Sex-specific Behaviors Research Articles

Convergent olfactory circuits for courtship in Drosophila revealed by ds-Tango.

Animals exhibit sex-specific behaviors that are governed by sexually dimorphic circuits. One such behavior in male Drosophila melanogaster, courtship, is regulated by various sensory modalities, including olfaction. Here, we reveal how sexually dimorphic olfactory pathways in male flies converge at the third-order, onto lateral horn output neurons, to regulate courtship. To achieve this, we developed ds-Tango, a modified version of the monosynaptic tracing and manipulation tool trans-Tango. In ds-Tango, two distinct configurations of trans-Tango are positioned in series, thus providing selective genetic access not only to the monosynaptic partners of starter neurons but also to their disynaptic connections. Using ds-Tango, we identified a node of convergence for three sexually dimorphic olfactory pathways. Silencing this node results in deficits in sex recognition of potential partners. Our results identify lateral horn output neurons required for proper courtship behavior in male flies and establish ds-Tango as a tool for disynaptic circuit tracing.

Sex-specific vertical movements of spawning atlantic cod in coastal habitats inferred from acoustic telemetry.

Fish spawning location and behaviour can be challenging to detect, especially in deep water. Here we utilise two large acoustic telemetry datasets from western and mid Norway to study the vertical movement dimension of individual Atlantic cod Gadus morhua spawning behaviour in their natural habitats. The datasets comprise ~ 6million depth detections from 644 sexed, mature cod, collected at seven different Norwegian coastal cod spawning grounds during 2017-2021. During the spawning period, females were typically found at shallower depths compared to males, while this pattern was much less pronounced or absent outside this period. Furthermore, we identify a hitherto undescribed sex-dependent vertical movement behaviour: periodic descents, where females made deep dives, putatively associated with egg release and spawning, approximately every third day. Females not showing this behaviour tended to occupy deeper positions in the water column than the "periodic descent" females and hence may approach and retreat from spawning males more horizontally. These observed sex-specific behaviours correspond well to the lek-like description of the cod mating system and with cod reproductive physiology, where females are known to mature and release batches of eggs at intervals of several days as part of a bet-hedging strategy.

Exploring gender as a sociocultural construct among cancer caregivers enrolling in a dyadic resiliency trial.

186 Background: Caregiving relations are essential for navigating cancer care among cancer curvivors (i.e., completed curative-intent treatment) and metavivors (i.e., living with incurable illness). Caregiving is associated with poor health outcomes, but little work explicates gender differences in specific sociocultural constructs that drive caregivers’ health outcomes. This study explores gender differences in caregiving relationship type (e.g., partner, friend) and psychosocial variables theorized to be impacted by caregiving stress, such as preventative health behaviors, self-compassion, depression/anxiety, informational/emotional social support and perceived caregiving relationship quality among caregivers of cancer curvivors and metavivors. Methods: 47 survivor-caregiver dyads (64% metavivors) enrolled in a pilot clinical trial of simultaneous remotely-delivered dyadic stress management groups at a tertiary care academic center. Eligible caregivers were those supporting survivors who had completed initial treatment for cancer with curative intent 3 months- 5 years ago OR were diagnosed with metastatic illness at least 3 months before enrollment. Data were collected via brief self-report baseline surveys measuring depression (PHQ-2), anxiety (GAD-2), self-compassion (SCS-12), informational/emotional support (PROMIS short forms-4a), including assessments of sex-specific cancer screening behavior (i.e., recommended breast, cervical, prostate, and colorectal screening) and relationship quality created for this study. Bivariate statistics compared caregivers based on self-reported gender identity (two-tailed p < .05) with Cohen’s D used to characterize strength of between-group differences (0.2 = small, 0.5 = medium, 0.8 = large). Results: Most caregivers ( M age = 56.9) were White (87%) women (64%) caring for men (53%). Women (79% partners, 17% family, 4% friends) and men (64% partners, 36% family) caregivers did not significantly differ in caregiving relationship type ( p = .33). Most caregivers were up-to-date with sex-specific screening recommendations for breast (83%), cervical (80%), and prostate (85%) cancer, though women vs. men were significantly less adherent to colon cancer screening (60% vs. 100%, p = .003). Significant gender differences emerged in (anxiety D = -0.69, p =.03) but not depression (D = -0.47, p = .14 or self-compassion (D = .58, p = .07), such that women experienced great distress. Finally, women reported not significantly greater informational/emotional support (Ds = -0.30 and -0.25, p s > .40) and relationship quality (D = -0.63, p = .05). Conclusions: When comparing the experiences of women and men currently in caregiving roles, gendered traits such as anxious emotional expression, as well as gender norms around self-focused preventative health behaviors may place women at increased risk for poor health outcomes. Clinical trial information: NCT05702723 .

Rodent reproductive behavior among males and females after exposure to endocrine-disrupting chemicals.

Sexual reproduction-from both physiological and behavioral perspectives-is dependent upon appropriate connections between a diverse, hormone-modulated network of neural regions. Importantly, these substrates are regulated by hormones across the lifespan from early development to adulthood, making them targets of endocrine-disrupting chemicals (EDCs). Rodents, such as mice and rats, are invaluable to the characterization of EDCs because of their sex-specific, stereotyped appetitive and consummatory reproductive behaviors. Phthalates, bisphenol A (BPA), and EDC mixtures pose a salient risk to the health of humans, wildlife, and livestock because these synthetic compounds are ubiquitous due to their widespread use in mass production of consumer and industrial goods. This review outlines how the hypothalamic-pituitary-gonadal axis regulates male and female sexual behaviors, and how phthalates and BPA can perturb appetitive and consummatory behaviors and impact neural substrates that modulate reproductive behavior. We will then discuss how to progress toward a clearer understanding of the reproductive and neurobiological changes that occur due to EDC exposure.

BNST CRF receptor type 1 modulates mechanical hypersensitivity induced by adolescent alcohol exposure in adult female mice.

Alcohol exposure during adolescence has been linked to long-lasting behavioral consequences, contributing to the development of alcohol use disorder. Negative affect and chronic pain during alcohol withdrawal are critical factors influencing problematic alcohol use and relapse. Our previous research demonstrated that adolescent intermittent ethanol (AIE) vapor exposure elicits sex-specific negative affect-like behavior in adult mice following stress exposure. Additionally, AIE induces persistent mechanical hypersensitivity, which is accompanied by increased activation of corticotropin-releasing factor receptor type 1 (CRFR1) neurons in the dorsolateral bed nucleus of the stria terminalis (dlBNST). This study extends previous work by investigating plasma corticosterone levels and CRFR1 protein expression in the dlBNST following restraint stress exposure in adult mice with an AIE history. We also aim to explore the role of dlBNST CRFR1 signaling in mediating negative affect-like behavior and mechanical hypersensitivity. Female mice exhibited elevated plasma corticosterone levels compared to males following restraint stress. Moreover, females with AIE history showed higher expression of CRFR1 protein in the dlBNST compared to air controls. Antagonism of CRFR1 in the dlBNST blocked AIE-induced mechanical hypersensitivity in adult females but did not affect stress-induced negative affect-like behavior. In alcohol-naïve females, intra-dlBNST administration of a CRFR1 agonist induced mechanical hypersensitivity. These findings provide new insights into the neurobiological mechanisms underlying stress-induced negative affect and pain-related behavior, both influenced by a history of adolescent alcohol exposure. The results suggest that CRFR1 antagonists warrant further investigation for their potential in addressing alcohol-related chronic pain.

The Ultramorphology and Sexual Dimorphism of Antennae and Sensilla in the Pale Grass Blue, Pseudozizeeria maha (Lepidoptera: Lycaenidae).

The pale grass blue, Pseudozizeeria maha, is a small lycaenid butterfly widely distributed across Asia. Due to its exclusively diurnal lifestyle and conspicuous sexual dimorphism in wing coloration, vision has traditionally been regarded as the primary sensory system driving various behaviors. However, non-visual sensory systems related to sex-specific behavioral responses, such as antennae, have received far less attention. This study investigated the morphological characteristics and sensilla types of the antennae in adult P. maha using scanning electron microscopy, with a focus on potential sexual dimorphism. The antennae of adult P. maha are clavate, with no significant sexual differences in overall morphology. Six types of antennal sensilla were identified: Böhm bristles, sensilla squamiformia, sensilla trichodea, sensilla chaetica, sensilla basiconica, and sensilla coeloconica, with no sexual dimorphism observed in their morphological types or dimensions. Remarkably, the sensilla coeloconica exhibit significant sexual dimorphism, with a more prominent presence in females. This finding suggests that female P. maha may rely more on olfactory cues for some sex-specific behaviors, such as oviposition site selection.

Cellular evolution of the hypothalamic preoptic area of behaviorally divergent deer mice.

Genetic variation is known to contribute to the variation of animal social behavior, but the molecular mechanisms that lead to behavioral differences are still not fully understood. Here, we investigate the cellular evolution of the hypothalamic medial preoptic area (MPOA), a brain region that plays a critical role in social behavior, across two sister species of deer mice (Peromyscus maniculatus and P. polionotus) with divergent social systems. These two species exhibit large differences in mating and parental care behavior across species and sex. Using single-nucleus RNA-sequencing, we build a cellular atlas of the MPOA for males and females of both Peromyscus species. We identify four cell types that are differentially abundant across species, two of which may account for species differences in parental care behavior. Our data further implicate two sex-biased cell types to be important for the evolution of sex-specific behavior. Finally, we show a remarkable reduction of sex-biased gene expression in P. polionotus, a monogamous species that also exhibits reduced sexual dimorphism in parental care behavior. Our MPOA atlas is a powerful resource to investigate how molecular neuronal traits may be evolving to give rise to innate differences in social behavior across animal species.

Highly contiguous genome assembly of Drosophila prolongata-a model for evolution of sexual dimorphism and male-specific innovations.

Drosophila prolongata is a member of the melanogaster species group and rhopaloa subgroup native to the subtropical highlands of Southeast Asia. This species exhibits an array of recently evolved male-specific morphological, physiological, and behavioral traits that distinguish it from its closest relatives, making it an attractive model for studying the evolution of sexual dimorphism and testing theories of sexual selection. The lack of genomic resources has impeded the dissection of the molecular basis of sex-specific development and behavior in this species. To address this, we assembled the genome of D. prolongata using long-read sequencing and Hi-C scaffolding, resulting in a highly complete and contiguous (scaffold N50 2.2 Mb) genome assembly of 220 Mb. The repetitive content of the genome is 24.6%, the plurality of which are long terminal repeats retrotransposons (33.2%). Annotations based on RNA-seq data and homology to related species revealed a total of 19,330 genes, of which 16,170 are protein-coding. The assembly includes 98.5% of Diptera BUSCO genes, including 93.8% present as a single copy. Despite some likely regional duplications, the completeness of this genome suggests that it can be readily used for gene expression, genome-wide association studies (GWAS), and other genomic analyses.

Exposure to PFAS chemicals induces sex-dependent alterations in key rate-limiting steps of lipid metabolism in liver steatosis.

Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (Acadm, Acox1, Cpt2, Cyp4a1-3) and downregulation of lipid transport genes (Apoa1, Apoa5, Pltp). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis (Pck1) and bile acid synthesis (Cyp7a1) were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis (Scd) showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis.

Sex-specific developmental gene expression atlas unveils dimorphic gene networks in C. elegans

Sex-specific traits and behaviors emerge during development by the acquisition of unique properties in the nervous system of each sex. However, the genetic events responsible for introducing these sex-specific features remain poorly understood. In this study, we create a comprehensive gene expression atlas of pure populations of hermaphrodites and males of the nematode Caenorhabditis elegans across development. We discover numerous differentially expressed genes, including neuronal gene families like transcription factors, neuropeptides, and G protein-coupled receptors. We identify INS-39, an insulin-like peptide, as a prominent male-biased gene expressed specifically in ciliated sensory neurons. We show that INS-39 serves as an early-stage male marker, facilitating the effective isolation of males in high-throughput experiments. Through complex and sex-specific regulation, ins-39 plays pleiotropic sexually dimorphic roles in various behaviors, while also playing a shared, dimorphic role in early life stress. This study offers a comparative sexual and developmental gene expression database for C. elegans. Furthermore, it highlights conserved genes that may underlie the sexually dimorphic manifestation of different human diseases.

Macrophage memories of early-life injury drive neonatal nociceptive priming

The developing peripheral nervous and immune systems are functionally distinct from those of adults. These systems are vulnerable to early-life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e., "neonatal nociceptive priming"). The underpinnings of this phenomenon are unclear, although previous work indicates that macrophages are trained by inflammation and injury. Our findings show that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming, possibly due to a long-lasting remodeling in chromatin structure. The p75 neurotrophic factor receptor is an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This "pain memory" is long lasting in females and can be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury.

Sex Differences in Clustering Unhealthy Lifestyles Among Survivors of COVID-19: Latent Class Analysis.

The COVID-19 pandemic has underscored the significance of adopting healthy lifestyles to mitigate the risk of severe outcomes and long-term consequences. This study focuses on assessing the prevalence and clustering of 5 unhealthy lifestyle behaviors among Vietnamese adults after recovering from COVID-19, with a specific emphasis on sex differences. The cross-sectional data of 5890 survivors of COVID-19 in Vietnam were analyzed from December 2021 to October 2022. To examine the sex differences in 5 unhealthy lifestyle behaviors (smoking, drinking, unhealthy diet, physical inactivity, and sedentary behavior), the percentages were plotted along with their corresponding 95% CI for each behavior. Latent class analysis was used to identify 2 distinct classes of individuals based on the clustering of these behaviors: the "less unhealthy" group and the "more unhealthy" group. We examined the sociodemographic characteristics associated with each identified class and used logistic regression to investigate the factors related to the "more unhealthy" group. The majority of individuals (male participants: 2432/2447, 99.4% and female participants: 3411/3443, 99.1%) exhibited at least 1 unhealthy behavior, with male participants being more susceptible to multiple unhealthy behaviors. The male-to-female ratio for having a single behavior was 1.003, but it escalated to 25 for individuals displaying all 5 behaviors. Male participants demonstrated a higher prevalence of combining alcohol intake with sedentary behavior (949/2447, 38.8%) or an unhealthy diet (861/2447, 35.2%), whereas female participants tended to exhibit physical inactivity combined with sedentary behavior (1305/3443, 37.9%) or an unhealthy diet (1260/3443, 36.6%). Married male participants had increased odds of falling into the "more unhealthy" group compared to their single counterparts (odds ratio [OR] 1.45, 95% CI 1.14-1.85), while female participants exhibited lower odds (OR 0.65, 95% CI 0.51-0.83). Female participants who are underweight showed a higher likelihood of belonging to the "more unhealthy" group (OR 1.11, 95% CI 0.89-1.39), but this was not observed among male participants (OR 0.6, 95% CI 0.41-0.89). In both sexes, older age, dependent employment, high education, and obesity were associated with higher odds of being in the "more unhealthy" group. The study identified notable sex differences in unhealthy lifestyle behaviors among survivors of COVID-19. Male survivors are more likely to engage in unhealthy behaviors compared to female survivors. These findings emphasize the importance of tailored public health interventions targeting sex-specific unhealthy behaviors. Specifically, addressing unhealthy habits is crucial for promoting post-COVID-19 health and well-being.

The role of fruitless in specifying courtship behaviors across divergent Drosophila species.

Sex-specific behaviors are critical for reproduction and species survival. The sex-specifically spliced transcription factor fruitless (fru) helps establish male courtship behaviors in invertebrates. Forcing male-specific fru (fruM) splicing in Drosophila melanogaster females produces male-typical behaviors while disrupting female-specific behaviors. However, whether fru's joint role in specifying male and inhibiting female behaviors is conserved across species is unknown. We used CRISPR-Cas9 to force FruM expression in female Drosophila virilis, a species in which males and females produce sex-specific songs. In contrast to D. melanogaster, in which one fruM allele is sufficient to generate male behaviors in females, two alleles are needed in D. virilis females. D. virilis females expressing FruM maintain the ability to sing female-typical song as well as lay eggs, whereas D. melanogaster FruM females cannot lay eggs. These results reveal potential differences in fru function between divergent species and underscore the importance of studying diverse behaviors and species for understanding the genetic basis of sex differences.

Disentangling genetic, plastic and social learning drivers of sex-specific foraging behaviour in Trinidadian guppies (Poecilia reticulata).

Evolutionary biologists have long been interested in parsing out the roles of genetics, plasticity and their interaction on adaptive trait divergence. Since males and females often have different ecological and reproductive roles, separating how their traits are shaped by interactions between their genes and environment is necessary and important. Here, we disentangle the sex-specific effects of genetic divergence, developmental plasticity, social learning and contextual plasticity on foraging behaviour in Trinidadian guppies (Poecilia reticulata) adapted to high- or low-predation habitats. We reared second-generation siblings from both predation regimes with or without predator chemical cues, and with adult conspecifics from either high- or low-predation habitats. We then quantified their foraging behaviour in water with and without predator chemical cues. We found that high-predation guppies forage more efficiently than low-predation guppies, but this behavioural difference is context-dependent and shaped by different mechanisms in males and females. Higher foraging efficiency in high-predation females is largely genetically determined, and to a smaller extent socially learned from conspecifics. However, in high-predation males, higher foraging efficiency is plastically induced by predator cues during development. Our study demonstrates sex-specific differences in genetic versus plastic responses in foraging behaviour, a trait of significance in organismal fitness and ecosystem dynamics.

Sex-specific negative affect-like behaviour and parabrachial nucleus activation induced by BNST stimulation in adult mice with adolescent alcohol history.

Adolescent alcohol use is a strong predictor for the subsequent development of alcohol use disorders later in life. Additionally, adolescence is a critical period for the onset of affective disorders, which can contribute to problematic drinking behaviours and relapse, particularly in females. Previous studies from our laboratory have shown that exposure to adolescent intermittent ethanol (AIE) vapour alters glutamatergic transmission in the bed nucleus of the stria terminalis (BNST) and, when combined with adult stress, elicits sex-specific changes in glutamatergic plasticity and negative affect-like behaviours in mice. Building on these findings, the current work investigated whether BNST stimulation could substitute for stress exposure to increase the latency to consume a palatable food in a novel context (hyponeophagia) and promote social avoidance in adult mice with AIE history. Given the dense connections between the BNST and the parabrachial nucleus (PBN), a region involved in mediating threat assessment and feeding behaviours, we hypothesized that increased negative affect-like behaviours would be associated with PBN activation. Our results revealed that the chemogenetic stimulation of the dorsolateral BNST induced hyponeophagia in females with AIE history, but not in female controls or males of either group. Social interaction remained unaffected in both sexes. Notably, this behavioural phenotype was associated with higher activation of calcitonin gene-related peptide and dynorphin cells in the PBN. These findings provide new insights into the neurobiological mechanisms underlying the development of negative affect in females and highlight the potential involvement of the BNST-PBN circuitry in regulating emotional responses to alcohol-related stimuli.

C and N stable isotopes enlighten the trophic behaviour of the dugong (Dugong dugon)

The dugong (Dugong dugon), a large marine mammal herbivore of the Indo-Pacific, is vulnerable to extinction at a global scale due to a combination of human-related threats including habitat degradation. The species forages on seagrass habitats (marine phanerogams) and plays a key role in the functioning and sensitivity of these declining coastal ecosystems. The trophic behaviour and plasticity of dugong populations in response to extrinsic and intrinsic factors are therefore crucial features to both dugong and seagrass conservation. Yet, this knowledge remains limited to few visual observations and analyses of mouth, stomach or faecal contents of stranded individuals. We take advantage of a long-term monitoring of stranded individuals from the endangered New Caledonian population to depict features of dugongs’ trophic ecology from Carbon and Nitrogen stable isotopes. A total of 59 dugong skin samples were used to portrait the stable isotope niche of dugongs according to their sex and maturity. In light of previous work conducted in New Caledonia, a subset of these samples was used to model the trophic mix of dugong males and females. Our stable isotope mixing models used C and N isotope values of 10 taxa bbelonging to five divisions of metazoans, plants, and chromists. Our results represent the first estimate of the species dietary niche in the isotopic space. They suggest that the diet of dugong calves overlaps more with that of adult females (δ13C: − 6.38 ± 1.13 ‰; δ15N: 2.49 ± 1.10 ‰) than males (δ13C: − 5.92 ± 1.10 ‰; δ15N: 3.69 ± 1.28 ‰). Further, we highlight differences in the expected trophic mix of dugong adult males and females. From these, we formulate a sex-specific foraging behaviour hypothesis in dugongs, whereby lactating females could forage over smaller spatial ranges but more diverse food sources thanmales. The study emphasizes the importance of long-term stranding monitoring programs to study the ecology of marine mammals.. Finally, it depicts an ecological feature that may contribute to the sensitivity of vulnerable dugongs to ongoing changes on tropical coastal ecosystems.

Hydric physiology and ecology of a federally endangered desert lizard.

Animals can respond to extreme climates by behaviourally avoiding it or by physiologically coping with it. We understand behavioural and physiological thermoregulation, but water balance has largely been neglected. Climate change includes both global warming and changes in precipitation regimes, so improving our understanding of organismal water balance is increasingly urgent. We assessed the hydric physiology of US federally endangered blunt-nosed leopard lizards (Gambelia sila) by measuring cutaneous evaporative water loss (CEWL), plasma osmolality and body condition. Measurements were taken throughout their active season, the short period of year when these lizards can be found aboveground. Compared to a more mesic species, G. sila had low CEWL which is potentially desert-adaptive, and high plasma osmolality that could be indicative of dehydration. We hypothesized that throughout the G. sila active season, as their habitat got hotter and drier, G. sila would become more dehydrated and watertight. Instead, CEWL and plasma osmolality showed minimal change for females and non-linear change for males, which we hypothesize is connected to sex-specific reproductive behaviours and changes in food availability. We also measured thermoregulation and microhabitat use, expecting that more dehydrated lizards would have lower body temperature, poorer thermoregulatory accuracy and spend less time aboveground. However, we found no effect of CEWL, plasma osmolality or body condition on these thermal and behavioural metrics. Finally, G. sila spends considerable time belowground in burrows, and burrows may serve not only as essential thermal refugia but also hydric refugia.

Hormone profiles of the African pygmy mouse Mus minutoides, a species with XY female sex reversal.

In mammals, most sex differences in phenotype are controlled by gonadal hormones, but recent work on transgenic mice has shown that sex chromosomes can have a direct influence on sex-specific behaviors. In this study, we take advantage of the naturally occurring sex reversal in a mouse species, Mus minutoides, to investigate for the first time the relationship between sex chromosomes, hormones, and behaviors in a wild species. In this model, a feminizing variant of the X chromosome, named X*, produces three types of females with different sex chromosome complements (XX, XX*, and X*Y), associated with alternative behavioral phenotypes, while all males are XY. We thus compared the levels of three major circulating steroid hormones (testosterone, corticosterone, and estradiol) in the four sex genotypes to disentangle the influence of sex chromosomes and sex hormones on behavior. First, we did not find any difference in testosterone levels in the three female genotypes, although X*Y females are notoriously more aggressive. Second, in agreement with their lower anxiety-related behaviors, X*Y females and XY males display lower baseline corticosterone concentration than XX and XX* females. Instead of a direct hormonal influence, this result rather suggests that sex chromosomes may have an impact on the baseline corticosterone level, which in turn may influence behaviors. Third, estradiol concentrations do not explain the enhanced reproductive performance and maternal care behavior of the X*Y females compared to the XX and XX* females. Overall, this study highlights that most of the behaviors varying along with sex chromosome complement of this species are more likely driven by genetic factors rather than steroid hormone concentrations.

IMMU-35. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES BY ACTIVATING THE COMPLEMENT SYSTEM

Abstract Interaction between tumor and neural cells drives the progression of glioblastoma (GBM), which is characterized by enhanced immunosuppressive myeloid cell accumulation. Our previous results revealed that myeloid-derived suppressor cell subsets (MDSCs) play a central role in tumorigenesis in a sex-specific manner, with monocytic MDSCs (mMDSCs) accumulating in male tumors and granulocytic MDSCs (gMDSCs) correlating with a worse outcome in females. However, host factors governing sex differences in MDSC subset activity remained unknown. Here, we report that g-aminobutyric acid (GABA) receptor expression by gMDSCs informs their sex-specific behavior. We observed that only female gMDSCs but not male gMDSCs or mMDSCs from either sex respond to GABA by upregulating the antiviral innate immune pathway. As part of this signature, GABA-stimulated female gMDSCs had higher complement 1qa (C1qa) expression. To test the potential role of the GABA pathway on GBM outcome, we tested the GABA analogue pregabalin in preclinical models. Female mice treated with pregabalin succumbed to disease earlier, consistent with our previous observation that gMDSCs have a central role in GBM progression in females. In contrast, pregabalin treatment had no effect in male mice with tumors or immunocompromised female mice. To further evaluate whether C1q is a relevant physiological target, we performed single-cell sequencing of tumor-infiltrating versus circulating MDSC subsets and detected high levels of C1q expression in gMDSCs from tumors. C1q KO transgenic female mice had significantly better outcomes compared to wild-type littermates upon implantation with syngeneic mouse GBM lines, while C1q expression status did not impact the outcome in males. Correspondingly, only in female patients C1q expression correlated with poor prognosis. Collectively, these results identify a neuron-immune-cancer communication axis and indicate that GABA and C1q alter anti-tumor immune responses in a sex-specific manner. These results support the future assessment of the GABA pathway and complement inhibitors as potential immunotherapy agents.

Effect of Sex and Sex Hormones on SARS-COV-2: A Review Article

When men are exposed to the coronavirus infection (SARS-CoV-2), compared with women, they will suffer from more severe consequences of this disease, leading to a higher death rate. These differences are probably due to sex-specific behaviors, genetic and hormonal factors, and sex differences in biological pathways associated with SARS-CoV-2 infection. Several socio-behavioral factors are involved in pathogenesis in men compared to women. However, sexual-biological differences and their effects on SARS-COV-2 outcomes have received less scholarly attention. Sexual-biological differences between healthy populations and age- and sex-specific conditions such as pregnancy and menopause also play a role. More extensive studies on gender-specific differences and robust analyses are needed to determine how gender can alter the cellular and molecular pathways associated with SARS-CoV-2. This will improve biomarker interpretation and clinical management of SARS-COV-2 patients by facilitating a personalized medicine approach to risk stratification, prevention, and treatment. The present review summarizes the available literature on the proposed molecular and cellular markers associated with SARS-COV-2 infection, their association with health outcomes, and any gender-specific variation reported.