Sex Differences Research Articles

Sex-based utilization of guideline recommended statin therapy and cardiovascular disease outcomes: Data from a multisite healthcare network primary prevention cohort

BackgroundIn the US, women have similar cardiovascular death rates as men. However, less is known about sex differences in statin use for primary prevention and associated atherosclerotic cardiovascular disease (ASCVD) outcomes. MethodsStatin prescriptions using electronic health records were examined in patients without ASCVD (myocardial infarction (MI), revascularization or ischemic stroke) between 2013 and 2019. Guideline-directed statin intensity (GDSI) at index (at least moderate intensity, defined per pooled-cohort equation) and follow-up visits were compared between sexes across ASCVD risk groups, defined by the pooled-cohort equation. Cox regression hazard ratios were calculated for statin use and outcomes (myocardial infarction, stroke/transient ischemic attack (TIA), and all-cause mortality) stratified by sex. Interaction terms (statin and sex) were applied. ResultsAmong 282,298 patients, (mean age ∼ 50 years) 17.1 % women and 19.5 % men were prescribed any statin at index visit. Time to GDSI was similar between sexes, but the proportion of high-risk women on GDSI at follow-up were lower compared to high-risk men (2-years: 27.7 vs 32.0 %, and 5-years: 47.2 vs 55.2 %, p < 0.05). When compared to GDSI, no statin use was associated with higher risk of MI and ischemic stroke/TIA among both sexes. High-risk women on GDSI had a lower risk of mortality (HR=1.39 [1.22–1.59]) vs. men (HR=1.67 [1.50–1.86]) of similar risk (p value interaction=0.004). ConclusionIn a large contemporary healthcare system, there was underutilization of statins across both sexes in primary prevention. High-risk women were less likely to remain on GDSI compared to high-risk men. GDSI significantly improved the survival in both sexes regardless of ASCVD risk group. Future strategies to ensure continued use of GDSI, specifically among women, should be explored.

Sex differences in extinction and reinstatement of nicotine discrimination in rats: The effects of reinforcer devaluation.

Sex differences in extinction and reinstatement of nicotine discrimination in rats: The effects of reinforcer devaluation.

Allele frequency dynamics under sex-biased demography and sex-specific inheritance in a pedigreed jay population

Abstract Sex-biased demography, including sex-biased survival or migration, can alter allele frequency changes across the genome. In particular, we can expect different patterns of genetic variation on autosomes and sex chromosomes due to sex-specific differences in life histories, as well as differences in effective population size, transmission modes, and the strength and mode of selection. Here, we demonstrate the role that sex differences in life history played in shaping short-term evolutionary dynamics across the genome. We used a 25-year pedigree and genomic dataset from a long-studied population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of sex-biased demography and inheritance in shaping genome-wide allele frequency trajectories. We used gene dropping simulations to estimate individual genetic contributions to future generations and to model drift and immigration on the known pedigree. We quantified differential expected genetic contributions of males and females over time, showing the impact of sex-biased dispersal in a monogamous system. Due to female-biased dispersal, more autosomal variation is introduced by female immigrants. However, due to male-biased transmission, more Z variation is introduced by male immigrants. Finally, we partitioned the proportion of variance in allele frequency change through time due to male and female contributions. Overall, most allele frequency change is due to variance in survival and births. Males and females make similar contributions to autosomal allele frequency change, but males make higher contributions to allele frequency change on the Z chromosome. Our work shows the importance of understanding sex-specific demographic processes in characterizing genome-wide allele frequency change in wild populations.

The impact of frailty on clinical outcomes of older patients undergoing enhanced recovery after lumbar fusion surgery: A prospective cohort study.

Frailty is recognized as a surrogate for physiological age and has been established as a valid and independent predictor of postoperative morbidity, mortality, and complications. ERAS can enhance surgical safety by minimizing stress responses in frail patients, enabling surgeons to discharge patients earlier. However, the question of whether and to what extent the frailty impacts the post-ERAS outcomes in older patients remains. An evidence-based ERAS program was implemented in our center from January 2019. This is a prospective cohort study of patients aged ≥75 years who underwent open transforaminal lumbar interbody fusion (TLIF) for degenerative spine disease from April 2019 to October 2021. Frailty was assessed with the Fried frailty scale (FP scale), and patients were categorized as non/prefrail (FP 0-2) or frail (FP ≥ 3). The preoperative variables, operative data, postoperative outcomes and follow-up information were compared between the two groups. Univariate and multivariate logistic regression analyses were used to identify risk factors for 90-day major complications and prolonged length of hospital stay (LOS) after surgery. A total of 245 patients (age of 79.8 ± 3.4 yr) who had a preoperative FP score recorded and underwent scheduled TLIF surgery were included in the final analysis. Comparisons between non-frail and prefrail/frail patients revealed no significant difference in age, sex, and surgery-related variables. Even after adjusting for multiple comparisons, the association between Fried frailty and ADL-dependency, IADL-dependency, and malnutrition remained significant. Preoperative frailty was associated with increased rates of postoperative adverse events. A higher CCI grade was an independent predictor for 90-day major complications, while Fried frailty and MNA-SF scores <12 were predictive of poor postoperative recovery. Frail older patients had more adverse post-ERAS outcomes after TLIF compared to non/prefrail older patients. Continued research and multidisciplinary collaboration will be essential to refine and optimize protocols for surgical care in frail older adults.

Transcriptome Analysis of Left Versus Right Intrinsic Laryngeal Muscles Associated with Innervation.

Recurrent laryngeal nerve injury diagnosed as idiopathic or due to short-term surgery-related intubation exhibits a higher incidence of left-sided paralysis. While this is often attributed to nerve length, it is hypothesized there are asymmetric differences in the expression of genes related to neuromuscular function that may impact reinnervation and contribute to this laterality phenomenon. To test this hypothesis, this study analyzes the transcriptome profiles of the intrinsic laryngeal muscles (ILMs), comparing gene expression in the left versus right, with particular attention to genetic pathways associated with neuromuscular function. Laboratory experiment. RNA was extracted from the left and right sides of the rat posterior cricoarytenoid (PCA), lateral thyroarytenoid (LTA), and medial thyroarytenoid (MTA), respectively. After high-throughput RNA-Sequencing, 88 samples were organized into 12 datasets according to their age (P15/adult), sex (male/female), and muscle type (PCA/LTA/MTA). A comprehensive bioinformatics analysis was conducted to compare the left-right ILMs across different conditions. A total of 774 differentially expressed genes were identified across the 12 experimental groups, revealing age, sex, and muscle-specific differences between the left versus right ILMs. Enrichment analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways implicated several genes with a left-right laryngeal muscle asymmetry. These genes are associated with neuronal and muscular physiology, immune/inflammatory response, and hormone control. Bioinformatics analysis confirmed divergent transcriptome profiles between the left-right ILMs. This preliminary study identifies putative gene targets that will characterize ILM laterality. N/A Laryngoscope, 2024.

Molecular and Physiological Effects of 17α-methyltestosterone on Sex Differentiation of Black Rockfish, Sebastes schlegelii

It is widely known that all-female fish production holds economic value for aquaculture. Sebastes schlegelii, a preeminent economic species, exhibits a sex dimorphism, with females surpassing males in growth. In this regard, achieving all-female black rockfish production could significantly enhance breeding profitability. In this study, we utilized the widely used male sex-regulating hormone, 17α-methyltestosterone (MT) at three different concentrations (20, 40, and 60 ppm), to produce pseudomales of S. schlegelii for subsequent all-female offspring breeding. Long-term MT administration severely inhibits the growth of S. schlegelii, while short term had no significant impact. Histological analysis confirmed sex reversal at all MT concentrations; however, both medium and higher MT concentrations impaired testis development. MT also influenced sex steroid hormone levels in pseudomales, suppressing E2 while increasing T and 11-KT levels. In addition, a transcriptome analysis revealed that MT down-regulated ovarian-related genes (cyp19a1a and foxl2) while up-regulating male-related genes (amh) in pseudomales. Furthermore, MT modulated the TGF-β signaling and steroid hormone biosynthesis pathways, indicating its crucial role in S. schlegelii sex differentiation. Therefore, the current study provides a method for achieving sexual reversal using MT in S. schlegelii and offers an initial insight into the underlying mechanism of sexual reversal in this species.

An exploration into the causal relationships between educational attainment, intelligence, and wellbeing: an observational and two-sample Mendelian randomisation study

Educational attainment is associated with a range of positive outcomes, yet its impact on wellbeing is unclear, and complicated by high correlations with intelligence. We use genetic and observational data to investigate for the first time, whether educational attainment and intelligence are causally and independently related to wellbeing. Results from our multivariable Mendelian randomisation demonstrated a positive causal impact of a genetic predisposition to higher educational attainment on wellbeing that remained after accounting for intelligence, and a negative impact of intelligence that was independent of educational attainment. Observational analyses suggested that these associations may be subject to sex differences, with benefits to wellbeing greater for females who attend higher education compared to males. For intelligence, males scoring more highly on measures related to happiness were those with lower intelligence. Our findings demonstrate a unique benefit for wellbeing of staying in school, over and above improving cognitive abilities, with benefits likely to be greater for females compared to males.

Detrimental Impact of Atrial Fibrillation among Patients Hospitalized for Acute Exacerbation of COPD: Results of a Population-Based Study in Spain from 2016 to 2021

Background/Objectives: To analyze changes in the prevalence of atrial fibrillation (AF) in patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease (AE-COPD); to evaluate hospital outcomes according to AF status, assessing sex differences; to identify factors associated with AF presence; and to analyze variables associated with in-hospital mortality (IHM) in AE-COPD patients with AF. Methods: We used data from the Registry of Specialized Care Activity-Basic Minimum Data Set (RAE-CMBD) to select patients aged ≥40 years with COPD in Spain (2016–2021). We stratified the study population according to AF presence and sex. The propensity score matching (PSM) methodology was employed to create comparable groups based on age, admission year, and comorbidities at the time of hospitalization. Results: We identified 399,196 hospitalizations that met the inclusion criteria. Among them, 20.58% had AF. The prevalence of AF rose from 2016 to 2021 (18.26% to 20.95%), though the increase was only significant in men. The median length of hospital stay (LOHS) and IHM were significantly higher in patients with AF than in those without AF. After PSM, IHM remained significantly higher for man and women with AF. Older age, male sex, and several comorbidities were factors associated with AF. Additionally, older age, male sex, different comorbidities including COVID-19, hospitalization in the year 2020, mechanical ventilation, and intensive care unit (ICU) admission were associated with higher IHM in patients with AE-COPD and AF. Conclusions: AF prevalence was high in patients hospitalized for AE-COPD, was higher in men than in women, and increased over time. AF presence was associated with worse outcomes. The variables associated with IHM in hospitalized AE-COPD patients with AF were older age, male sex, different comorbidities including COVID-19 presence, hospitalization in the year 2020, need of mechanical ventilation, and ICU admission.

Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice

BackgroundAutism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD.MethodsTo fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice.ResultsThe results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes.ConclusionsThese results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS.

No sex difference in preen oil chemical composition during incubation in Kentish plovers.

Preen oil, the secretion from the uropygial gland of birds, may have a specific function in incubation. Consistent with this, during incubation, the chemical composition of preen oil is more likely to differ between sexes in species where only one sex incubates than in species where both sexes incubate. In this study, we tested the generality of this apparent difference, by investigating sex differences in the preen oil composition of a shorebird species, the Kentish plover (Anarhynchus, formerly Charadrius, alexandrinus). As both sexes incubate in this species, we predicted the absence of sex differences in preen oil composition during incubation. In the field, we sampled preen oil from nine females and 11 males during incubation, which we analysed with gas chromatography-mass spectrometry (GC-MS). Consistent with predictions, we found no sex difference in preen oil composition, neither in beta diversity (Bray-Curtis dissimilarities) nor in alpha diversity (Shannon index and number of substances). Based on these results, we cannot conclude whether preen oil has a function during incubation in Kentish plovers. Still, we discuss hypothetical roles, such as olfactory crypsis, protection against ectoparasites or olfactory intraspecific communication, which remain to be tested.

Diet, sexual dimorphism, and fertility aspects of Melanophryniscus fulvoguttatus (Mertens, 1937) from Central-East Brazil

Melanophryniscus fulvoguttatus is a small toad that inhabits the Cerrado, Atlantic Forest, and humid Chaco of South America. Due to its aposematic coloration and behavior, it is a species that may present chemical defenses such as alkaloids and a restricted diet similar to other species of the genus. Although it was described in the early 20th century, there is still little information on its natural history and ecology. Here, we described the diet, tested the sexual dimorphism, and calculated the fertility index of M. fulvoguttatus based on a sample of eight males and 21 females from a population within the Cerrado. Sexual dimorphism was assessed using 15 morphometric measures; diet was calculated as an index of relative importance by prey item and tested for sex differences; fertility was tested for relations between body size and the number of eggs; and we also estimated the reproductive investment. Our results demonstrate that this population’s diet consisted mostly of ant species, with Pheidole radoszkowskii being the most important, followed by Crematogaster sp. and Cyphomyrmex transversus. Regarding sexual dimorphism, we observed that females were significantly larger than males, with a positive relationship between female size and the number of eggs. We did not find significant differences in the diets of males and females. Although the diet and reproductive aspects of M. fulvoguttatus are similar to those of its congeneric species, further studies are needed in order to address the relationship between the species diet and its chemical defenses.

The gut microbiome in alcohol use disorder and alcohol-associated liver disease: A systematic review of clinical studies.

Evidence suggests that a relationship exists between the gut microbiome and the pathogenesis of alcohol use disorder (AUD) and alcohol-associated liver disease (AALD). This systematic review identified studies that investigated the gut microbiome in individuals with an AUD or an AALD. A search was conducted on October 27, 2022, in PubMed, Web of Science, and Embase databases. Fifty studies satisfied eligibility criteria. Most studies found evidence for gut dysbiosis in individuals with AUD and AALD. Microbiome intervention studies have mostly been conducted in AALD patients; fecal microbial transplant interventions show the most promise. Because most studies were conducted cross-sectionally, the causal relationship between the gut microbiome and alcohol use is unknown. Furthermore, almost all studies have been conducted in predominantly male populations, leaving critical questions regarding sex differences and generalizability of the findings. The study summaries and recommendations provided in this review seek to identify areas for further research and to highlight potential gut microbial interventions for treating AUD and AALD.

Microbial influences on severity and sex bias of systemic autoimmunity.

Commensal microbes have the capacity to affect development and severity of autoimmune diseases. Germ-free (GF) animals have proven to be a fine tool to obtain definitive answers to the queries about the microbial role in these diseases. Moreover, GF and gnotobiotic animals can be used to dissect the complex symptoms and determine which are regulated (enhanced or attenuated) by microbes. These include disease manifestations that are sex biased. Here, we review comparative analyses conducted between GF and Specific-Pathogen Free (SPF) mouse models of autoimmunity. We present data from the B6;NZM-Sle1NZM2410/AegSle2NZM2410/AegSle3NZM2410/Aeg-/LmoJ (B6.NZM) mouse model of systemic lupus erythematosus (SLE) characterized by multiple measurable features. We compared the severity and sex bias of SPF, GF, and ex-GF mice and found variability in the severity and sex bias of some manifestations. Colonization of GF mice with the microbiotas taken from B6.NZM mice housed in two independent institutions variably affected severity and sexual dimorphism of different parameters. Thus, microbes regulate both the severity and sexual dimorphism of select SLE traits. The sensitivity of particular trait to microbial influence can be used to further dissect the mechanisms driving the disease. Our results demonstrate the complexity of the problem and open avenues for further investigations.

Classification performance of the Sella-Tunis et al. (2017) sex estimation method in Czech population: different posterior probability threshold approaches.

In this study we tested classification performance of a sex estimation method from the mandible originally developed by Sella-Tunis et al. (2017) on a heterogeneous Israeli population. Mandibular linear dimensions were measured on 60 CT scans derived from the Czech living population. Classification performance of Israeli discriminant functions (DFs-IL) was analyzed in comparison with calculated Czech discriminant functions (DFs-CZ) while different posterior probability thresholds (currently discussed in the forensic literature) were employed. Our results comprehensively illustrate sensitivity of different discriminant functions to population differences in body size and degree of sexual dimorphism. We demonstrate that the error rate may be biased when presented per posterior probability threshold. DF-IL 1 showed least sensitivity to population origin and fulfilled criteria of sufficient classification performance when applied on the Czech sample with a minimum posterior probability threshold of 0.88 reaching overall accuracy ≥ 95%, zero sex bias, and 80% of classified individuals. The last parameter was higher in DF-CZ 1 which was the main difference between those two DFs suggesting relatively low dependance on population origin. As the use of population-specific methods is often prevented by complicated assessment of population origin, DF-IL 1 is a candidate for a sufficiently robust method that could be reliably applied outside the reference sample, and thus, its classification performance deserves further testing on more population samples.

PMCT-based sex determination using posterior segment of greater sciatic notch in North Indian population

BackgroundDigital tools, which offer superior accuracy compared to manual metrics, utilize radiological images for noninvasive data collection, providing a convenient means of obtaining skeletal data. The greater sciatic notch exhibits high sexual dimorphism and resistance to damage, and therefore serves as a viable tool for sex determination in poorly preserved skeletons, particularly in scenarios involving mass disasters, highly putrefied, and skeletonized cases. In addition to the width and depth of the greater sciatic notch, the length and angle of the posterior segment are highly specific parameters. This study aims to obtain accurate and standardized values for determining sex by measuring the posterior segment of the greater sciatic notch using postmortem computed tomography with a 16-slice multidetector row computed tomography scanner.ResultsThe study revealed that except for depth and the distance between the ischial spine and deepest point, all measured variables of the greater sciatic notch were greater for women than men on both sides. The length of the posterior segment and the posterior angle on both sides showed the highest positive correlation and provided highly significant differences between males and females. These findings not only reinforce the utility of the greater sciatic notch in sex determination but also highlight the potential for more accurate and noninvasive methods in forensic investigations.ConclusionsPostmortem computed tomography accurately determines sex by measuring the posterior sciatic notch segment, achieving a 90.9% accuracy rate. This study, the first of its kind in India, utilized postmortem computed tomography ruler measurements for sex determination, specifically evaluating the role of the posterior segment dimensions of the greater sciatic notch in the North Indian population.

Androgen levels in autism spectrum disorders: a systematic review and meta-analysis

BackgroundAccumulating evidence suggests that the autism spectrum disorder (ASD) population exhibits altered hormone levels, including androgens. However, studies on the regulation of androgens, such as testosterone and dehydroepiandrosterone (DHEA), in relation to sex differences in individuals with ASD are limited and inconsistent. We conducted the systematic review with meta-analysis to quantitatively summarise the blood, urine, or saliva androgen data between individuals with ASD and controls.MethodsA systematic search was conducted for eligible studies published before 16 January 2023 in six international and two Chinese databases. We computed summary statistics with a random-effects model. Publication bias was assessed using funnel plots and heterogeneity using I2 statistics. Subgroup analysis was performed by age, sex, sample source, and measurement method to explain the heterogeneity.Results17 case-control studies (individuals with ASD, 825; controls, 669) were assessed. Androgen levels were significantly higher in individuals with ASD than that in controls (SMD: 0.27, 95% CI: 0.06–0.48, P=0.01). Subgroup analysis showed significantly elevated levels of urinary total testosterone, urinary DHEA, and free testosterone in individuals with ASD. DHEA level was also significantly elevated in males with ASD.ConclusionAndrogen levels, especially free testosterone, may be elevated in individuals with ASD and DHEA levels may be specifically elevated in males.

Sex Differences Between Female and Male Individuals in Antipsychotic Efficacy and Adverse Effects in the Treatment of Schizophrenia.

Antipsychotics are core treatments for people living with psychotic disorders. Understanding individualised factors that influence both efficacy and adverse responses will improve outcomes. The objective of this study was to examine sex differences in antipsychotic-related efficacy and tolerability. This was a secondary analysis of data from phase 1 and 1a of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE); participants with schizophrenia were randomly assigned to double-blinded treatment with oral olanzapine, quetiapine, risperidone, ziprasidone or perphenazine. Measures included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions (CGI) scale and Calgary Depression Rating Scale, as well as self-reported side effects, medication compliance, dosage, weight measurements and various blood parameters. There were 1460 participants including 380 female and 1080 male individuals. Very few differences existed between male and female participants in response, adverse reactions, compliance or antipsychotic dosage. However, significantly more female participants than male participants reported constipation (28% vs 16%), dry mouth (50% vs 38%), gynecomastia/galactorrhea (11% vs 3%), incontinence/nocturia (16% vs 8%) and self reportedweight gain (37% vs 24%) [all p < 0.001]. Within the risperidone treatment group, there was a significantly greater increase in prolactin levels (p < 0.001) among female participants (n = 61) than male participants (n = 159). No overall differences in clinician-rated measures, weight gain or otherlaboratory indicators were found. While overall sex differences were limited across efficacy and tolerability for antipsychotic treatment, there were some specific findings with risperidone. Further examination of sex differences within antipsychotic trials will be important to improve efficacy and reduce adverse responses across as well as individualising care for people with schizophrenia.

STEMing together: a comparison of co-ed and all-female informal learning environments

STEMing together: a comparison of co-ed and all-female informal learning environments

Sexual dimorphism of the human fetal pelvis exists at the onset of primary ossification

Human adolescent and adult skeletons exhibit sexual dimorphism in the pelvis. However, the degree of sexual dimorphism of the human pelvis during prenatal development remains unclear. Here, we performed high-resolution magnetic resonance imaging-assisted pelvimetry on 72 human fetuses (males [M]: females [F], 34:38; 21 sites) with crown-rump lengths (CRL) of 50–225 mm (the onset of primary ossification). We used multiple regression analysis to examine sexual dimorphism with CRL as a covariate. Females exhibit significantly smaller pelvic inlet anteroposterior diameters (least squares mean, [F] 8.4 mm vs. [M] 8.8 mm, P = 0.036), larger subpubic angle ([F] 68.1° vs. [M] 64.0°, P = 0.034), and larger distance between the ischial spines relative to the transverse diameters of the greater pelvis than males. Furthermore, the sacral measurements indicate significant sex-CRL interactions. Our study suggests that sexual dimorphism of the human fetal pelvis is already apparent at the onset of primary ossification.

Early adversity causes sex-specific deficits in perforant pathway connectivity and contextual memory in adolescent mice

BackgroundEarly life adversity impairs hippocampal development and function across diverse species. While initial evidence indicated potential variations between males and females, further research is required to validate these observations and better understand the underlying mechanisms contributing to these sex differences. Furthermore, most of the preclinical work in rodents was performed in adult males, with only few studies examining sex differences during adolescence when such differences appear more pronounced. To address these concerns, we investigated the impact of limited bedding (LB), a mouse model of early adversity, on hippocampal development in prepubescent and adolescent male and female mice.MethodsRNA sequencing, confocal microscopy, and electron microscopy were used to evaluate the impact of LB and sex on hippocampal development in prepubescent postnatal day 17 (P17) mice. Additional studies were conducted on adolescent mice aged P29-36, which included contextual fear conditioning, retrograde tracing, and ex vivo diffusion magnetic resonance imaging (dMRI).ResultsMore severe deficits in axonal innervation and myelination were found in the perforant pathway of prepubescent and adolescent LB males compared to LB female littermates. These sex differences were due to a failure of reelin-positive neurons located in the lateral entorhinal cortex (LEC) to innervate the dorsal hippocampus via the perforant pathway in males, but not LB females, and were strongly correlated with deficits in contextual fear conditioning.ConclusionsLB impairs the capacity of reelin-positive cells located in the LEC to project and innervate the dorsal hippocampus in LB males but not female LB littermates. Given the critical role that these projections play in supporting normal hippocampal function, a failure to establish proper connectivity between the LEC and the dorsal hippocampus provides a compelling and novel mechanism to explain the more severe deficits in myelination and contextual freezing found in adolescent LB males.