The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus.

Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in peripartum humans and mice. In mice, our prior examination of the paraventricular nucleus (PVN) of the hypothalamus showed that pubertal stress led to an upregulation of baseline mRNA expression of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. In the current study, we further examined a potential mechanistic role for the IEGs in the PVN. We found that in pubertally stressed adult female, but not male, mice, intra-PVN allopregnanolone was sufficient to recapitulate the baseline IEG mRNA expression profile previously observed in pubertally stressed, pregnant mice. We also examined baseline IEG mRNA expression during adolescence, where we found that IEGs have developmental trajectories that showed sex-specific disruption by pubertal stress. Altogether, these data establish that IEGs may act as a key molecular switch involved in increased vulnerability to negative outcomes in adult, pubertally stressed animals. How the factors that produce vulnerability combine throughout the lifespan is key to our understanding of the etiology of stress-related disorders.

Development of an outcome indicator framework for a universal health visiting programme using routinely collected data.

BACKGROUND: Universal health visiting has been a cornerstone of preventative healthcare for children in the United Kingdom (UK) for over 100 years. In 2016, Scotland introduced a new Universal Health Visiting Pathway (UHVP), involving a greater number of contacts with a particular emphasis on the first year, visits within the home setting, and rigorous developmental assessment conducted by a qualified Health Visitor. To evaluate the UHVP, an outcome indicator framework was developed using routine administrative data. This paper sets out the development of these indicators. METHODS: A logic model was produced with stakeholders to define the group of outcomes, before further refining and aligning of the measures through discussions with stakeholders and inspection of data. Power calculations were carried out and initial data described for the chosen indicators. RESULTS: Eighteen indicators were selected across eight outcome areas: parental smoking, breastfeeding, immunisations, dental health, developmental concerns, obesity, accidents and injuries, and child protection interventions. Data quality was mixed. Coverage of reviews was high; over 90% of children received key reviews. Individual item completion was more variable: 92.2% had breastfeeding data at 6-8 weeks, whilst 63.2% had BMI recorded at 27-30 months. Prevalence also varied greatly, from 1.3% of children's names being on the Child Protection register for over six months by age three, to 93.6% having received all immunisations by age two. CONCLUSIONS: Home visiting services play a key role in ensuring children and families have the right support to enable the best start in life. As these programmes evolve, it is crucial to understand whether changes lead to improvements in child outcomes. This paper describes a set of indicators using routinely-collected data, lessening additional burden on participants, and reducing response bias which may be apparent in other forms of evaluation. Further research is needed to explore the transferability of this indicator framework to other settings.

Comparative Screening of DalPhos/Ni Catalysts in C-N Cross-couplings of (Hetero)aryl Chlorides Enables Development of Aminopyrazole Cross-couplings with Amine Base.

A systematic competitive evaluation of the DalPhos ligand family in nickel-catalyzed N-arylation chemistry is reported, involving primary (linear and branched) and secondary alkylamines, as well as a primary five-membered heteroarylamine (aminopyrazole), in combination with a diverse set of test electrophiles and bases (NaOtBu, K2 CO3 , DBU/NaTFA). In addition to providing optimal ligand/catalyst identification, and bringing to light methodology limitations (e. g., unwanted C-O cross-coupling with NaOtBu), our survey enabled the development of the first efficient catalyst system for heteroatom-dense C-N cross-coupling of aminopyrazoles and related nucleophiles with (hetero)aryl chlorides by use of an amine 'dual-base' system.

Nickel-Catalyzed O-Arylation of Primary or Secondary Aliphatic Alcohols with (Hetero)aryl Chlorides: A Comparison of Ni(I) and Ni(II) Precatalysts.

A comparative experimental and computational study examining the interplay of the ancillary ligand structure and Ni oxidation state in the Ni-catalyzed C(sp2)-O cross-coupling of (hetero)aryl chlorides and primary or secondary aliphatic alcohols is presented, focusing on PAd-DalPhos (L1)-, CyPAd-DalPhos (L2)-, PAd2-DalPhos (L3)-, and DPPF (L4)-ligated [(L)NiCl]n (n = 1 or 2) and (L)Ni(o-tol)Cl precatalysts. Both L1 and L2 were found to outperform the other ligands examined, with the latter proving to be superior overall. While Ni(II) precatalysts generally outperformed Ni(I) species, in some instances the catalytic abilities of Ni(I) precatalysts were competitive with those of Ni(II). Density-functional theory calculations indicate the favorability of a Ni(0)/Ni(II) catalytic cycle featuring turnover-limiting C-O bond reductive elimination over a Ni(I)/Ni(III) cycle involving turnover-limiting C-Cl oxidative addition.

Nickel-Catalyzed Chemoselective Arylation of Amino Alcohols.

A systematic evaluation of competitive bisphosphine/Ni-catalyzed C-N versus C-O cross-couplings involving model compounds enabled development of hitherto unknown chemoselective O- and N-arylation of amino alcohols with (hetero)aryl chloride electrophiles, without recourse to protection group chemistry. Use of the CyPAd-DalPhos pre-catalyst C2 enabled particularly challenging O-arylation chemoselectivity in amino alcohols featuring branched primary and secondary alkylamine groups, while selective N-arylation was observed in substrates featuring less-hindered linear alkylamine and aniline reacting groups. Useful reaction scope in the (hetero)aryl chloride was achieved throughout, and the ability to conduct such transformations using benchtop handling of materials is demonstrated.

Young people's experiences of COVID-19 messaging at the start of the UK lockdown: lessons for positive engagement and information sharing.

BACKGROUND: To reduce COVID-19 infection rates during the initial stages of the pandemic, the UK Government mandated a strict period of restriction on freedom of movement or 'lockdown'. For young people, closure of schools and higher education institutions and social distancing rules may have been particularly challenging, coming at a critical time in their lives for social and emotional development. This study explored young people's experiences of the UK Government's initial response to the pandemic and related government messaging. METHODS: This qualitative study combines data from research groups at the University of Southampton, University of Edinburgh and University College London. Thirty-six online focus group discussions (FGDs) were conducted with 150 young people (Southampton: n = 69; FGD = 7; Edinburgh: n = 41; FGD = 5; UCL: n = 40; FGD = 24). Thematic analysis was conducted to explore how young people viewed the government's response and messaging and to develop recommendations for how to best involve young people in addressing similar crises in the future. RESULTS: The abrupt onset of lockdown left young people shocked, confused and feeling ignored by government and media messaging. Despite this, they were motivated to adhere to government advice by the hope that life might soon return to normal. They felt a responsibility to help with the pandemic response, and wanted to be productive with their time, but saw few opportunities to volunteer. CONCLUSIONS: Young people want to be listened to and feel they have a part to play in responding to a national crisis such as the COVID-19 epidemic. To reduce the likelihood of disenfranchising the next generation, Government and the media should focus on developing messaging that reflects young people's values and concerns and to provide opportunities for young people to become involved in responses to future crises.

Animal models built for women's brain health: Progress and potential.

Women and men have different levels of risk for a variety of brain disorders. Despite this well-known epidemiological finding, preclinical work utilizing animal models has historically only included male animals. The policies of funders to require consideration of sex as a biological variable has shifted the momentum to include female animals in preclinical neuroscience and to report findings by sex. However, there are many biological questions related to brain health that go beyond sex differences and are indeed specific to women. Here, the focus is on why animal models should be utilized in the pursuit of understanding women's brain health, a brief overview of what they have provided thus far, and why they still hold tremendous promise. This review concludes with a set of suggestions for how to begin to pursue translational animal models in a way that facilitates rapid success and harnesses the most powerful aspects of animal models.

The development of cage phosphine 'DalPhos' ligands to enable nickel-catalyzed cross-couplings of (hetero)aryl electrophiles.

Nickel-catalyzed cross-couplings of (hetero)aryl electrophiles with a diversity of nucleophiles (nitrogen, oxygen, carbon, and others) have evolved into competitive alternatives to well-established palladium- and copper-based protocols for the synthesis of (hetero)aryl products, including (hetero)anilines and (hetero)aryl ethers. A survey of the literature reveals that the use of cage phosphine (CgP) 'DalPhos' (DALhousie PHOSphine) bisphosphine-type ligands operating under thermal conditions currently offers the most broad substrate scope in nickel-catalyzed cross-couplings of this type, especially involving (hetero)aryl chlorides and phenol-derived electrophiles. The development and application of these DalPhos ligands is described in a ligand-specific manner that is intended to serve as a guide for the synthetic chemistry end-user.

Sex differences in stress-induced cortisol response among infants of mothers exposed to childhood adversity.

BACKGROUND: Adverse childhood experiences (ACEs) increase risk for mental illness in women and their children, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a role. The impact of ACEs on the HPA axis may be strongest when ACEs occur prepubertally and in those exposed to abuse ACEs. METHODS: To test this, we measured salivary cortisol in 96 mother-infant dyads while mothers were separated from their infant experiencing a laboratory stressor. Mothers completed the ACE questionnaire, ACEs occurring prepubertally (pACEs) were measured, and mother-infant dyads were grouped based on maternal pACE history: no pACEs, 1+ pACEs with abuse, or 1+ pACEs but no abuse. RESULTS: Mothers with 1+ pACEs exhibited decreases in cortisol (relative to pre-infant stressor), which differed significantly from the cortisol increase mothers with no pACEs experienced, regardless of abuse presence (p=.001) or absence (p=.002). These 1+ pACE groups did not differ from one another (p=.929). Significant sex differences in infant cortisol were observed in infants of mothers with 1+ pACEs (regardless of abuse) but not in infants of mothers with no pACEs. When mothers had 1+ pACEs, males showed decreases in cortisol in response to a stressor whereas females demonstrated increases, and males and females differed significantly when their mothers had 1+ pACEs with (p=0.025) and without (p=0.032) abuse. CONCLUSIONS: Regardless of maternal exposure to childhood abuse, in response to a stressor, prepubertal ACEs were associated with lower cortisol response in mothers and sex differences in six-month-old infants, with males showing a lower cortisol response than females.

Immediate early genes as a molecular switch for lasting vulnerability following pubertal stress in mice.

Why individuals have negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted glucocorticoid response within the hypothalamic-pituitary-adrenal axis in both peripartum humans and mice. In mice, we examined puberty-stress reprogramming in the paraventricular nucleus (PVN) of the hypothalamus, which initiates the HPA axis response. We found that pubertal stress led to an upregulation of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. Here, we examined the response of the IEGs in the PVN to the primary disruption of pubertal stress in early adolescence and to the secondary disruption of increased allopregnanolone in pregnancy. We found that in adult female, but not male, mice previously stressed during puberty, intra-PVN allopregnanolone was sufficient to recapitulate the pubertal stress associated baseline IEG expression profile. We also examined baseline IEG expression during adolescence, where we found that IEGs have sex-specific developmental trajectories that were disrupted by pubertal stress. Altogether, these data establish that IEGs can act as a key molecular switch that leads to increased vulnerability to negative outcomes in adult, pubertally stressed animals. Understanding how the factors that produce vulnerability combine throughout the lifespan will further our understanding of the etiology of negative outcomes and will help guide both the nature and timing of potential treatments.

Intestinal microbial circadian rhythms drive sex differences in host immunity and metabolism.

Circadian rhythms dynamically regulate sex differences in metabolism and immunity, and circadian disruption increases the risk of metabolic disorders. We investigated the role of sex-specific intestinal microbial circadian rhythms in host metabolism using germ-free and conventionalized mice and manipulation of dietary-derived fat, fiber, and microbiota-accessible carbohydrates. Our findings demonstrate that sex differences in circadian rhythms of genes involved in immunity and metabolism depend on oscillations in microbiota, microbial metabolic functions, and microbial metabolites. Further, we show that consuming an obesogenic, high-fat, low-fiber diet produced sex-specific changes in circadian rhythms in microbiota, metabolites, and host gene expression, which were linked to sex differences in the severity of metabolic dysfunction. Our results reveal that microbial circadian rhythms contribute to sex differences in immunity and metabolism and that dietary factors can entrain new circadian rhythms and modify the magnitude of sex differences in host-microbe circadian dynamics.

Understanding the use of telehealth in the context of the Family Nurse Partnership and other early years home visiting programmes: A rapid review.

Overview: This rapid review sought to understand the use of telehealth in early parenthood programmes sharing similarities with the Family Nurse Partnership. Methods: A rapid review protocol was developed in accordance with Cochrane Rapid Reviews Methods Guidance. Medline, Cochrane Library, and CINAHL databases were searched. Inclusion criteria were developed using population, intervention, comparator, outcome, study design, and timeframe components. Two reviewers searched, screened, and extracted data. AMSTAR was used for critical appraisal. Results were synthesised narratively. Results: Searches yielded 18 studies out of 881 for inclusion. Findings were identified across seven domains: acceptability and accessibility; therapeutic relationships; flexibility offered by telehealth; participation and engagement; confidentiality and privacy; equipment and technical considerations; and training and support. Conclusion: Telehealth provides unique opportunities to improve access to early years health services for young mothers. However, considerable accessibility barriers remain in the form of connectivity issues, access to appropriate technology, and the acceptability of remote healthcare delivery. This review presents a timely overview of the opportunities and challenges associated with the use of telehealth in early parenthood and family-based programmes.

Developmental Timing of Trauma in Women Predicts Unique Extracellular Vesicle Proteome Signatures.

BACKGROUND: Exposure to traumatic events is a risk factor for negative physical and mental health outcomes. However, the underlying biological mechanisms that perpetuate these lasting effects are not known. METHODS: We investigated the impact and timing of sexual trauma, a specific type of interpersonal violence, experienced during key developmental windows of childhood, adolescence, or adulthood on adult health outcomes and associated biomarkers, including circulating cell-free mitochondrial DNA levels and extracellular vesicles (EVs), in a predominantly Black cohort of women (N = 101). RESULTS: Significant changes in both biomarkers examined, circulating cell-free mitochondrial DNA levels and EV proteome, were specific to developmental timing of sexual trauma. Specifically, we identified a large number of keratin-related proteins from EVs unique to the adolescent sexual trauma group. Remarkably, the majority of these keratin proteins belong to a 17q21 gene cluster, which suggests a potential local epigenetic regulatory mechanism altered by adolescent trauma to impact keratinocyte EV secretion or its protein cargo. These results, along with changes in fear-potentiated startle and skin conductance detected in these women, suggest that sexual violence experienced during the specific developmental window of adolescence may involve unique programming of the skin, the body's largest stress organ. CONCLUSIONS: Together, these descriptive studies provide novel insight into distinct biological processes altered by trauma experienced during specific developmental windows. Future studies will be required to mechanistically link these biological processes to health outcomes.

Relationships Among Childhood Maltreatment, Limbic System Dysfunction, and Eating Disorders in College Women.

The mechanisms linking childhood maltreatment and eating pathology are not fully understood. We examined the mediating role of limbic system dysfunction in the relationships between three forms of childhood maltreatment (parental psychological maltreatment, parental physical maltreatment, and parental emotional neglect) and eating disorder symptoms. A convenience sample of college women (N = 246, M age = 19.62, SD = 2.41) completed measures of maltreatment (Parent-Child Conflict Tactics Scales and the Parental Bonding Instrument), limbic system dysfunction (Limbic System Questionnaire), and eating pathology (Eating Disorder Examination Questionnaire). We hypothesized that there would be an indirect effect of each type of childhood maltreatment on eating disorder symptoms via limbic system irritability. Results generally supported the hypotheses. Examination of the individual paths that defined the indirect effect indicated that higher reported childhood maltreatment was associated with greater limbic irritability symptoms, and higher limbic irritability symptomatology was related to higher total eating disorder scores. There were no significant direct effects for any of the proposed models. Findings are in line with research supporting the role of limbic system dysfunction as a possible pathway in the maltreatment-eating disorder link. Given that limbic system dysfunction may underlie behavioral symptoms of eating disorders, efforts targeting limbic system dysfunction associated with child maltreatment might best be undertaken at an early developmental stage, although interventions for college women struggling with eating disorders are also crucial.

Stand Up for Health: Programme theory for an intervention to reduce sedentary behaviour in contact centres.

BACKGROUND: Contact centre staff spend up to 95 % of their day seated, which can lead to a range of negative health outcomes. The aim of this study was to develop a programme theory for a complex intervention to reduce sedentary behaviour in contact centres. METHODS: The 6SQuID model was used. A literature review, and focus groups at one contact centre were used to: understand the problem (step 1); identify modifiable factors (step 2); and develop a theory of change (step 3). A workshop shaped a theory of action (step 4), and the programme theory was refined after testing activities over 6 months (step 5). The intervention is currently undergoing further evaluation and feasibility testing in a larger scale stepped wedge randomised controlled study in 11 contact centres (Step 6). RESULTS: Step 1: Limited opportunity to sit less, and move more at work was identified as the main problem. Step 2: Modifiable factors were identified at four levels of the centre. Step 3: A theory of change was developed around cultural norms and individual behaviour change. Step 4: Actions were developed to 'activate' the theory of change. Step 5: Activities were implemented, and adapted over 6 months and the programme theory was refined. CONCLUSION: The programme theory behind this intervention is robust, evidence based, adaptive and transferable.

The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model.

Newborns are colonized by maternal microbiota that is essential for offspring health and development. The composition of these pioneer communities exhibits individual differences, but the importance of this early-life heterogeneity to health outcomes is not understood. Here we validate a human microbiota-associated model in which fetal mice are cesarean delivered and gavaged with defined human vaginal microbial communities. This model replicates the inoculation that occurs during vaginal birth and reveals lasting effects on offspring metabolism, immunity, and the brain in a community-specific manner. This microbial effect is amplified by prior gestation in a maternal obesogenic or vaginal dysbiotic environment where placental and fetal ileum development are altered, and an augmented immune response increases rates of offspring mortality. Collectively, we describe a translationally relevant model to examine the defined role of specific human microbial communities on offspring health outcomes, and demonstrate that the prenatal environment dramatically shapes the postnatal response to inoculation.

Mapping past human land use using archaeological data: A new classification for global land use synthesis and data harmonization.

In the 12,000 years preceding the Industrial Revolution, human activities led to significant changes in land cover, plant and animal distributions, surface hydrology, and biochemical cycles. Earth system models suggest that this anthropogenic land cover change influenced regional and global climate. However, the representation of past land use in earth system models is currently oversimplified. As a result, there are large uncertainties in the current understanding of the past and current state of the earth system. In order to improve representation of the variety and scale of impacts that past land use had on the earth system, a global effort is underway to aggregate and synthesize archaeological and historical evidence of land use systems. Here we present a simple, hierarchical classification of land use systems designed to be used with archaeological and historical data at a global scale and a schema of codes that identify land use practices common to a range of systems, both implemented in a geospatial database. The classification scheme and database resulted from an extensive process of consultation with researchers worldwide. Our scheme is designed to deliver consistent, empirically robust data for the improvement of land use models, while simultaneously allowing for a comparative, detailed mapping of land use relevant to the needs of historical scholars. To illustrate the benefits of the classification scheme and methods for mapping historical land use, we apply it to Mesopotamia and Arabia at 6 kya (c. 4000 BCE). The scheme will be used to describe land use by the Past Global Changes (PAGES) LandCover6k working group, an international project comprised of archaeologists, historians, geographers, paleoecologists, and modelers. Beyond this, the scheme has a wide utility for creating a common language between research and policy communities, linking archaeologists with climate modelers, biodiversity conservation workers and initiatives.

It's the fiber, not the fat: significant effects of dietary challenge on the gut microbiome.

BACKGROUND: Dietary effects on the gut microbiome play key roles in the pathophysiology of inflammatory disorders, metabolic syndrome, obesity, and behavioral dysregulation. Often overlooked in such studies is the consideration that experimental diets vary significantly in the proportion and source of their dietary fiber. Commonly, treatment comparisons are made between animals fed a purchased refined diet that lacks soluble fiber and animals fed a standard vivarium-provided chow diet that contains a rich source of soluble fiber. Despite the well-established critical role of soluble fiber as the source of short chain fatty acid production via the gut microbiome, the extent to which measured outcomes are driven by differences in dietary fiber is unclear. Further, the interaction between sex and age in response to dietary transition is likely important and should also be considered. RESULTS: We compared the impact of transitioning young adult and 1-year aged male and female mice from their standard chow diet to a refined low soluble fiber diet on gut microbiota community composition. Then, to determine the contribution of dietary fat, we also examined the impact of transitioning a subset of animals from refined low-fat to refined high-fat diet. We used a serial sampling strategy coupled with 16S rRNA marker gene sequencing to examine consequences of recurrent dietary switching on gut microbiota community dynamics. Analysis revealed that the transition from a chow diet to a refined diet that lacks soluble fiber accounted for most of the variance in community structure, diversity, and composition across all groups. This dietary transition was characterized by a loss of taxa within the phylum Bacteroidetes and expansion of Clostridia and Proteobacteria in a sex- and age-specific manner. Most notably, no changes to gut microbiota community structure and composition were observed between mice consuming either refined low- or high-fat diet, suggesting that transition to the refined diet that lacks soluble fiber is the primary driver of gut microbiota alterations, with limited additional impact of dietary fat on gut microbiota. CONCLUSION: Collectively, our results show that the choice of control diet has a significant impact on outcomes and interpretation related to diet effects on gut microbiota. As the reduction of soluble fiber may influence synthesis of microbial metabolites that are important for regulating metabolic, immune, behavioral, and neurobiological outcomes, additional studies are now needed to fully delineate the contribution of fat and fiber on the gut microbiome. Video Abtract.

Study protocol: a mixed-methods realist evaluation of the Universal Health Visiting Pathway in Scotland.

INTRODUCTION: The growing political emphasis on the early years reflects the importance of these formative years of life. Health visitors in the UK are uniquely positioned to improve health outcomes for children and families and to reduce health inequalities. Recently, there has been a policy change in Scotland in an attempt to enhance the delivery of the universal health visiting service. This study aims to examine the extent to which the enhanced Universal Health Visiting Pathway is implemented and delivered across Scotland and to assess any associated impacts. METHODS AND ANALYSIS: A mixed-methods study incorporating four methodological components and uses realist evaluation as the overall conceptual framework. It comprises three phases (1) initial programme theory development; (2) programme theory validation and (3) programme theory refinement. The programme theory validation will use interview and focus group data of parents and health visitors, and conduct a case note review at five study sites. It also involves a national survey of parents and health visitors and routine data analysis of existing secondary data. The analyses of the ensuing qualitative and quantitative data will be carried out using a convergent mixed-methods approach to ensure continuous triangulation of multiple data. The findings of the evaluation will provide contextually relevant understanding of how the Universal Health Visiting Pathway works and evidence the impact of increased investments in health visiting in Scotland. ETHICS AND DISSEMINATION: This protocol has been approved by the School of Health in Social Science Research Ethics Committee, University of Edinburgh. Additional approvals have been granted/will be sought from the Public Benefit and Privacy Panel for health and social care in Scotland for the case note review,survey and routine data analysis elements of the evaluation. The findings will be prepared as reports to the funders and presented at conferences. It will be submitted for publication in peer-reviewed journals.

Pubertal adversity alters chromatin dynamics and stress circuitry in the pregnant brain.

Women who have experienced adverse childhood events (ACEs) around puberty are at the greatest risk for neuropsychiatric disorders across the lifespan. This population is exceptionally vulnerable to neuropsychiatric disease presentation during the hormonally dynamic state of pregnancy. We previously established that chronic adversity around puberty in female mice significantly altered their HPA axis function specifically during pregnancy, modeling the effects of pubertal ACEs we also reported in women. We hypothesized that the pregnancy hormone, allopregnanolone, was involved in presentation of the blunted stress response phenotype by its interaction with the molecular programming that had occurred during pubertal adversity experience. Here, in adult mice previously stressed during puberty, allopregnanolone administration was sufficient to reproduce the decreased corticosterone response after acute stress. Examination of neuronal activation and the electrophysiological properties of CRF neurons in the paraventricular nucleus of the hypothalamus (PVN) found no significant changes in synaptic function that corresponded with the blunted HPA axis reactivity. However, at the chromatin level, utilization of ATAC-Seq profiling demonstrated a dramatic remodeling of DNA accessibility in the PVN following pubertal adversity. Altogether, these data establish a potential molecular mechanism whereby adversity during puberty can enact lasting transcriptional control that manifests only during a unique period of the lifespan where dynamic hormonal changes occur. These results highlight a biological process that may impart an increased risk for a highly vulnerable population, whereby pubertal programming of the PVN results in aberrant HPA axis responsiveness when exposed to the hormonal changes unique to pregnancy.