Developmental Psychobiology

Background: Alcohol and cannabinoids are frequently used during pregnancy, however their combined effects on offspring outcomes are currently under-investigated. In this study, co-exposure was compared to single-drug and drug-free exposures for influences on adult alcohol-seeking and cannabinoid system proteomics. Methods: Pregnant C57BL/6J mice received ethanol vapor (ALC), CP-55,940 (0.75 mg/kg; CB), both (ALC+CB), or neither on gestational days 12-15. Beginning on Postnatal Day 200, male and female offspring underwent home-cage ethanol drinking (N=108) and operant self-administration, progressive-ratio, extinction, and reinstatement testing (N=96). CNR1 and CNRIP1 protein abundance was quantified in the medial prefrontal cortex (mPFC) and dorsomedial striatum (N=57) and compared to within-subject drinking behaviors. Results: Prenatal CB exposure increased cumulative home-cage ethanol intake, primarily in males. At 40% ethanol under progressive-ratio schedules, ALC+CB males consumed more than all other male groups, whereas all exposed female groups consumed more than controls. ALC+CB males also showed greater extinction responding than all other male groups and greater reinstatement intake relative to baseline than CON and ALC males. ALC+CB increased mPFC CNR1 in males relative to all other groups, whereas CB and ALC+CB reduced mPFC CNR1 in females. Higher mPFC CNR1 was associated with fixed-ratio and 40% progressive-ratio intake, extinction, and reinstatement exclusively in males. Conclusions: Prenatal co-exposure produced a persistent male phenotype of enhanced ethanol seeking that was distinct from either exposure alone and accompanied by elevated mPFC CNR1. This behavioral and molecular convergence justifies future investigations manipulating corticostriatal cannabinoid signaling to attenuate exposure-induced ethanol consumption in late adulthood.

BackgroundThe maturation of the autonomic nervous system (ANS) has been suggested to play a crucial role in the development of emotion regulation and later psychosocial functioning. However, longitudinal evidence linking early autonomic development to long-term outcomes remains limited. This longitudinal study investigated the interplay between birth-related factors, early autonomic activity, and psychosocial outcomes across development. MethodsThe sample comprised 101 participants followed from two weeks to 14 years of age, with heart rate (HR) and vagally ediated heart rate variability (vmHRV) assessed at 2 weeks, 6 weeks, 3 months, 14 months, and 14 years. Linear models were used to examine associations between birth-related factors and early HR and vmHRV, as well as whether HR and vmHRV trajectories during the first 14 months predicted psychosocial outcomes at 5 and 14 years. ResultsMultiple birth-related factors significantly predicted HR and vmHRV at two weeks after birth. Moreover, flatter age-related increases in vmHRV and weaker decreases in HR during infancy predicted higher maternally reported psychosocial difficulties at 14 years in males only, with no such effects at 5 years or in females. ConclusionsThese findings underscore the importance of early autonomic maturation in shaping later psychosocial functioning, with effects on adolescent outcomes observed in males only. Early ANS trajectories may represent meaningful predictors of neurodevelopmental outcomes, highlighting their potential relevance for early identification of later psychosocial risk in a sex-specific manner.

Background and aimVery preterm birth (VPT; [≤]32 weeks gestation) is associated with an increased risk of later psychiatric disorders, including psychosis. Although psychosis typically emerges in adulthood, subclinical early signs along the psychosis continuum, such as psychotic-like experiences (PLEs), can be observed much earlier. We therefore aimed to study PLEs in childhood in VPT individuals recruited from a clinical cohort compared with full-term (FT) controls. We subsequently investigated whether findings could be replicated in an independent population-based cohort. MethodsPrimary analyses were conducted in the Brain, Immunity and Psychopathology (BIPP) study, including 197 children born VPT recruited through Neonatal Intensive Care Units and 72 FT controls assessed at a mean age of 10.50{+/-}1.77 years. Between-group differences in PLEs were then examined in the Adolescent Brain Cognitive Development (ABCD) study, including 149 children born VPT and 9519 FT controls assessed at a mean age of 9.94 {+/-} 0.63 years. PLEs were assessed using the Prodromal Questionnaire-Brief Child Version (PQ-BC), yielding frequency and distress-related scores for both the total scale and three specific domains (unusual thought content, perceptual abnormalities, disorganised speech). Regression models tested associations between birth status (VPT and control) and PQ-BC scores adjusting for age, sex, and socio-economic status, with secondary models additionally adjusting for cognitive ability and broader psychopathology. Pooled analyses examined cohort effects (BIPP and ABCD) and cohort-by-group status (VPT and control) interactions. ResultsIn BIPP, VPT birth was associated with higher PQ-BC total ({beta}=1.61, p=0.004) and distress scores ({beta}=0.78, p=0.039), with the strongest and most consistent associations observed for perceptual abnormalities across total score (sum of endorsed items), distressing items, and distress severity scores (all p[≤]0.01). These associations were attenuated but largely persisted after adjustment for cognitive ability and broader psychopathology, particularly for perceptual abnormalities. In ABCD, VPT birth was not significantly associated with global or domain-specific PQ-BC outcomes. DiscussionVPT birth is associated with increased vulnerability to PLEs in childhood, particularly in the domain of perceptual abnormalities. The lack of clear replication in the population-based ABCD cohort may reflect differences in the composition of its VPT subgroup, which may not fully represent VPT individuals typically seen in clinical cohorts.

It is estimated that approximately fifty percent of the population will encounter at least one traumatic event during their lifetime; however, only six percent develop Posttraumatic Stress Disorder (PTSD), a trauma-related disorder characterized by persistent alterations in affect and cognition, including an exaggerated fear response. It is well established that females (9.7%) are more than twice as likely as males (3.6%) to be diagnosed with PTSD. Nevertheless, a significant challenge remains in understanding how the severity of traumas experienced in childhood versus adulthood influences PTSD development across sexes. To address this challenge effectively, the adoption of preclinical animal models that accurately reflect these key characteristics is crucial. The Stress Enhanced Fear Learning (SEFL) paradigm in rodents encapsulates some of these complexities associated with PTSD, such as persistent fear sensitization following exposure to acute trauma. This study investigates how stress severity and developmental timing affect the long-term maintenance of SEFL in male and female rats. Juvenile and adult rats were initially subjected to no stress (control, context only), low stress (1 footshock), moderate stress (3 footshocks), or high stress (15 footshocks), followed by an extinction session either one day (recent) or sixty days (remote) later. Subsequently, to evaluate SEFL in a new context, all subjects received a single footshock and were tested the following day. Shortly after stress induction, all groups displayed SEFL. Although the effects persisted for sixty days in adult males and juvenile females, even at the lowest stress level, they were significantly reduced in juvenile males and adult females. These findings offer novel insights into sex-related differences in the persistence of SEFL and introduce new considerations regarding how the timing of developmental stressors influences future threat encoding and fear responses.

Early-life stress is associated with alterations in amygdala volume, but findings vary across studies and species. Rodent models typically report increased amygdala volume, whereas human studies often find reductions or mixed effects. We propose the amygdala burnout hypothesis, which suggests that early-life stress alters amygdala developmental trajectories, producing initial volumetric increases that are followed by reductions later in life. To test this hypothesis, we examined amygdala development across rodent and human cohorts spanning adolescence to older adulthood. In rodents, chronic stress was associated with increased amygdala nuclei volumes during adolescence. Comparable increases were observed in adolescents from the IMAGEN consortium, with evidence of a dose-dependent association between childhood stress and amygdala developmental trajectories. In contrast, analyses of older adults from the UK Biobank revealed reduced bilateral amygdala volume associated with early-life stress. Together, these findings support a developmental model that reconciles previously conflicting observations across species and age groups. Early-life stress is associated with alterations in amygdala volume, but findings vary across studies and species. Rodent models typically report increased amygdala volume, whereas human studies often find reductions or mixed effects. We propose the amygdala burnout hypothesis, which suggests that early-life stress alters amygdala developmental trajectories, producing initial volumetric increases that are followed by reductions later in life. To test this hypothesis, we examined amygdala development across rodent and human cohorts spanning adolescence to older adulthood. In rodents, chronic stress was associated with increased amygdala nuclei volumes during adolescence. Comparable increases were observed in adolescents from the IMAGEN consortium, with evidence of a dose-dependent association between childhood stress and amygdala developmental trajectories. In contrast, analyses of older adults from the UK Biobank revealed reduced bilateral amygdala volume associated with early-life stress. Together, these findings support a developmental model that reconciles previously conflicting observations across species and age groups.

Stressors experienced during the postnatal period may increase vulnerability to mental health disorders, including postpartum depression and anxiety. In rodents, maternal separation (MS) has been shown to alter behaviours in dams, but these observations have been made almost exclusively in rats and thus robust mouse models of postpartum mental health disorders using this stressor remain limited. Here we first examined, in mice, the effects of MS on maternal caregiving and on anxiety- and depressive-like behaviours. As stress-induced inflammatory activation in the gut-brain axis has been associated with behavioural alterations in non-postpartum contexts, changes in pro-inflammatory cytokines and tight junction proteins in the brain and intestinal tract were also examined. Female C57BL/6N mice were assigned to a No Separation (NS) or a MS condition that consisted of 3-hour daily separation sessions from postnatal days (P) 2 to 14. Maternal care behaviours were assessed on P3 and P7, followed by anxiety- and depressive-like behaviours on P22 and P23, and the collection of the medial prefrontal cortex (mPFC) and colon on P24 to determine the expression of selected genes. Caregiving patterns in MS dams fluctuated throughout the early postnatal period. Although behaviours and gene expression outcomes remained unchanged by MS, grooming time in the splash test was correlated with the expression of different genes in the mPFC. These findings suggest that C57BL/6 mouse dams may be less sensitive to the actions of MS on behaviour and on brain and intestinal markers of inflammation and barrier permeability, at least when examined shortly after weaning.

Stress is a physiological, adaptive, and preliminary response of the organism to situations of threats and instability caused by environmental and psychological stressors. The chronicity and predictability of stressors are important variables in determining neurobehavioral outcomes. While unpredictable chronic stress (UCS) protocols typically induce depressive-like phenotypes in rodents, in zebrafish the effects of these protocols are assessed using anxiety-like outcomes. This study aimed to analyze the effects of an unpredictable UCS on depressive-type behavioral parameters and brain lipid peroxidation in zebrafish. A 14-day UCS protocol was used, with 10 different types of stressors administered twice daily in a random manner, using draws, for greater unpredictability. Animals underwent the Novel Tank Test (anxiety-like outcome) and the Social Preference Test (depressive-like outcome) 24 hours after the end of the UCS protocol. Biochemical data were collected using a thiobarbituric acid reactive substances (TBARS) assay to quantify malondialdehyde (MDA), an indicator of lipid peroxidation. The findings suggest that prolonged exposure to stressors causes damage to the organism, with increased anxiety and decreased social preference, highlighting zebrafish as an efficient model in the investigation of the neurobiological and neuropathological mechanisms of stress.

Early life stress (ELS) is associated with altered social cognition, but the neurodevelopmental mechanisms of this association remain understudied. In the present longitudinal study spanning 20-years, eighty-nine young adults performed the Reading the Mind in the Eyes Test (RMET) with a matched control condition during fMRI. Two ELS indices were inspected separately: a prospective cumulative risk score based on caregiver wellbeing during pregnancy and first year of life, and a retrospective self-report of adverse experiences by the participants in late adolescence. Neural outcomes were characterized by univariate activation, representational similarity analysis (RSA), and inter-subject RSA. Inter-subject RSA tested two pairwise approaches to intersubject similarity in ELS: absolute pairwise difference, and pairwise average. Prospective ELS was associated with better RMET performance, and one region survived correction across 360 cortical regions tested in RSA and IS-RSA: left anterior inferior frontal sulcus. The IS-RSA effect was pairwise average: low-exposure participants shared a more typical neural representational geometry, while high-exposure participants demonstrated increasing neural representational idiosyncrasy. Additionally, higher prospective ELS was associated with weaker RMET-versus-control separation within the same region. Retrospective ELS yielded no behavioral nor neural associations. The present study offers novel findings relating to neural representations of mentalizing using the RMET, alongside their neurodevelopmental susceptibility to ELS. The present study additionally highlights implications relating to the differentiation of mentalizing from lexical-semantic and semantic-control demands for future research.

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.

Communicative abilities acquired over the first year of life are foundational for language development. Understanding the neural mechanisms underlying these abilities can explain individual differences and improve predictions of later language outcomes. While prior research on neural markers of language development has focused predominantly on oscillatory neural activity, the underlying aperiodic component of the neural signal may provide further insights into cortical maturation by indirectly reflecting variation in neural excitation/inhibition (E/I) balance. In neurodevelopmental conditions, both reduced and elevated aperiodic activity are linked to atypical development, and initial evidence from at-risk cohorts also relates aperiodic activity to language outcome. Moving beyond clinical populations, the present study examined whether aperiodic activity during neonatal resting-state EEG relates to 12-month communicative abilities in typically developing infants. Aperiodic offset and exponent were extracted from resting-state EEG recorded two weeks after birth in n = 50 neonates using the FOOOF algorithm. At 12 months, communicative abilities were assessed with the parent-report CSBS-DP Infant-Toddler Checklist. Quadratic regression analyses showed an inverted U-shaped relationship between the neonatal aperiodic exponent and communicative abilities: both lower and higher exponent values were associated with poorer outcomes, with intermediate values linked to better abilities. No robust association was found for the offset. These findings suggest that aperiodic activity captures variability in early communicative development, with an optimum at intermediate levels, consistent with a balanced E/I state. The scope of aperiodic brain activity as a developmental marker may thus extend beyond clinical populations to predicting communicative development in healthy infants.

Early-life psychosocial adversity increases vulnerability to stress-related disorders and may begin as early as prior to conception via maternal stress. Consequently, early-life stress (ELS) in offspring may accumulate across early development. The short-allele variant of the serotonin transporter (SERT) gene has been implicated in depression risk and higher anxiety sensitivity following stress exposure, but for cumulative ELS it is unknown whether behavioral effects depend on the SERT genotype. In this study, we used heterozygous SERT knockout (SERT+/-) rats to model reduced SERT expression similar to human short-allele carriers. To investigate the effects of cumulative ELS on offspring behavioral phenotype, dams were exposed to stress before, during and after pregnancy, combined with offspring postnatal maternal separation. Cognitive, affective, and social behaviors were assessed in wild-type (WT) and SERT+/- (HET) male and female adults. Maternal care and anhedonia-like behaviors in dams were also assessed. Dams exposed to the cumulative stress (STR) displayed increased arched-back licking and grooming compared to controls (CTR). In the offspring, HET rats showed increased social investigation and tended to display hyperactivity compared to WT. Anxiety-like behavior was higher in HET females compared to WT females, with no genotype differences in males. Independent of genotype, STR rats consumed less sucrose and showed impaired object recognition compared to CTR; however, HET-STR rats performed better in the object recognition than WT-STR rats. A significant SERT genotype x cumulative ELS x sex interaction revealed opposing, sex-dependent effects on anxiety-like behavior. HET-STR females showed more anxiety-like responses relative to HET-CTR and WT-STR females, as well as HET-STR males. In contrast, HET-STR males were less anxious than HET-CTR and WT-STR males. Reduced SERT expression is linked to more social investigation alongside increased anxiety, particularly in SERT+/- females. While cumulative ELS did not induce robust anxiety-like and depressive-like phenotypes, overall, it impaired memory performance, an effect partially mitigated in SERT+/- rats. Notably, the SERT genotype differentially modulated anxiety-like behavior in male versus female offspring, increasing vulnerability in SERT+/- females while reducing it in SERT+/- males, an effect further amplified by exposure to cumulative ELS. These results underscore sex as a critical determinant in the interaction between genetic susceptibility and cumulative exposure to early adversity in shaping affective outcomes.

Early-life adversity is associated with highly variable developmental outcomes, but identifying sources of this heterogeneity is difficult because variation in outcome is typically accompanied by variation in exposure. Animal models provide experimental leverage by standardizing features of the early environment while allowing variation in developmental experience and outcome to remain observable. Using a graded limited bedding and nesting model spanning normative rearing, moderate restriction, and severe scarcity, we asked what distinguishes social outcomes among animals exposed to the same resource restriction. Severe scarcity increased adverse maternal handling while leaving organized nurturing behaviors intact. Following the P8-P12 rearing manipulation, pups were tested outside the home cage in a P13 social approach assay. Severe scarcity reduced the proportion of pups that approached the dam, but outcomes varied substantially among scarcity litters. Greater typical maternal pup transport predicted greater approach, whereas a greater proportion of rough transport predicted poorer approach. Transport composition did not differ across rearing conditions, but its relationship with social behavior did. Amygdala intercalated-cell recruitment also covaried with social approach under severe scarcity despite limited condition-level differences in regional c-Fos. Plasma corticosterone differed across rearing conditions but did not covary detectably with the principal caregiving, behavioral, or neural measures. Maternal transport and intercalated-cell recruitment were not robustly associated, identifying separable experiential and neural correlates of behavioral variation. These findings show that standardizing an environmental constraint does not produce uniform developmental experience or outcome, and that caregiving experiences preserved across rearing conditions can distinguish social outcomes under severe scarcity.

Stressful experiences are a major risk factor for the development of neuropsychiatric disorders in vulnerable individuals. Identifying features that can distinguish stress-susceptible from resilient individuals remains a central goal in stress neurobiology. Due to the routine exclusion of female subjects from stress research or the use of male-defined criteria in behavioral characterization of subjects post-stress, female stress responses and vulnerability profiles remain poorly understood. This work aimed to gain a better understanding of sex-specific stress responses to social defeat stress. Here, we used a novel paired male-female social defeat paradigm and tracked subjects longitudinally in a ''two-hit'' design to evaluate responses to both acute social defeat stress (ASDS) and chronic social defeat stress (CSDS), and to determine how prior stress exposure influences subsequent vulnerability. We found that both ASDS and CSDS induces changes in social avoidance/approach behavior in males but not females, as measured by a classic social interaction ratio. Prior ASDS exposure enhanced susceptibility to subsequent CSDS most clearly in males, with females displaying specific changes in corner zone occupancy. Furthermore, we observed divergent anxiety profiles between males and females in a post-stress behavioral battery. Finally, females exhibited specific stress-related locomotor responses following ASDS. Together, these findings suggest that females may adopt distinct behavioral strategies following social defeat stress.

Courtship is an essential component of reproductive success for many species and many courtship behaviors, such as vocalization, are energetically demanding. In order to successfully balance investment in courtship with feeding and foraging, individuals must be aware of their current energy balance, and hormonal signals of energetic state have been found to influence social signal effort across a variety of species. Ghrelin is one hormone that plays an important role in regulating energy balance by signaling hunger and promoting feeding. Previous studies have investigated the role of ghrelin in courtship, aggression, and mating behavior. In this study, we build on prior work by investigating the effects of ghrelin on ultrasonic vocalizations (USV) and other courtship behaviors of male mice. We expand on previous research by observing ghrelin's effects over longer interactions, allowing us to understand how ghrelin impacts the dynamics of USV production over time. Our results show that while males initially vocally court females at a high rate regardless of treatment, ghrelin reduces overall USV production by increasing the rate of decline of vocalization. Surprisingly, despite its effects on vocal courtship, we found no significant differences in the production or timing of other, non-vocal, courtship behaviors. This study deepens our understanding of the role of hormones traditionally associated with controlling hunger and feeding in regulating social behaviors.

Interpersonal physiological synchrony (IPS) between interaction partners has been studied as a marker of social connectedness and coordination. However, little is known about how such interpersonal synchrony relates to the intrapersonal coordination of individuals' own autonomic systems during team interaction. The present study examined whether IPS and intrapersonal physiological synchrony (IAPS), defined as the within-person coordination of heart rate (HR), respiration, and electrodermal activity (EDA), function as competing or complementary regulatory processes. It also examined whether IAPS is state- or trait-like and whether teams high or low in both IPS and IAPS had better outcomes. Fifty five newly formed triads (N = 165; Mage = 23.87, 77% female) participated in a laboratory interaction including passive shared experiences and active collaborative tasks while continuous physiological activity was recorded. Synchrony within individuals and between team members was quantified using multidimensional recurrence quantification analysis. Across interaction segments, IAPS was positively associated with IPS in both HR and EDA, with stronger and more consistent associations during active teamwork versus during passive social contexts. These findings contradict a trade-off hypothesis and instead support a synergistic relationship between IAPS and IPS. IAPS exhibited state-like dynamics and sensitivity to features of the context, i.e., consistency within similar interaction contexts and higher in passive versus active social segments. Further, IAPS had limited associations with individual difference measures. Exploratory analyses indicated that teams characterized by both high IAPS and high IPS demonstrated more favorable outcomes, reflected in either higher objective task performance or greater perceived team efficacy depending on physiological modality. Together, these results suggest that effective team coordination is supported not only by IPS but also by the capacity to maintain coherent internal autonomic organization. They further highlight IAPS as a dynamic component of social functioning that merits exploration alongside interpersonal processes.

Disruptions to maternal behaviors that emerge during the peripartum period have been shown to have lasting physiological and behavioral consequences for offspring. In addition to effects on offspring, disrupted maternal behaviors have been associated with peripartum mood and anxiety disorders. Therefore, it is critical for the wellbeing of both mother and offspring to identify upstream risk factors for the disruption of maternal behavior. We have previously found that pubertal stress leads to a blunted hypothalamic-pituitary-adrenal (HPA) axis response in peripartum humans and mice. Given that dysfunction of the HPA axis is associated with both PMADs and disrupted maternal behavior, we examined how pubertal stress influenced maternal behavior throughout peripartum in mice using a pup retrieval test. We found that pubertal stress led to faster pup retrieval, but a less predictable pattern of maternal behavior, as well as a blunted HPA axis response during pregnancy. We also examined whether maternal pubertal stress influenced offspring behavior in adolescence and adulthood. We found sex-specific differences in risk-taking behavior during adolescence that are no longer present in adulthood. Finally, we used in situ hybridization to examine gene expression during pregnancy in the medial preoptic area of the hypothalamus, a region implicated in maternal behavior. Following pubertal stress, we found cell-type specific changes in the expression of genes necessary for the expression of maternal behavior. Collectively, these findings contribute to our understanding of upstream risk factors for peripartum disruptions to maternal behavior and the lasting effects of pubertal stress on both mother and offspring.

Empirical evidence from traditional inhibitory control tasks regarding inhibitory deficits in high autistic traits has been mixed, indicating that this issue remains controversial. Although sex differences are widely documented in autistic cognitive profiles, their role in inhibitory gating mechanisms remains underexplored. Given that the expression of inhibitory gating deficits may be modulated by the social versus non-social nature of stimuli, and no prior study has investigated this topic by integrating both sex differences and stimulus domain, we addressed these two questions with the attribute amnesia paradigm. We manipulated stimulus type (non-social vs. social). In Experiment 1, participants performed a location task with animal drawings as targets and were unexpectedly asked to report animal identity on a surprise trial. High autistic trait females showed significantly higher accuracy on the surprise trial than all other groups, reflecting a failure to actively filter out task-irrelevant non-social information, that is, a reduced inhibitory gating efficiency. In Experiment 2, using face stimuli and a self-vs. other-face design, this gating deficit was no longer expressed: all groups performed at chance levels on the identity judgment, regardless of autistic trait level, sex, or face type. This dissociation aligns with a dual-mechanism framework: the inhibitory gating deficit in high autistic trait females is specific to non-social stimuli and masked by camouflaging for social ones. This study demonstrates that the inhibitory gating deficit in high autistic trait females is not a global impairment but rather a stimulus-dependent one, highlighting the need to consider sex and stimulus type.

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.

Anxiety disorders are among the most common psychiatric illnesses, with a significantly higher prevalence in females than in males. The open field (OF) and the elevated plus maze (EPM) are the two assays used most often to model anxiety-like behavior in mice. It is usually assumed that they index a common underlying trait, yet few studies have investigated this in a large group of male and female mice using an advanced analytical approach. The goal of these studies was to determine sex differences in locomotor activity and anxiety-like behavior in the OF and the EPM, and to establish which behavioral parameters correlate between the tests. Adult male and female C57BL/6 mice (n = 61; 29 male, 32 female) were given a single 15 min session in the OF, analyzed as a whole and in three consecutive 5 min blocks, and a single 5 min EPM trial. Males and females did not differ on any OF measure over the cumulative 15-minute session. Locomotion and stereotypy declined over time with females habituating faster than males while center exploration did increase. In the EPM, females made more closed-arm entries than males while open-arm exploration was identical. Every significant correlation between the two tests involved an activity measure. All four pairs formed between OF and EPM activity parameters were significant whereas none of the six pairs formed between OF center parameters and EPM open-arm parameters were significant. Hierarchical clustering revealed the same structure, placing the activity measures of both tests in one cluster, the EPM open-arm measures in a second, and the two OF center measures in a third. The cross-test activity correlation was strongest during the initial five minutes of the OF and weakened as the session progressed. These studies indicate that the OF and EPM yield convergent measures of activity, but divergent measures of anxiety-like behavior.

Laboratory stress tasks are widely used to assess individual differences in acute stress reactivity, yet it remains unclear how these responses correspond to stress experienced in everyday life. Here, we combined the Montreal imaging stress task (MIST) with ecological momentary assessment (EMA) over three months to assess acute and everyday stress in 67 healthy women. Greater within-person variability in everyday stress, but not average stress levels, were associated with stronger overall stress-related brain responses (b = 0.73, p = .039), with a whole-brain association particularly evident in the bilateral caudate (rROI = .32, pcluster.FWE < .001). Greater everyday stress variability was also associated with stronger stress-related functional connectivity between the ventromedial prefrontal cortex (vmPFC) and parietal and posterior medial regions (pcluster.FWE < .001). We conclude that acute neural stress responses relate more closely to fluctuations in perceived stress than to how stressed an individual feels on average. This suggests that laboratory stress tasks capture acute stress responsivity that is distinct from average stress exposure, highlighting the importance of considering what these tasks measure when interpreting individual differences in acute stress responses.