Contextual fear generalization is a hallmark of psychiatric disorders including post-traumatic stress disorder (PTSD), generalized anxiety disorder and panic disorder. Among these disorders, PTSD is particularly associated with contextual fear generalization. However, the mechanisms by which fear responses extend to similar contexts remain unclear. Here we tested whether corticotropin-releasing hormone (CRH) neurons in the dorsal bed nucleus of the stria terminalis (dBNST) contribute to contextual fear generalization. Using a contextual fear generalization paradigm with variable shock timing, we observed that intense foot shock conditioning enhanced freezing responses in both the training context and the generalization context in adult male mice, accompanied by elevated dBNST activity. Fiber photometry showed that dBNST CRH neurons were strongly engaged by foot shock and exhibited clear activity changes around freezing onset during both training and generalization tests. Functionally, chemogenetic inhibition of dBNST CRH neurons reduced freezing responses in the generalization test, whereas activation increased generalized freezing and promoted contextual fear generalization. Mechanistically, local pharmacological blockade of CRH receptor 1 (CRHR1) within the dBNST reduced freezing responses in the generalization test, indicating that CRHR1-dependent signaling within the dBNST contributes to fear generalization. Together, these findings identify dBNST CRH neurons and local CRHR1 signaling as key components underlying contextual fear generalization.
The year 2025 marked Seymour “Gig” Levine’s centennial birthday. This volume provides an opportunity to recognize his scientific genius and the extraordinary impact he had on the fields of developmental psychobiology and stress. Gig Levine was among the first scientists to demonstrate that early-life experiences, whether aversive or rewarding, shape hormonal responses to stressful events later in life. His work, conducted primarily in rodents and non-human primates examined the influence of early-life experiences, maternal mediation, and cognitive appraisal of challenging situations on hormonal and behavioral responses to stress in the offspring. This special issue brings together original research articles and reviews addressing developmental aspects of the hypothalamus-pituitary-adrenal (HPA) axis and highlights how multiple environmental factors linked to parental behavior and glucocorticoid action can have long-term consequences for multiple systems in the offspring.
This research investigated two maternal processes that affect neurodevelopment: 1) the prenatal endowment of maternal iron that supports growth-related iron needs, and 2) the exposure to maternal bacteria and breast milk that shape the postnatal assemblage of the infant's gut microbiota. A primary aim was to extend prior results indicating that the bacterial profile of nursing infant monkeys should normally be dominated by a high abundance of Bifidobacteria (Phylum Actinomycetota), and that the presence of higher abundance of taxa in the Phylum Pseudomonadota provides a sentinel indicator of slower brain maturation. This perspective was applied to additional infants who became anemic subsequently at the end of the nursing period. Fecal and blood specimens were collected from 41 infant rhesus monkeys; diffusion tensor imaging scans were acquired at one year of age. Atlas-based fiber tract analyses examined fractional anisotropy (FA) values in three major myelinated projections: the cingulum (CG), uncinate fascicularis (UF), and inferior longitudinal fascicularis (ILF). Fecal samples were collected from nursing infants at 2 months postpartum, prior to the onset of infantile anemia, and analyzed with 16S ribosomal RNA gene amplicon sequencing. The analysis focused on the 4 most abundant phyla. Pseudomonadota were inversely associated with FA in the cingulum tract. Sixteen of the 41 infants subsequently became iron deficient between 4 and 8 months of age and there was an overall trend for a negative influence on FA values. The findings convey that both gut bacterial profiles and iron status during infancy can influence the myelination of important tracts connecting the temporal lobe with other cortical areas.
Background:Adolescence is a critical window for autonomic and limbic development and a period of elevated risk for depression. Although autonomic and limbic system function have, independently, been linked to depression, they are coupled and both influenced by early life stress (ELS). We do not yet know, however, whether the association of autonomic activity and limbic connectivity with depressive symptoms differs across dimensions of ELS. Methods:Participants were 93 youth (Mage = 12.3) who completed the Trier Social Stress Test (TSST) with continuous electrocardiogram (ECG) recording. ECG-derived high-frequency heart rate variability (RespHRV) was assessed across the baseline, reactivity, and recovery phases of the TSST. Hippocampal-amygdala connectivity was estimated from resting-state data acquired just before the TSST using the Tian atlas. We tested whether RespHRV recovery and connectivity were jointly associated with depressive symptoms and whether ELS dimensions of threat, unpredictability, and deprivation moderated this association. Results:Greater RespHRV during recovery was associated with more negative right hippocampal tail-left lateral amygdala connectivity (β = -0.42, q = 0.002). In a joint model, threat (β = -0.34, p = .007) and deprivation (β = -0.36, p = .009 independently moderated this association. Specifically, more negative connectivity predicted fewer symptoms when paired with weaker RespHRV recovery in high-ELS youth, but with stronger RespHRV recovery in low-ELS youth. Conclusions:Whether autonomic-limbic coupling buffers or confers risk for depression depends on the early environment in which it developed.
Introduction:Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in obsessive-compulsive disorder (OCD), but epigenetic changes in HPA axis-related genes remain poorly understood. We investigated whether DNA methylation of the glucocorticoid receptor gene (NR3C1), particularly within exon 1F, is associated with OCD and examined its relationship with stress resilience and early-life trauma. Methods:A total of 275 patients with OCD and 200 healthy controls (aged 19-40 years) were recruited. DNA methylation at three CpG sites within NR3C1 exon 1F was measured using pyrosequencing. Group differences were examined using multivariate analysis of covariance (MANCOVA), and structural equation modeling (SEM) was conducted to evaluate resilience-mediated pathways linking NR3C1 methylation, early-life trauma, and OCD status. Results:Compared to healthy controls, DNA methylation at NR3C1 exon 1F was significantly reduced in women with OCD (p < 0.001), which remained significant in a drug-naïve or drug-free subset. No overall multivariate difference was observed in men. SEM revealed that stress resilience partially mediated the association between NR3C1 methylation and OCD status (indirect β = -0.117, p = 0.014). While early-life trauma was associated with lower methylation at a specific CpG site, the mediation effect of DNA methylation between trauma and OCD did not reach statistical significance. Conclusion:These findings suggest that epigenetic alterations of NR3C1 may contribute to stress-related vulnerability in OCD, with resilience representing a key psychological pathway linking stress-related biological processes, including HPA-axis regulation, to clinical outcomes.
The mineralocorticoid receptor (MR) plays a pivotal role in modulating the neuroendocrine stress response and cognitive function. While recent evidence highlights the importance of MRs in glutamatergic neurons in regulating anxiety-like behavior, the specific contribution of MRs within inhibitory networks remains incompletely understood. To address this gap, we generated a mouse model with targeted ablation of MR in forebrain GABAergic neurons (MRDlx). Comprehensive behavioral profiling revealed a profound, state-dependent cognitive phenotype in male MRDlx mice. Under non-stressful baseline conditions, these mice exhibited impaired object recognition memory, while under aversive learning paradigms, such as the Morris water maze and fear conditioning, they displayed enhanced spatial and contextual memory. Furthermore, male MRDlx mice demonstrated significant behavioral lack of adaptation to 21 days of chronic social defeat stress (CSDS). Notably, these changes were highly sex-influenced, as female MRDlx mice did not exhibit the same baseline cognitive deficits or subsequent stress resistance. Mechanistically, in vitro hippocampal electrophysiological recordings from male mice showed that acute corticosterone (CORT) application, which typically suppresses long-term potentiation (LTP), failed to impair LTP in MRDlx slices, indicating a marked resistance to CORT-induced suppression. Together, our findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states. Ablating this regulatory mechanism confers robust behavioral and synaptic stress resistance, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
Over the past decades, alterations in gut microbiota composition have emerged as a key contributor to the neurobiology of stress-related psychiatric conditions, including Major Depressive Disorder (MDD). Clinical and preclinical evidence consistently demonstrates correlational associations indicating that the gut microbiota not only responds to stress but also modulates the host stress response, thereby influencing behavioral domains relevant to depressive symptomatology. However, relatively few studies have investigated the causal relationship between stress-induced microbiota alterations and stress-associated behavioral impairments. Here, we examined the role of the enteric microbiota in stress-related behaviors using fecal microbiota transplantation (FMT) from animals exposed to a Chronic Unpredictable Stress (CUS) protocol to reproduce stress-associated behavioral phenotypes in recipient mice. Donor animals subjected to a 28-day CUS protocol exhibited behavioral alterations across despair-like, anhedonia-like, and anxiety-like domains, as assessed by the Novelty Suppressed Feeding, Sucrose Spray, Tail Suspension, and Elevated Plus Maze tests. FMT from stressed donors successfully transferred similar behavioral alterations to recipient animals. Dysregulated expression of synapsin 1 (Syn1) and oligodendrocyte transcription factor 1 (Olig1) was observed in the prefrontal cortex of both donor and recipient animals. In the hippocampus, CUS-exposed donors showed reduced Olig1 and a trend toward reduced Sox2 expression, whereas no significant hippocampal changes were detected in FMT recipients, suggesting that prefrontal, but not hippocampal, molecular alterations are preferentially transferable via the gut microbiota. Sequencing of the V4 region of the 16S rRNA gene revealed increased relative abundance of Lachnospiraceae and Parabacteroides and reduced Lactobacillales in both stressed donors and FMT recipients. In contrast, recipients of control microbiota exhibited higher levels of genera commonly associated with gut homeostasis, including Bacteroides, Ligilactobacillus and Lactobacillus. Together, our findings demonstrate that stress-induced microbiota alterations can mediate the transmission of stress-associated behavioral and molecular alterations, particularly in the prefrontal cortex, supporting the relevance of the gut-brain axis in stress-related disorders, while the underlying signaling mechanisms remain to be elucidated.
Chronic stress is a major risk factor for anxiety disorders and is often accompanied by disruptions in female reproductive cyclicity, but the stress-responsive neural populations that shape these comorbid behavioral and physiological outcomes remain poorly defined. The bed nucleus of the stria terminalis (BNST) is a major node for sustained anxiety and stress integration, yet the contribution of genetically defined BNST neurons to restraint stress is not fully resolved in females. Here, we identify proenkephalin-expressing neurons in the anterior dorsal BNST (adBNSTPENK) as a restraint-responsive population that constrains anxiety-like behaviors and modulates cytology-based estrous cycle organization. Acute chemogenetic inhibition of adBNSTPENK neurons produced anxiety-like behaviors in females, whereas activation attenuated acute restraint stress (ARS)-induced anxiety-like behaviors. Female mice subjected to chronic restraint stress (CRS) exhibited both anxiety-like avoidance and disrupted estrous-cycle organization, which can be mitigated by sustained activation of adBNSTPENK neurons. These findings suggest that adBNSTPENK neurons form a stress-recruited limbic circuit node that buffers stress-induced anxiety-like behaviors and is associated with improved vaginal cytology-based estrous-cycle organization under chronic stress.
Reward seeking is an essential component of human behavior. Anhedonia (reduced motivation for and pleasure in reward) is a core feature of several mental illnesses. Early life adversity associates with later impairments in reward behaviors and related psychopathology; however, specific aspects of early adversity that lead to disrupted reward behaviors are unknown. Capitalizing on evidence that unpredictable signals to the developing brain constitute adversity and influence neurodevelopment, we examined whether exposure to perinatal unpredictable maternal signals associated with diminished reward responsivity, and probed causality using experiments in mice. We analyzed a longitudinal human study (N=158 mother/child dyads) and a controlled prospective mouse study (N=111 pups; 17 litters). In humans, exposure to unpredictable signals during late gestation was assessed by maternal mood entropy (a measure of how disordered or random signals are). In mice, unpredictable maternal care behaviors were experimentally induced during the neonatal period, and maternal care entropy was similarly computed. Aspects of anhedonia were determined by adolescent self-report and diminished behavioral responses to palatable food in young adult mice. Across species, unpredictable maternal signals were associated with reduced reward responsivity in males, but not females. Associations persisted after accounting for income and maternal psychopathology in humans, and for cohort and litter effects in mice. These findings indicate a robust, sex-dependent link between early exposure to maternal unpredictability and disrupted reward processing. The convergence of cross-species results indicates that unpredictability of maternal signals plays a role in shaping reward behaviors in males, with implications for the developmental origins of mental illness.
Mitochondrial dysfunction is increasingly implicated in stress-related disorders, including post-traumatic stress disorder (PTSD) and depression, but its relationship to inflammatory signalling and circuit-level vulnerability remains unclear. Here, we investigated region-specific mitochondrial adaptations across two experimental approaches of stress in rodents: stress-enhanced fear learning (SEFL) and chronic unpredictable stress (CUS), modelling PTSD- and depression-like phenotypes, respectively. Behavioural data were analysed using a novel, data-driven clustering approach to define stress-responsive phenotypes (e.g., susceptible, resilient, depressive), alongside quantification of mitochondrial oxidative phosphorylation (OXPHOS) markers across the hippocampus, basolateral amygdala, and prefrontal cortex (prelimbic and infralimbic subregions), and circulating plasma inflammatory markers. Hippocampal mitochondrial adaptations diverged between experimental approaches, with SEFL-susceptible animals showing broad upregulation of OXPHOS complexes, whereas CUS-depressive animals exhibited more restrictive mitochondrial alterations. In contrast, the basolateral amygdala showed convergent mitochondrial adaptations across models, with increased Complex V expression observed in vulnerable phenotypes. Within the prefrontal cortex, stress effects were regionally dissociable, with the prelimbic cortex showing SEFL-specific, phenotype-dependent mitochondrial alterations, implicating it as a putative node in stress sensitisation in PTSD-like phenotypes. Plasma TNF-α levels were significantly elevated in a phenotype- and time-dependent manner and were associated with regional mitochondrial adaptations, consistent with a role for systemic inflammatory signalling in modulating stress-related neurobiological plasticity and energy states. These data support a multi-level model in which behavioural phenotypes reflect underlying inflammatory-mitochondrial states distributed across hippocampal, amygdala, and prefrontal circuits, providing a potential explanatory framework linking systemic inflammatory signalling, circuit-specific mitochondrial function, and vulnerability to PTSD- and depressive-like pathology.
Maternal separation is a widely used early-life stress (ELS) paradigm in rodents. Disrupted maternal care by separation of pups from the dam for several hours per day across neonatal and juvenile development has been found to alter hypothalamic-pituitary-adrenal axis function, molecular and circuit-level brain development and function, and behaviors associated with anxiety, depression, and cognition. However, dams have been found to temporarily increase their care towards pups upon reunion - typically associated with positive outcome measures - calling into question whether this increase in care compensates for care lost during separation. Using a mouse model of ELS, we quantified maternal home cage behaviors from postnatal day P2-16 across three observation periods per day (prior to maternal separation, immediately following reunion, and several hours following reunion), with maternal separation beginning on P10. Four composite variables of home cage behavior frequency were created: total dam-pup contact, rough contact, no contact, and dam self-care. Consistent with previous reports, we found a transient increase in care upon reunion, along with an increase in rough contact and a decrease in dam self-care. We then calculated geometric area-under-curve across the day and found that the increase in total contact among ELS litters does not result in overall more care, as indicated in previous publications, but rather a temporal reorganization of care. These findings provide important nuance to understand how maternal separation disrupts offspring care.
Survival depends on adaptive decision-making wherein the benefits of seeking food are weighed against the risk of threats, a process influenced by internal states like hunger. Highly palatable, calorie-dense foods, such as a high-fat-containing diet (HFD), potently drive feeding even in the absence of hunger. However, it remains unclear whether approach-avoidance conflict is shaped by the interaction between hunger state, motivation for rewards of differing palatability, and the lasting effects of chronic high-fat diet exposure (cHFD). Here, we examined how hunger, reward value, and cHFD exposure affect behavioral strategies for resolving approach-avoidance conflict. We established a modified platform-mediated avoidance (PMA) task where mice resolve conflict between approaching a reward and avoiding a footshock. In this task, we systematically manipulated three key variables: (1) hunger state [via 6-hour (6h) vs. 23-hour (23h) food restriction], (2) reward type (sucrose vs. a high-fat liquid (HF-reward)), and (3) diet history (cHFD vs. control diet). We found that hunger, reward value, and diet pre-exposure shaped conflict resolution. Hunger increased risk-taking, with 23h food-restricted mice seeking more rewards than mice with limited 6h food restriction. Similarly, HF-reward increased approach behavior even under 6h food restriction. Importantly, cHFD pre-exposure robustly suppressed reward-seeking during conflict, overriding the motivational effects of both hunger and acute reward value. These findings highlight the interaction between internal states (e.g., hunger), reward value, and environmental factors (e.g., diet) in shaping behavior during conflict.
The regular intake of moderate doses of coffee is increasingly recognized as a lifestyle factor associated with a lower incidence of depressive-like conditions; however, there is still a debate on the relative effects of caffeinated and decaffeinated coffee. We now resorted to a model of chronic unpredictable stress to compare how the regular drinking of caffeinated and decaffeinated coffee impacted on stress-induced deterioration of mood and memory in adult mice. Stressed mice displayed lower weight gain, increased locomotion and greater anxiety, lower motivation in the splash test, less struggling and greater immobility in the forced swimming test, increased anhedonia in the sucrose preference test and decreased spatial reference memory in the object displacement and modified Y-maze tests. The continuous intake of caffeinated, but not decaffeinated, coffee attenuated all these stress-induced mood and memory deficits. Moreover, the intake of caffeinated, but not decaffeinated coffee, also attenuated the stress-induced decrease of long-term potentiation in hippocampal synapses and of brain-derived neurotrophic factor levels in frontocortical synapses, a neurophysiological and neurochemical signature of mood deterioration. These results prompt caffeine as a prominent coffee constituent responsible for the benefits of the regular intake of coffee on stress-induced behavioral deficits.
Early life adversity has lasting effects on neuroendocrine function and increases risk for psychopathology and metabolic disease. Stress and metabolism are closely intertwined, with critical periods for early life stress overlapping those for metabolic programming. Early life adversity models in rodents have the potential to affect development through multiple pathways, including nutrition, parental behavior, and direct physical stress. In the current study, we investigate how a limited bedding and nesting material (LBN) postnatal environment affects maternal behavior, milk composition, and acute metabolic outcomes in rat offspring. We examined the impact of LBN exposure during two postnatal windows (Early: P0-6 and/or Late: P6-13) and effects of key elements of early experiences (maternal behavior and nutrition) on acute metabolic outcomes, with assessment of sex-specific effects in pups. LBN shifted maternal behavioral phenotype, increased dam milk corticosterone and triglyceride concentration, affected serum metabolic and pituitary hormones in pups, and increased pup estimated daily energy expenditure. Differential gene expression analyses of the liver and arcuate nucleus of the hypothalamus showed timing and sex-specific effects of LBN. LBN predicted expression of genes related to amino acid biosynthesis, protein assembly, and developmental transitions. These effects were associated with individual milk components, pup sex, and pup weight. Collectively, these findings demonstrate that early life adversity alters acute metabolic outcomes through multiple, interacting pathways that may contribute to increased vulnerability to endocrine and metabolic dysfunction later in life.
This essay assumes an historical perspective intended to highlight the major contributions of Seymour “Gig” Levine to the conceptual scaffold that guides so much of the current research in development and psychopathology. I suggest that perhaps Levine's most important contribution was to establish an experimental framework that served to transition the clinical observations of Freud and the attachment theories of Bowlby into modern Psychology/Psychiatry.
Background:Adolescent interpersonal stress increases depression risk, and chronic low-grade inflammation may act as a potential underlying biological mechanism. Methods:We explored longitudinal associations between interpersonal stress, inflammation, and depressive symptoms from adolescence to young adulthood, using DNA methylation (DNAm) indices of C-reactive protein (CRP) from saliva. Data were collected from N = 434 adolescents (RADAR-Y study, 56.4% male) and analyzed in preregistered structural equation models. Interpersonal stress was estimated from repeated measures of parent-adolescent conflict, parental psychological control, parental criticism, and peer victimization. Results:Interpersonal stress was not associated with DNAm indices of CRP at age 17 or age 25, nor with depressive symptoms at age 27. In exploratory analyses examining parent versus peer-related stress separately, higher negative parenting-but not peer victimization-was nominally associated with one out of three DNAm indices of CRP at age 17 (Hillary index, β = .15, p = .035), with no association at age 25. Conclusion:This study did not show an association of either interpersonal stress or inflammation with later depressive symptoms and thereby could not identify inflammation as a potential mediator. Our findings tentatively suggest timing-dependent differential effects of family versus peer-related stress on epigenetic indices of inflammation, which may be further explored in future studies.
Early life stress (ELS) is a major risk factor for reactive and pathological aggression that can persist long after the original stress exposure. Across species, ELS produces enduring alterations in the neural circuits that regulate social behavior and aggression, yet the molecular, structural, and circuit mechanisms that stabilize these changes remain poorly defined. Emerging evidence implicates N-methyl-D-aspartate receptor (NMDAR)-dependent structural plasticity in aggression circuits as a mechanism linking early adversity to persistent aggressive behavior. In this review, we present a hypothesis-driven narrative that synthesizes clinical, postmortem, imaging, and preclinical evidence to define a testable framework for future research. We focus on how ELS may recruit NMDAR signaling to reshape excitatory connectivity within aggression circuits, with particular emphasis on the posterior ventral medial amygdala to ventrolateral ventromedial hypothalamus pathway. Within this pathway, preclinical studies suggest that ELS increases dendritic spine density, promotes excitatory shaft synaptogenesis, and biases synaptic input toward proximal dendritic locations predicted to exert stronger effects on neuronal firing. We propose that this location-specific remodeling may increase circuit excitability, thereby lowering the threshold for aggressive responding. We further examine the translational potential of targeting NMDAR-dependent plasticity, focusing on the clinically available antagonists ketamine and memantine. By integrating molecular, structural, circuit-level, and clinical perspectives, we propose that NMDAR-dependent control of synapse formation and location represents a plausible mechanism through which ELS persistently biases neural circuits that regulate aggression. Targeting these processes may provide new strategies for reducing pathological aggression following ELS.
This study examined the influence of infant-mother attachment security on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol stress responses in 14-month-old infants. Eighty-two mother-infant dyads participated in the Strange Situation Procedure (SSP), with salivary cortisol sampled across four time points. Infant attachment security, maternal depressive symptoms, and infant temperament were assessed longitudinally over the first postnatal year. Infant cortisol trajectories differed by attachment security: insecurely attached infants had significantly higher baseline cortisol, which declined following the SSP, whereas securely attached infants had lower baseline cortisol and a trend toward increased cortisol post-stressor. Maternal cortisol declined over time for all groups, with no differences between mothers of secure and insecure infants. Mothers of securely attached infants experienced sub-clinical depressive symptoms at 32 weeks pre-partum, with a decline of symptoms to a normal range during the first year postpartum. Negative infant temperament increased over the first year but was not associated with attachment security or cortisol response. These findings demonstrate that infant-mother attachment quality shapes infant HPA axis regulation independent of maternal depressive symptoms or negative infant temperament, suggesting the importance of early identification and intervention for attachment difficulties to promote adaptive stress physiology in infants.
Early life adversity (ELA) is a heterogeneous construct that can include the consequences of poverty, maltreatment, or serious accidents. This study characterized associations between subtypes of ELA and the physiological responses of multiple systems to acute psychosocial stress. Studies to date have focused on HPA axis reactivity, often neglecting the stress-reactive SNS, HPG axis, metabolic, and innate immune systems. We hypothesized that emotional, physical, and non-intentional ELA would differentially affect stress reactivity in each of these systems. Nine salivary samples, collected serially across the administration of a Trier Social Stress Test for Children (TSST-C), were collected from 92 adolescents [mean age 13.9 (SD = 1.57)] and assayed for cortisol, testosterone, DHEA, uric acid, salivary ɑ-amylase, and interleukin-6 (IL-6). Emotional ELA was associated with a steeper cortisol response to the stressor [b(SE) = 0.007 (0.003), p = .013]. Physical ELA was associated with IL-6 having steeper activation [b(SE) = 0.002 (0.001), p = .047] and recovery slopes [b(SE) = 0.00002 (0.00001), p = .03]. After accounting for age, sex, and body mass index, associations between physical ELA and IL-6 were attenuated. Findings are aligned with the theory of biological salience, which states physiological systems are differentially sensitive to experiences of adversity throughout childhood. Indeed, that different types of ELA are differentially associated with stress reactivity suggests a need for specificity and nuance in studies exploring associations between childhood environment and later biological functioning. Different forms of ELA are likely differentially salient to physiological systems that have distinct and evolutionarily conserved functions which may shape how the individual responds to psychosocial stress later in life. If confirmed with further evidence, biological salience may help to explain previously equivocal associations between ELA and adverse lifespan health outcomes.
