Sex Bias In Prevalence Research Articles

The interplay between X-chromosome functional dosage and circadian regulation in females.

Biological factors and mechanisms that drive higher prevalence of insomnia in females are poorlyunderstood. This study focused on the neurological consequences of X-chromosome functional imbalancesbetween sexes. Benefited from publicly available large-scale genetic, transcriptional and epigenomic data, we curated andcontrasted different gene lists: (1) X-liked genes, including assignments for X-chromosome inactivation patterns anddisease associations; (2) sleep-associated genes; (3) gene expression markers for the suprachiasmatic nucleus. We show that X-linked markers for the suprachiasmatic nucleus are significantly enriched for clinicallyrelevant genes in the context of rare genetic syndromes and brain waves modulation. Considering female-specific patterns on brain transcriptional programs becomes essential whendesigning health care strategies for mental and sleep illnesses with sex bias in prevalence.

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain.

Genetic disruption of synaptic proteins results in a whole variety of human neuropsychiatric disorders including intellectual disability, schizophrenia or autism spectrum disorder (ASD). In a wide range of these so-called synaptopathies a sex bias in prevalence and clinical course has been reported. Using an unbiased proteomic approach, we analyzed the proteome at the interaction site of the pre- and postsynaptic compartment, in the prefrontal cortex, hippocampus, striatum and cerebellum of male and female adult C57BL/6J mice. We were able to reveal a specific repertoire of synaptic proteins in different brain areas as it has been implied before. Additionally, we found a region-specific set of novel synaptic proteins differentially expressed between male and female individuals including the strong ASD candidates DDX3X, KMT2C, MYH10 and SET. Being the first comprehensive analysis of brain region-specific synaptic proteomes from male and female mice, our study provides crucial information on sex-specific differences in the molecular anatomy of the synapse. Our efforts should serve as a neurobiological framework to better understand the influence of sex on synapse biology in both health and disease.

Gender-Specific Effect of 5-HT and 5-HIAA on Threshold Level of Behavioral Symptoms and Sex-Bias in Prevalence of Autism Spectrum Disorder.

Platelet hyperserotonemia in a subset of Autism Spectrum Disorder (ASD) probands, efficacy of selective serotonin reuptake inhibitors (SSRIs) in reducing behavioral deficits and gender-bias in normal serotonin (5-hydroxy tryptamine or 5-HT) synthesis suggest disruption in stringent regulation of serotonin metabolism in ASD. Therefore, we investigated the changes in 5-HT and 5-hydroxy indole acetic acid (5-HIAA) in ASD probands to assess its effect on the behavior of male and female probands. ASD cases (n = 215) were examined using childhood autism rating scale (CARS). Platelet 5-HT (104 cases and 26 controls) and platelet/plasma 5-HIAA (73 cases and 17 controls) were estimated using high performance liquid chromatography coupled with electrochemical detector (HPLC-ECD). In male probands, we observed increase in platelet 5-HT content in association with increase in the score for adaptive responses and increase in platelet 5-HIAA levels with concomitant decline in the score for intellectual response. Age did not influence the neurochemical parameters, but imitation, listening responses and nonverbal communication scores decreased with age. Conversely in female probands, plasma 5-HIAA level significantly attenuated with age, when platelet 5-HT content remained unchanged. Interestingly, platelet/plasma 5-HT and plasma 5-HIAA were higher in female controls. Female probands displayed severe autism-associated behaviors. Overall results indicate gender-bias in 5-HT and 5-HIAA regulation, which probably increases the threshold level of ASD phenotypes in the females, thereby affecting ASD prevalence in a sex-specific manner.

Microglia Sculpt Sex Differences in Social Behavior

Microglia are increasingly recognized as developmental sculptors of neural circuits. In this issue of Neuron, VanRyzin etal. (2019) demonstrate a novel mechanism by which endocannabinoids drive microglia to phagocytose newborn astrocytes in the medial amygdala of male rats, promoting sex differences in social play behavior.

Abstract # 3106 Sex-biased mitochondrial and behavioral alterations following early-life immune activation

Autism Spectrum Disorders (ASDs) are a collection of complex neurodevelopmental disorders characterized by repetitive behavior and alterations in social interaction/communication. ASD occurs in 1 in 68 children in the US, with a strong sex bias in prevalence ( ∼ 4 males affected to every 1 female). Multiple reports have revealed pervasive immune and mitochondrial abnormalities in ASD patients. Increasing evidence suggests that mitochondrial function is inhibited during proinflammatory microglial activation, although no sex differences remain underexplored. Postmortem analyses of brains from children with ASD revealed significant decreases in expression of mitochondrial electron transport chain (ETC) subunits; however, analyses did not distinguish between cell type or sex. In an early-life immune activation (lipopolysaccharide;LPS) model of ASD, we isolated microglia from prefrontal cortex of PN30 mice. By PCR array, we found that ∼ 96% of mitochondrial ETC genes were strongly diminished by LPS in male microglia, while only ∼ 6% were similarly decreased in females, suggesting that reduced mitochondrial function may be implicated in microglial activation, particularly in males. We show that early-life LPS results in decreased social exploration in both males and females at PN15, but only increased latency to enter stranger bedding in male mice. By PN60, early-life LPS treatment resulted in decreased sociability and social novelty seeking in males only. These data indicate sex-biased deficits in social interaction and anxiety that are related to clinical manifestations of ASD.

Abstract # 3108 Combined exposure to air pollution and maternal stress induces sex-specific, autism-like social behavior deficits and gut dysbiosis in mice

Autism spectrum disorder (ASD) is characterized by impaired social interaction and communication, engagement in repetitive behaviors, and a sex bias in prevalence (higher in males). Importantly, recent epidemiological studies suggest that maternal exposure to air pollution during pregnancy may increase ASD risk. Furthermore, studies have shown that maternal stress during pregnancy increases the severity of ASD symptoms. Our lab has developed a novel mouse model of combined diesel exhaust particle (DEP) and maternal stress (MS) exposure. We hypothesized that this DEP/MS exposure would induce ASD-like behavioral deficits in male offspring only. In males only, we observed a significantly lower preference for social vs. non-social stimuli in DEP/MS-exposed mice as compared to controls. Moreover, while control males preferred to interact with a novel peer over their cage mate, DEP/MS-exposed males showed the opposite preference. DEP/MS exposure had no effect on repetitive behavior (marble-burying) or on anxiety-like behavior (as measured in an open field) in either sex. Finally, given the high comorbidity of ASD with gastrointestinal issues, we asked whether DEP/MS exposure would alter the composition of the gut microbiome. Our results suggest that DEP/MS exposure alters both alpha and beta diversity in the gut microbiome of male but not female offspring. We are currently using this model to investigating the neuro-immune mechanisms by which DEP/MS exposure induces sex-specific deficits in social behavior.

A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder

BackgroundAttention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. MethodsWe analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). ResultsGenetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98–1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11–1.18], p = 1.5E-15). ConclusionsOverall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

High incidence of the maternally inherited bacterium Cardinium in spiders

Inherited bacteria are now recognized as important players in arthropod evolution and ecology. Here, we test spiders, a group recently identified as possessing inherited bacteria commonly, for the presence of two reproductive parasites, Cardinium hertigii (Bacteroidetes group) and Wolbachia (alpha-proteobacteria), estimating incidence, prevalence, any sex bias in infection, and infection diversity, for a panel of field-collected specimens. We identify spiders as a hotspot for Cardinium. Present in 22% of the sampled species, incidence was significantly higher than that previously recorded in insects. Where present, Cardinium infection occurred at medium prevalence without evidence of sex bias in prevalence that would indicate sex-ratio distortion activity. Wolbachia was present in 37% of species, but revealed a gradation from being rare to very common. In one case, Wolbachia was found significantly more commonly in females than males, indicating it may act as a sex-ratio distorter in some species. Breeding work conducted on two species confirmed that Wolbachia and Cardinium were transmitted maternally, which represents the first proof of inheritance of these symbionts in spiders. Overall, this study demonstrates that the majority of spider species are infected with inherited bacteria, and their role in host biology clearly requires determination.

Cerebral glucose metabolism, CSF 5-HIAA levels, and aggressive behavior in rhesus monkeys

Considerable evidence suggests that low concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in CSF are associated with a history of aggressive behavior in both human and nonhuman primates. The purpose of this investigation was to examine the relationships among CSF 5-HIAA concentration, history of aggressive behavior, and cerebral glucose metabolism in a group of nonhuman primates whose CSF 5-HIAA had been sampled several times over the preceding 2 years and whose social behavior had been observed since birth. The subjects were nine adult male rhesus monkeys studied under isoflurane anesthesia. Cerebral glucose utilization was measured by [18F]fluorodeoxyglucose positron emission tomography. Aggressiveness ratings were made by a primatologist who had had frequent contact with the animals over several years. There was a significant negative correlation between ratings of aggressive behavior and CSF 5-HIAA concentrations. There was also a negative correlation between the dose of pentobarbital required to induce anesthesia and level of CSF 5-HIAA. Moreover, there were significant negative correlations between CSF 5-HIAA levels and both whole brain glucose utilization and regional glucose utilization in the orbital-frontal cortex. These results suggest that both increased aggressiveness and low concentrations of CSF 5-HIAA are associated with higher brain glucose metabolism in rhesus monkeys under standardized anesthesia. Aggressive nonhuman primates with low CSF 5-HIAA concentrations may have "innate" tolerance toward functional gamma-aminobutyric acid A receptor agonists such as pentobarbital, isoflurane, and possibly alcohol.