldosterone synthase inhibitor FAD286 (30 mg/kg per day, orally) or vehicle from PND3 to PND9. To verify the pharmacodynamic action of FAD286, serum and adrenal glands from 10-day-old pups were analysed. The remaining pups were weaned on PND21 and underwent open-field (PND23), elevated plus-maze (PND29) and salt-preference testing. At PND46, half of each group was exposed to restraint stress for 120 min. ResultsIn 10-day-old pups, treatment with FAD286 resulted in increased gene expression of CYP11B2 (aldosterone synthase) and CYP11B1 (11-beta-hydroxylase) in the adrenal glands, increased serum levels of corticosterone, and decreased concentrations of serum aldosterone. FAD286 did not modify the general locomotor activity assessed in juvenile rats. Inhibition of aldosterone synthase by FAD286 resulted in altered anxiety-like behaviour in a sex-dependent manner. Postnatal FAD286 treatment led to increased anxiety-like behaviour in female, but not male rats. During adolescence, early FAD286 treatment increased overall aldosterone concentrations without altering the aldosterone response to restraint. Basal corticosterone concentrations were unchanged, whereas the response to restraint was enhanced. ConclusionsThe present study demonstrates that transient inhibition of aldosterone synthesis during the SHRP led to alterations in anxiety-related behaviour and adrenocortical regulation later in development, with some behavioural effects being sex-dependent.

Adrenal chromaffin cells are key effectors of the sympathoadrenal response and play a central role in the organisms adaptation to environmental and physiological challenges. While cholinergic and pituitary adenylate cyclase-activating polypeptide (PACAP)-dependent mechanisms have long been recognized as major regulators of catecholamine secretion, increasing evidence indicates that connexin-mediated gap junctional communication provides an additional and highly dynamic level of control. Whether early-life experience modifies the adult capacity of chromaffin-cell networks to undergo stress-induced connexin remodeling remains unclear. Here, we examined adrenal medullary connexin expression in adult rats exposed to neonatal maternal separation (MS; 3 h daily, postnatal days 2-15) and later challenged with an 8-day unpredictable mild stress (UMS) protocol. Under basal adult conditions, MS did not produce an overt change in adrenal medullary Cx36 or Cx43 immunoreactivity relative to animal-facility-reared controls. In contrast, UMS increased connexin immunoreactivity in the adrenal medulla, and this response was amplified in animals with a history of MS. MS+UMS animals also displayed enhanced corticosterone responses to acute restraint stress. These findings suggest that neonatal MS does not impose a constitutively altered adult chromaffin-cell phenotype, but instead primes the future stress responsiveness of adrenal medullary connexin remodeling. We propose that chromaffin-cell gap junctions represent a substrate sensitive to stress history, through which developmental experience may influence sympathoadrenal and endocrine adaptation in adulthood.

The lactational period requires substantial metabolic and behavioral adaptations, and more than 70% of mothers report weight concerns and attempt weight loss by four months postpartum. Nevertheless, how distinct restrictive paradigms during lactation alter maternal behavior, and the extent to which associated neurochemical changes modulate these behaviors, remains poorly understood. In the current study, we modeled restrictive diets in lactating rats to evaluate caregiving behavior and its relationship to amygdalar redox status. Intermittent fasting (IF) and caloric restriction (CR) administered to lactating Wistar dams from postpartum day 0 to day 28 impaired maternal care, evidenced by delayed pup retrieval, reduced nest building, and decreased nursing frequency relative to ad libitum-fed controls. Both diets reduced body and adipose tissue weight, and energy efficiency. IF and CR increased impulsivity-like phenotype: CR doubled open-arm exploration in the elevated plus maze; IF and CR increased center-zone exploration in the open field by three- and two-fold, respectively; IF doubled time in the light-dark box light compartment. A composite maternal behavioral score showed impairment in dams in both IF and CR groups. At the neurochemical level, both diets reduced amygdalar superoxide dismutase activity, which correlated negatively with the maternal behavioral score. Both restrictive diets produced an underweight phenotype with weakened dam-pup interactions and increased impulsivity. These behavioral changes co-occurred with amygdalar redox imbalance, which correlated with the severity of maternal impairment. Overall, the study refines understanding of the nutritional and behavioral consequences of dietary restriction in lactation and implicates disrupted redox homeostasis as a plausible mechanism.

Despite the well-established health benefits of exercise, adherence to physical activity remains low, highlighting the need to identify biological factors that regulate the initiation and persistence of exercise behavior. Here, we tested whether ovarian hormone state at the onset of voluntary wheel running (VWR) influences both immediate and long-term exercise behavior in female rats. Females that initiated VWR during proestrus (Pro) ran farther, spent more time running, and ran at higher speeds on the first day of wheel access than females initiating VWR outside of Pro. Remarkably, initiating VWR during Pro also produced persistent increases in running distance, duration, speed, and escalation across subsequent weeks, despite normal cycling through other estrous phases. In contrast, exogenous estradiol (E2) administered at VWR initiation did not alter day-1 behavior, but increased running distance and duration across subsequent weeks without affecting running speed or escalation. To determine whether dorsal striatal dopamine contributes to these effects, we inhibited the substantia nigra (SN) to dorsolateral striatum (DLS) pathway on the first day of VWR. This manipulation reduced the immediate and long-term effects of initiating VWR during Pro on running duration and distance but not speed or escalation. These findings identify behavioral initiation as a critical window during which hormones and nigrostriatal signaling influence future engagement in physical activity. Furthermore, analysis of individual components of VWR architecture reveals that distinct features of VWR behavior can be dissociated mechanistically and thus could be used to investigate separate motivational processes underlying physical activity.

Rationale: Early life stress (ELS) is acknowledged to underlie cognitive and emotional abnormalities linked to stress-related mood disorders. ELS can lead to persistent biases in how uncertain feedback is processed to affect the flexibility of decision-making. Objectives: (1) To investigate the effects of ELS on the flexibility of rats trained on a serial probabilistic reversal learning (PRL) task involving spurious positive and negative feedback. (2) To elucidate the involvement of the stress hormone corticosterone and the noradrenergic and serotonergic systems in modulating how ELS affects PRL. Methods: Male and female rats were intermittently separated from maternal care on postnatal days five to nineteen, inclusively. As adults, the same rats were trained on a deterministic reversal learning task involving certain rewarded or non-rewarded outcomes followed by a PRL task where correct and incorrect responses were rewarded on 80% and 20% of trials, respectively. Dose-dependent effects of the beta-blocker, propranolol, selective serotonin reuptake inhibitor, citalopram and corticosterone were subsequently determined. Results: ELS resulted in an increased responsivity to feedback, specifically in males making more win-stay responses following a reward, that was associated with an increased punishment learning rate. In both control and MS rats, propranolol increased feedback sensitivity, but delayed updating following a rule switch. In contrast, neither citalopram nor corticosterone significantly affected reversal learning. Conclusions: ELS is sufficient to cause persistent changes in how feedback is processed by male rats on a reversal learning task. Activation of beta-adrenergic receptors may be necessary for updating learned associations during decision-making involving uncertain feedback.

Structured AbstractO_ST_ABSImportanceC_ST_ABSThymic involution in humans has traditionally been conceptualized as a linear, age-associated process. Animal studies suggest transient hormone-dependent fluctuations in thymus size during reproductive transitions, including across the estrous cycle, but translational evidence in humans remains limited. ObjectiveTo determine whether thymus size changes across the menstrual cycle in healthy women and whether these changes are associated with fluctuations in estradiol and progesterone levels. DesignObservational repeated-measures study using quantitative computed tomography (qCT). Data were collected as part of an imaging study examining menstrual cycle-related physiological variation. Participants underwent assessments during menses and the early luteal phase within the same menstrual cycle. Mixed-effects models with robust variance estimation evaluated associations between cycle phase, hormonal contraception, reproductive hormone levels, and thymus size. Thymus segmentation was independently conducted by 2 blinded raters. SettingSingle-center university-based imaging study conducted at the University of Iowa. ParticipantsThirty-one non-smoking women with regular menstrual cycles were included, of whom n = 16 used oral hormonal birth control and n = 15 did not use hormonal contraception. Exclusion criteria included pregnancy, breastfeeding, postmenopausal status, diabetes, body mass index greater than 30 kg/m2, hysterectomy, or use of long-term noncyclic hormonal contraception. Participants tracked menstrual cycles using temperature monitoring and ovulation kits before completing visits during menses and the early luteal phase. All participants provided informed consent before study participation. Main Outcomes and MeasuresPrimary outcome was thymus size measured in mm3 using ultra-low-dose qCT imaging. Secondary outcomes included serum estradiol and progesterone levels. ResultsEstradiol levels increased from menses to the early luteal phase independent of hormonal contraceptive status. Progesterone levels were significantly lower among women using hormonal birth control. Thymus size differed significantly by hormonal contraceptive group, with larger thymus volumes observed among women not using hormonal birth control. Among women not using hormonal contraception, 66.7% demonstrated thymic involution from menses to the early luteal phase, compared with 37.5% of women using hormonal contraception. Estradiol and progesterone significantly interacted in predicting thymus size. Conclusions and RelevanceThese findings provide first-in-human evidence suggesting that thymus involution demonstrates short-term dynamics across the menstrual cycle and may be influenced by reproductive hormones and hormonal contraception. Key PointsO_ST_ABSQuestionC_ST_ABSDoes thymus size change dynamically across the human menstrual cycle in association with fluctuations in reproductive hormones and hormonal contraception use? FindingsIn this repeated-measures quantitative computed tomography study of n = 31 healthy women, thymus size demonstrated within-person variation across the menstrual cycle. Greater thymic involution was associated with larger increases in estradiol, whereas increases in thymus size were associated with larger increases in progesterone; thymus size also differed significantly by hormonal contraceptive status. MeaningThese findings suggest that thymic involution in humans may demonstrate short-term hormone-dependent dynamics beyond age-related atrophy, with potential implications for sex differences in immune regulation and inflammatory disease.

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.

Fear conditioning studies have historically relied on freezing as the primary measure of conditioned fear despite evidence that defensive responding is behaviorally diverse and sexually dimorphic. The endogenous opioid system, particularly mu-opioid receptor (MOR) signaling, is known to regulate fear learning and conditioned analgesia, yet its role in alternative fear-related behaviors and sex differences remains unclear. Here, we investigated the effects of systemic naloxone administration prior to auditory fear conditioning on freezing, darting, shock responsivity, and ultrasonic vocalizations (USVs) in male and female rats. Adult Sprague Dawley rats received naloxone (5 mg/kg, i.p.) or saline prior to conditioning and underwent fear recall testing 24 hours later. Naloxone produced sex- and behavior-specific effects across conditioning and recall. During conditioning, naloxone increased freezing in males during baseline and early tone presentations, while females exhibited reduced shock-response velocity and increased post-shock freezing. Naloxone did not significantly alter darting or USV production during conditioning. During recall, freezing behavior did not differ across groups. Naloxone-treated females, however, exhibited a distinct alarm-calling pattern, with fewer callers overall but increased call output among those that vocalized. These findings suggest that MOR antagonism differentially alters distinct components of fear expression in a sex-dependent manner and support the idea that freezing and alarm calling may reflect separable aspects of fear processing.

IntroductionAnorexia nervosa (AN) is more prevalent in women than men, although rates in men are rising. Animal models can provide insight into whether this differential prevalence is rooted in biological mechanisms, but prior studies have yielded conflicting findings. Using the activity-based anorexia (ABA) model, we previously demonstrated that female mice exhibit distinct vulnerable and resilient phenotypes. Here, we use this phenotypic framework to investigate sex differences in ABA susceptibility. MethodsWe tested young adult male C57BL/6N mice using the same ABA protocol used to test age-matched C57BL/6N females. Individual differences in daily bodyweight, food intake, water intake, and wheel running were analyzed and compared across sexes. ResultsMales exhibit the same vulnerable and resilient phenotypes as females, with no sex difference in the proportion of mice exhibiting each phenotype or the repertoire of behaviors characterizing them. In both sexes, vulnerable mice exhibit catastrophic weight loss driven by excessive light cycle running, while resilient mice exhibit weight stabilization driven by adaptive changes in consumption. Running during the feeding window revealed that vulnerability is not driven by a decision to run instead of eat in either sex. ConclusionsABA models adaptive and maladaptive responses to food restriction in both sexes. Behavioral responses to starvation are similar across sexes, suggesting that sex differences in AN prevalence may be driven by stronger sociocultural pressures faced by women to lose weight.

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.

Hormonal regulation of patch-leaving decision-making remains poorly understood. Here, young adult male and female Long-Evans rats were tested in a patch-leaving task before and after orchiectomy (ORCH), ovariectomy (OVX), or sham surgery, and were subsequently assessed in an impulsive-choice task. Patch leaving was measured under long- and short-travel conditions. Before surgery, males showed longer overstay than females during long-travel sessions, whereas no clear sex difference was detected during short-travel sessions. After surgery, orchiectomy did not produce a uniform shift in patch leaving but selectively disrupted the progressive reduction in overstay that normally emerged across repeated long-travel sessions. By contrast, ovariectomy produced weaker effects and did not reveal a comparably robust change in female patch leaving. Spatial and idle occupancy analyses showed that gonadectomy also altered within-patch behavior, with orchiectomy most strongly increasing idling-related measures in males, whereas ovariectomy more strongly redistributed female patch occupancy. Estrous stage did not significantly organize pre-surgical female overstay. Greater impulsive choice was associated with smaller post-surgical reductions in long-travel overstay in the unadjusted analysis. Together, these findings indicate that testicular hormones selectively support patch-leaving adaptation under high travel cost.

To better understand how animals cope with increasingly variable and challenging environments, there is a need to study how prolonged exposure to elevated glucocorticoid hormones (i.e. one mediator of the stress response) affects their physiology. While glucocorticoid elevation is known to increase oxidative stress and accelerate cellular ageing, there is evidence that king penguins (Aptenodytes patagonicus) can prevent oxidative stress during acute stress exposure, suggesting that species may differ in their sensitivity to glucocorticoids downstream negative effects. As king penguins thrive in a seemingly harsh environment, we hypothesized that they may be able to limit the deleterious effects usually associated with chronic glucocorticoid elevation, either through resistance (i.e. prevention of downstream negative effect) or resilience (i.e. rapid recovery following transient negative effect). To test this hypothesis, we experimentally elevated corticosterone levels in incubating king penguins and quantified treatment effects on a suite of physiological traits at multiple time points across incubation and early chick-rearing, up to ca. 2 months after implantation. Corticosterone-treated individuals showed a prolonged increase in corticosterone and decrease in body condition, confirming our treatment likely mimicked sustained stress exposure. Heterophil-to-lymphocyte ratio was only increased transiently, and there was no clear evidence that treatment influenced oxidative stress or telomere length maintenance. Plasma energy metabolites were mainly affected early after implantation, with rapid recovery over time. Overall, our results suggest that adult king penguins show at least moderate resistance and resilience to chronic corticosterone elevation, especially in preventing cellular integrity loss, though at-sea physiological effects remain to be determined.

People often must decide how long to continue waiting for rewards that will arrive at an uncertain time in the future. We propose that these persistence decisions involve weighing the benefits of continued waiting against opportunity costs of waiting, a balance that may shift over time. This framework suggests that persistence decisions share neural mechanisms with foraging decisions, which require ongoing comparisons between a current resource and possible alternatives. Dopamine and serotonin have been proposed to play opposing roles in foraging, with dopamine promoting exploration and serotonin promoting exploitation. Here we investigated their roles in persistence. In a within-subjects, double-blind, placebo-controlled study in young adults (n = 42), we examined the effects of increasing dopamine with L-dopa and increasing serotonin with escitalopram. We predicted that L-dopa would decrease persistence and escitalopram would increase it. Participants also completed patch-foraging, time perception, risk tolerance, and temporal discounting tasks to explore potential mechanisms of drug effects on persistence. Escitalopram increased persistence, after adjusting for the effects of anxiety and condition order, such that participants waited longer for rewards after taking the serotonergic drug. L-dopa did not influence persistence. In exploratory analyses controlling for age, however, L-dopa reduced persistence and increased exploration in foraging.

Risk for opioid use disorder (OUD) is substantially heritable, yet its genetic architecture remains only partly understood. This study examined oxycodone intake in two nearly isogenic rat strains, Wistar Kyoto More Immobile (WMI) and Less Immobile (WLI), and their reciprocal female F1 offspring. The parental strains differ in depression-like behavior and substance use vulnerability, with WMI rats consuming more oxycodone than WLI controls. Voluntary consumption was measured with an operant licking self-administration protocol that delivered 60 l drug per reward. Across four experimental stages, oxycodone concentrations increased from 0.025 to 0.1 mg/ml, and session durations increased from 1 to 4 hours. Female offspring showed a parent-of-origin effect. F1 females sired by WMI fathers (WLIxWMI) displayed accelerated escalation during the transition from 1-hour to 4-hour sessions in Stage 2 and consumed more oxycodone than reciprocal WMIxWLI females across expanded-access stages. This vulnerability was associated with increased licking during the drug-unavailable timeout period. In WMI and reciprocal WMIxWLI female, consumption was regulated by the drugs subjective value, as measured by lick microstructure, during Stages 1 and 2. This relationship was absent in WLIxWMI females during Stage 2. Together, these findings suggest that paternal WMI lineage is associated with a rapid transition to high oxycodone intake and cue-directed drug seeking, and identify a parent-of-origin effect that may contribute to female vulnerability to addiction.

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.

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.