Pandemic beyond the virus: maternal COVID-related postnatal stress is associated with infant temperament.

BACKGROUND: Studies have shown that infant temperament varies with maternal psychosocial factors, in utero illness, and environmental stressors. We predicted that the pandemic would shape infant temperament through maternal SARS-CoV-2 infection during pregnancy and/or maternal postnatal stress. To test this, we examined associations among infant temperament, maternal prenatal SARS-CoV-2 infection, maternal postnatal stress, and postnatal COVID-related life disruptions. METHODS: We tested 63 mother-infant dyads with prenatal maternal SARS-CoV-2 infections and a comparable group of 110 dyads without infections. To assess postnatal maternal stress, mothers completed the Perceived Stress Scale 4 months postpartum and an evaluation of COVID-related stress and life disruptions 6 months postpartum. Mothers reported on infant temperament when infants were 6-months-old using the Infant Behavior Questionnaire-Revised (IBQ-R) Very Short Form. RESULTS: Maternal SARS-CoV-2 infection during pregnancy was not associated with infant temperament or maternal postnatal stress. Mothers with higher self-reported postnatal stress rated their infants lower on the Positive Affectivity/Surgency and Orienting/Regulation IBQ-R subscales. Mothers who reported greater COVID-related life disruptions rated their infants higher on the Negative Emotionality IBQ-R subscale. CONCLUSIONS: Despite no effect of prenatal maternal SARS-CoV-2 infection, stress and life disruptions incurred by the COVID-19 pandemic were associated with infant temperament at 6-months. IMPACT: SARS-CoV-2 infection during pregnancy is not associated with postnatal ratings of COVID-related life disruptions, maternal stress, or infant temperament. Postnatal ratings of maternal stress during the COVID-19 pandemic are associated with normative variation in maternal report of infant temperament at 6 months of age. Higher postnatal ratings of maternal stress are associated with lower scores on infant Positive Affectivity/Surgency and Orienting/Regulation at 6 months of age. Higher postnatal ratings of COVID-related life disruptions are associated with higher scores on infant Negative Emotionality at 6 months of age.

Highlights from the Era of Open Source Web-Based Tools.

High digital connectivity and a focus on reproducibility are contributing to an open science revolution in neuroscience. Repositories and platforms have emerged across the whole spectrum of subdisciplines, paving the way for a paradigm shift in the way we share, analyze, and reuse vast amounts of data collected across many laboratories. Here, we describe how open access web-based tools are changing the landscape and culture of neuroscience, highlighting six free resources that span subdisciplines from behavior to whole-brain mapping, circuits, neurons, and gene variants.

Geotemporal analysis of perinatal care changes and maternal mental health: an example from the COVID-19 pandemic.

Our primary objective was to document COVID-19 induced changes to perinatal care across the USA and examine the implication of these changes for maternal mental health. We performed an observational cross-sectional study with convenience sampling using direct patient reports from 1918 postpartum and 3868 pregnant individuals collected between April 2020 and December 2020 from 10 states across the USA. We leverage a subgroup of these participants who gave birth prior to March 2020 to estimate the pre-pandemic prevalence of specific birthing practices as a comparison. Our primary analyses describe the prevalence and timing of perinatal care changes, compare perinatal care changes depending on when and where individuals gave birth, and assess the linkage between perinatal care alterations and maternal anxiety and depressive symptoms. Seventy-eight percent of pregnant participants and 63% of postpartum participants reported at least one change to their perinatal care between March and August 2020. However, the prevalence and nature of specific perinatal care changes occurred unevenly over time and across geographic locations. The separation of infants and mothers immediately after birth and the cancelation of prenatal visits were associated with worsened depression and anxiety symptoms in mothers after controlling for sociodemographic factors, mental health history, number of pregnancy complications, and general stress about the COVID-19 pandemic. Our analyses reveal widespread changes to perinatal care across the US that fluctuated depending on where and when individuals gave birth. Disruptions to perinatal care may also exacerbate mental health concerns, so focused treatments that can mitigate the negative psychiatric sequelae of interrupted care are warranted.

Vertical Transmission and Neonatal Outcomes Following Maternal SARS-CoV-2 Infection During Pregnancy.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 200 million people worldwide and has likely exposed millions of neonates to SARS-CoV-2 in utero. A large body of literature has examined the possibility of vertical transmission from pregnant women infected with SARS-CoV-2 to their neonates. In this chapter, we review mechanisms of-and evidence for-vertical transmission of SARS-CoV-2, including transplacental, through other biospecimens and breastfeeding, and discuss neonatal outcomes following in utero exposure. Based on the available literature, we conclude vertical transmission of SARS-CoV-2 is rare, and exposed neonates generally show favorable health outcomes.

The effect of coronavirus disease 2019 on newborns.

PURPOSE OF REVIEW: To evaluate the available literature regarding effects of coronavirus disease 2019 (COVID-19) on newborns, ranging from effects related to in utero and perinatal exposure to maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, to pandemic-related stress and socioeconomic changes. RECENT FINDINGS: Several large studies and national registries have shown that the risk of vertical transmission from SARS-CoV-2-infected mothers to newborns is rare and does not appear to be related to postnatal care policies such as mother-newborn separation and breastfeeding. Newborns exposed to SARS-CoV-2 in utero are at higher risk for preterm delivery for reasons still under investigation. When newborns do acquire SARS-CoV-2 infection, their disease course is usually mild. Long-term follow-up data are lacking, but preliminary reports indicate that, similarly to prior natural disasters, being born during the pandemic may be associated with developmental risk. SUMMARY: Although risk of vertical or perinatal transmission is low across a range of postnatal care practices, early indicators suggest developmental risk to the generation born during the pandemic. Long-term follow-up data are critically needed to determine the developmental impact of in utero and early life exposure to SARS-CoV-2 and the COVID-19 pandemic.

Selective Loss of Thin Spines in Area 7a of the Primate Intraparietal Sulcus Predicts Age-Related Working Memory Impairment.

Brodmann area 7a of the parietal cortex is active during working memory tasks in humans and nonhuman primates, but the composition and density of dendritic spines in area 7a and their relevance both to working memory and cognitive aging remain unexplored. Aged monkeys have impaired working memory, and we have previously shown that this age-induced cognitive impairment is partially mediated by a loss of thin spines in prefrontal cortex area 46, a critical area for working memory. Because area 46 is reciprocally connected with area 7a of the parietal cortex and 7a mediates visual attention integration, we hypothesized that thin spine density in area 7a would correlate with working memory performance as well. To investigate the synaptic profile of area 7a and its relevance to working memory and cognitive aging, we investigated differences in spine type and density in layer III pyramidal cells of area 7a in young and aged, male and female rhesus macaques (Macaca mulatta) that were cognitively assessed using the delayed response test of working memory. Area 7a shows age-related loss of thin spines, and thin spine density positively correlates with delayed response performance in aged monkeys. In contrast, these cells show no age-related changes in dendritic length or branching. These changes mirror age-related changes in area 46 but are distinct from other neocortical regions, such as V1. These findings support our hypothesis that cognitive aging is driven primarily by synaptic changes, and more specifically by changes in thin spines, in key association areas.SIGNIFICANCE STATEMENT This study advances our understanding of cognitive aging by demonstrating the relevance of area 7a thin spines to working memory performance. This study is the first to look at cognitive aging in the intraparietal sulcus, and also the first to report spine or dendritic measures for area 7a in either young adult or aged nonhuman primates. These results contribute to the hypothesis that thin spines support working memory performance and confirm our prior observation that cognitive aging is driven by synaptic changes rather than changes in dendritic morphology or neuron death. Importantly, these data show that age-related working memory changes are not limited to disruptions of the prefrontal cortex but also include an association region heavily interconnected with prefrontal cortex.

Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering.

The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age-related cognitive decline has been linked to synapse loss and/or alterations of synaptic proteins that impair function in regions such as the hippocampus and prefrontal cortex. These synaptic alterations are likely reversible, such that maintenance of synaptic health in the face of aging is a critically important therapeutic goal. Here, we show that riluzole can protect against some of the synaptic alterations in hippocampus that are linked to age-related memory loss in rats. Riluzole increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals. Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength. These findings further elucidate neuroplastic changes in glutamatergic circuits with aging and advance therapeutic development to prevent and treat age-related cognitive decline.

Subregional, dendritic compartment, and spine subtype specificity in cocaine regulation of dendritic spines in the nucleus accumbens.

Numerous studies have found that chronic cocaine increases dendritic spine density of medium spiny neurons in the nucleus accumbens (NAc). Here, we used single-cell microinjections and advanced 3D imaging and analysis techniques to extend these findings in several important ways: by assessing cocaine regulation of dendritic spines in the core versus shell subregions of NAc in the mouse, over a broad time course (4 h, 24 h, or 28 d) of withdrawal from chronic cocaine, and with a particular focus on proximal versus distal dendrites. Our data demonstrate subregion-specific, and in some cases opposite, regulation of spines by cocaine on proximal but not distal dendrites. Notably, all observed density changes were attributable to selective regulation of thin spines. At 4 h after injection, the proximal spine density is unchanged in the core but significantly increased in the shell. At 24 h, the density of proximal dendritic spines is reduced in the core but increased in the shell. Such downregulation of thin spines in the core persists through 28 d of withdrawal, whereas the spine density in the shell returns to baseline levels. Consistent with previous results, dendritic tips exhibited upregulation of dendritic spines after 24 h of withdrawal, an effect localized to the shell. The divergence in regulation of proximal spine density in NAc core versus shell by cocaine correlates with recently reported electrophysiological data from a similar drug administration regimen and might represent a key mediator of changes in the reward circuit that drive aspects of addiction.

Methodology for Safe and Effective Subcutaneous Implantation of Wireless Biotelemetry Sensor Devices in Rodents.

In this work, a methodology for assessing the impact of implantation surgery on laboratory mice on behavior was created. The study included the design of several implants fabricated on various printed circuit board (PCB) technologies with overall diameters between 26-28mm and weights between 4.5-6.5g. 11 adult CD1 mice were implanted with the devices and their behavior was analyzed using common behavioral benchmark tests. The results show that implants designed to be 10% of the animal's body weight showed no adverse effects on mobility or social behavior. These results illustrate a method to identify and reduce the adverse behavioral changes inherent to device implantation. Additional considerations for implant surgery are provided. These results are validated with the implantation of a Bluetooth Low Energy (BLE) wireless sensor tag. The implanted wireless tag showed an average Received Signal Strength Indicator (RSSI) of 62.96dBm with a standard deviation of 4.95dBm and a variance of 24.5 dBm2. The high RSSI and variance values show that the implant was working well inside of the mouse's body and that the mouse was fully recovered and readily exploring its surroundings.Clinical Relevance-This work 1) studies the behavioral impact of implantable wireless biopotential devices. This will help clinical researchers conducting behavioral studies using sensor implants. 2) demonstrates a working implanted BLE wireless model inside of a mouse. Various wireless connectivity metrics are studied.

Factor Structure of the Postpartum Bonding Questionnaire in a US-Based Cohort of Mothers.

As research efforts in the field of pediatrics are oriented toward a better understanding of the synergistic relationship between different facets of early relational health (ERH) and child development and wellbeing, it is essential to focus on the quality of research instruments available for measuring different components of ERH. This study investigates the measurement characteristics of a widely used parent/caregiver-reported measure of bonding, the Postpartum Bonding Questionnaire (PBQ), in a US-based sample (n=610) of English-speaking biological mothers who completed the PBQ at 4 months postpartum. To evaluate the factor structure of the PBQ, confirmatory and exploratory statistical techniques were employed. The current study failed to replicate the PBQ's original 4-factor structure. Exploratory factor analysis results supported the creation of a 14-item abbreviated measure, the PBQ-14. The PBQ-14 showed evidence of good psychometric properties, including high internal consistency (ω=.87) and correlation with depression (r=.44, p<.001) assessed using the Patient Health Questionnaire (PHQ-9), as would be expected. The new unidimensional PBQ-14 is suitable for use in the US as a measure of general postnatal parent/caregiver-to-infant bonding.

Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.

The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied at a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in male mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity, and exhibited distinct molecular mitochondrial phenotype signatures. This work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the male mouse brain.

Deciduous tooth biomarkers reveal atypical fetal inflammatory regulation in autism spectrum disorder.

Atypical regulation of inflammation has been proposed in the etiology of autism spectrum disorder (ASD); however, measuring the temporal profile of fetal inflammation associated with future ASD diagnosis has not been possible. Here, we present a method to generate approximately daily profiles of prenatal and early childhood inflammation as measured by developmentally archived C-reactive protein (CRP) in incremental layers of deciduous tooth dentin. In our discovery population, a group of Swedish twins, we found heightened inflammation in the third trimester in children with future ASD diagnosis relative to controls (n = 66; 14 ASD cases; critical window: -90 to -50 days before birth). In our replication study, in the US, we observed a similar increase in CRP in ASD cases during the third trimester (n = 47; 23 ASD cases; -128 to -21 days before birth). Our results indicate that the third trimester is a critical period of atypical fetal inflammatory regulation in ASD.

Advancing early relational health: a collaborative exploration of a research agenda.

Here, we introduce the Early Relational Health (ERH) Learning Community's bold, large-scale, collaborative, data-driven and practice-informed research agenda focused on furthering our mechanistic understanding of ERH and identifying feasible and effective practices for making ERH promotion a routine and integrated component of pediatric primary care. The ERH Learning Community, formed by a team of parent/caregiver leaders, pediatric care clinicians, researchers, and early childhood development specialists, is a workgroup of Nurture Connection-a hub geared toward promoting ERH, i.e., the positive and nurturing relationship between young children and their parent(s)/caregiver(s), in families and communities nationwide. In response to the current child mental health crisis and the American Academy of Pediatrics (AAP) policy statement promoting ERH, the ERH Learning Community held an in-person meeting at the AAP national headquarters in December 2022 where members collaboratively designed an integrated research agenda to advance ERH. This agenda weaves together community partners, clinicians, and academics, melding the principles of participatory engagement and human-centered design, such as early engagement, co-design, iterative feedback, and cultural humility. Here, we present gaps in the ERH literature that prompted this initiative and the co-design activity that led to this novel and iterative community-focused research agenda, with parents/caregivers at the core, and in close collaboration with pediatric clinicians for real-world promotion of ERH in the pediatric primary care setting.

Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy.

Importance: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding. Objective: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months. Design, Setting, and Participants: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants. Exposures: Maternal symptomatic or asymptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language. Results: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (ß = 0.31; 95% CI, -2.97 to 3.58), gross motor (ß = 0.82; 95% CI, -1.34 to 2.99), fine motor (ß = 0.36; 95% CI, -0.74 to 1.47), expressive language (ß = -1.00; 95% CI, -4.02 to 2.02), or receptive language (ß = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores. Conclusions and Relevance: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.

IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity.

The neurobiological underpinnings of mood and anxiety disorders have been linked to the nucleus accumbens (NAc), a region important in processing the rewarding and emotional salience of stimuli. Using chronic social defeat stress, an animal model of mood and anxiety disorders, we investigated whether alterations in synaptic plasticity are responsible for the long-lasting behavioral symptoms induced by this form of stress. We hypothesized that chronic social defeat stress alters synaptic strength or connectivity of medium spiny neurons (MSNs) in the NAc to induce social avoidance. To test this, we analyzed the synaptic profile of MSNs via confocal imaging of Lucifer-yellow-filled cells, ultrastructural analysis of the postsynaptic density, and electrophysiological recordings of miniature EPSCs (mEPSCs) in mice after social defeat. We found that NAc MSNs have more stubby spine structures with smaller postsynaptic densities and an increase in the frequency of mEPSCs after social defeat. In parallel to these structural changes, we observed significant increases in IκB kinase (IKK) in the NAc after social defeat, a molecular pathway that has been shown to regulate neuronal morphology. Indeed, we find using viral-mediated gene transfer of dominant-negative and constitutively active IKK mutants that activation of IKK signaling pathways during social defeat is both necessary and sufficient to induce synaptic alterations and behavioral effects of the stress. These studies establish a causal role for IKK in regulating stress-induced adaptive plasticity and may present a novel target for drug development in the treatment of mood and anxiety disorders in humans.

Maternal Mental Health and Infant Development During the COVID-19 Pandemic.

Importance: The COVID-19 pandemic has prompted an unprecedented need to rapidly investigate the potential consequences for maternal mental health, infant and child development, and the mother-infant relationship. Observations: Globally, the mental health of pregnant and postpartum individuals has worsened during the pandemic regardless of infection status, and these concerning changes have disproportionally affected racial and ethnic minoritized people from underserved populations. Early indicators of infant neurobehavioral outcomes suggest that while in utero exposure to a maternal SARS-CoV-2 infection is likely negligible, limited data are available regarding the neurodevelopmental consequences for the generation of infants born during the pandemic. High maternal depression and grief during the COVID-19 pandemic are associated with lower levels of self-reported maternal-infant bonding. Yet nearly all published reports of child neurodevelopmental outcomes and dyadic functioning in the context of the pandemic rely on self-reported and parent-reported measures, which are subject to bias. Conclusions and Relevance: In the context of prior research, and considering the paucity of research on infant neurodevelopment following prenatal SARS-CoV-2 exposure and birth during the pandemic, robust scientific investigation is needed to detect indicators of compromised early outcomes that could inform widespread assessment and accessible intervention. We simultaneously caution against reflexive apprehension regarding the generation of children born during the COVID-19 pandemic.

Updating Clinical Practices to Promote and Protect Human Milk and Breastfeeding in a COVID-19 Era.

The COVID-19 pandemic has impacted breastfeeding and lactation globally, with clinical practices implemented early in the pandemic being mostly anti-breastfeeding, e.g., separation of mothers from their infants, and not evidence based. As the pandemic has progressed, evidence has emerged reconfirming the value of human milk and the importance of protecting and supporting breastfeeding, especially the initiation of lactation. However, it is clear that COVID-19 has changed the clinical care paradigm around breastfeeding and lactation support and, as such, it is imperative that practices adapt and evolve to maintain the emphasis on lactation support. We participated in a round table conference aiming to rescue and develop protocols and practices that support breastfeeding during the COVID-19 pandemic. One key area to target will be to maximize the use of the antenatal period. The early identification of lactation risk factors together with the development of person-centered methods to deliver breastfeeding information and education to parents-to-be will be critical. In addition, the establishment of a hospital culture that values breastfeeding and prioritizes the use of human milk will be integral for the motivation of health care professionals. That culture will also support active management of the initiation of lactation and the development of a 'back-up plan' toolkit to support the mother experiencing lactation difficulties. Post-discharge support will also be crucial with the development of both in-person and virtual lactation support programs, in particular for the immediate post-discharge period to benefit mothers who experience an early discharge process. These measures will allow for a new, adapted framework of practice that acknowledges the current COVID-19 paradigm and maintains the emphasis on the need to protect and support breastfeeding and the use of human milk.

Structure and function differences in the prelimbic cortex to basolateral amygdala circuit mediate trait vulnerability in a novel model of acute social defeat stress in male mice.

Stressful life events are ubiquitous and well-known to negatively impact mental health. However, in both humans and animal models, there is large individual variability in how individuals respond to stress, with some but not all experiencing long-term adverse consequences. While there is growing understanding of the neurobiological underpinnings of the stress response, much less is known about how neurocircuits shaped by lifetime experiences are activated during an initial stressor and contribute to this selective vulnerability versus resilience. We developed a model of acute social defeat stress (ASDS) that allows classification of male mice into "susceptible" (socially avoidant) versus "resilient" (expressing control-level social approach) one hour after exposure to six minutes of social stress. Using circuit tracing and high-resolution confocal imaging, we explored differences in activation and dendritic spine density and morphology in the prelimbic cortex to basolateral amygdala (PL→BLA) circuit in resilient versus susceptible mice. Susceptible mice had greater PL→BLA recruitment during ASDS and activated PL→BLA neurons from susceptible mice had more and larger mushroom spines compared to resilient mice. We hypothesized identified structure/function differences indicate an overactive PL→BLA response in susceptible mice and used an intersectional chemogenetic approach to inhibit the PL→BLA circuit during or prior to ASDS. We found in both cases that this blocked ASDS-induced social avoidance. Overall, we show PL→BLA structure/function differences mediate divergent behavioral responses to ASDS in male mice. These results support PL→BLA circuit overactivity during stress as a biomarker of trait vulnerability and potential target for prevention of stress-induced psychopathology.