Biology subjects

Hrncir, H.

Publications and source records attributed to Hrncir, H..

8 recordsLinked to original sources

bioRxiv2026

Gonadal and sex chromosomal contributions to sex differences in mammalian brain organization

Sex differences in brain development may contribute to well-known sex differences in behavior and neuropsychiatric risk - making it important to comprehensively map and mechanistically annotate normative sex differences in brain organization. Most sex differences in mammalian brain organization have previously been attributed to differential effects of gonadal hormones based on outcomes from rodent endocrine manipulations at canonical subcortical foci of male-biased brain volume. However, a systematic quantification of both gonadal and sex chromosome dosage (SCD) contributions across all regions of sex-biased brain volume has been lacking. Here, using structural neuroimaging scans from wild-type (n=670) and transgenic mice that dissociate gonadal, X-, and Y-chromosome effects (n=181), we show that: many more brain regions are volumetrically sex-biased than previously recognized; gonadal effects dominate throughout this expanded map of sex differences; several regions also show prominent SCD contributions to anatomical sex differences, which can both reinforce or counteract gonadal effects in a regionally specific manner. Targeted single nucleus RNA sequencing at a region of female-biased cerebellar volume reveals that combined gonadal and SCD effects also drive sex-biased cellular gene expression. These findings revise our understanding of the spatial distribution and causal basis of sex-differences in the mammalian brain, illuminating a key axis of biological variation in health and disease.

neuroscience↗

bioRxiv2025

Relative contribution of gonads and sex chromosomes to sex differences in cell-type gene expression in the mouse medial septum and sex-biased disease risk

BackgroundWhile sex differences in the brain have traditionally been attributed to gonadal hormones, emerging evidence points to regulation by sex chromosomes. This study aims to differentiate the influence of gonads versus sex chromosomes on cellular gene expression in the mouse medial septum (MS), a critically understudied brain region. MethodsUsing single nucleus RNA-sequencing and the Sex Chromosome Trisomy mouse model, we (1) quantified sex differences in cellular gene expression and (2) isolated sex-biasing effects by identifying perturbed cell types, differentially expressed genes, biological pathways, and gene networks, which were integrated with GWAS data to explore links with sex-biased human phenotypes. ResultsOur analysis revealed that volumetric sex differences in the MS are mirrored by widespread transcriptomic changes across cell types. Critically, genetic effects displayed elevated relevance compared to sex hormones in driving sex-biased gene expression. These effects converge to regulate synaptic/neuronal development, transcriptional regulation, and cellular metabolism. Sex chromosome-associated DEGs were enriched for various human disorders, suggesting a cellular and mechanistic basis for their sex-biased patterns. ConclusionsOur findings challenge the classical gonad-centric views of sexual differentiation, as the MS displays sex-biased transcriptional regulation driven by sex chromosome-associated effects that are highly relevant for human health.

neuroscience↗

bioRxiv2024

Mouse Brain Extractor: Brain segmentation of mouse MRI using global positional encoding and SwinUNETR

In spite of the great progress that has been made towards automating brain extraction in human magnetic resonance imaging (MRI), challenges remain in the automation of this task for mouse models of brain disorders. Researchers often resort to editing brain segmentation results manually when automated methods fail to produce accurate delineations. However, manual corrections can be labor-intensive and introduce interrater variability. This motivated our development of a new deep-learning-based method for brain segmentation of mouse MRI, which we call Mouse Brain Extractor. We adapted the existing SwinUNETR architecture (Hatamizadeh et al., 2021) with the goal of making it more robust to scale variance. Our approach is to supply the network model with supplementary spatial information in the form of absolute positional encoding. We use a new scheme for positional encoding, which we call Global Positional Encoding (GPE). GPE is based on a shared coordinate frame that is relative to the entire input image. This differs from the positional encoding used in SwinUNETR, which solely employs relative pairwise image patch positions. GPE also differs from the conventional absolute positional encoding approach, which encodes position relative to a subimage rather than the entire image. We trained and tested our method on a heterogeneous dataset of N=223 mouse MRI, for which we generated a corresponding set of manually-edited brain masks. These data were acquired previously in other studies using several different scanners and imaging protocols and included in vivo and ex vivo images of mice with heterogeneous brain structure due to different genotypes, strains, diseases, ages, and sexes. We evaluated our methods results against those of seven existing rodent brain extraction methods and two state-of-the art deep-learning approaches, nnU-Net (Isensee et al., 2018) and SwinUNETR. Overall, our proposed method achieved average Dice scores on the order of 0.98 and average HD95 measures on the order of 100 {micro}m when compared to the manually-labeled brain masks. In statistical analyses, our method significantly outperformed the conventional approaches and performed as well as or significantly better than the nnU-Net and SwinUNETR methods. These results suggest that Global Positional Encoding provides additional contextual information that enables our Mouse Brain Extractor to perform competitively on datasets containing multiple resolutions.

neuroscience↗

bioRxiv2022

A cross-species study of sex chromosome dosage effects on mammalian brain anatomy

All eutherian mammals show chromosomal sex determination with contrasting sex chromosome dosages (SCDs) between males (XY) and females (XX). Studies in transgenic mice and humans with sex chromosome trisomy (SCT) have revealed direct SCD effects on regional mammalian brain anatomy, but we lack a formal test for cross-species conservation of these effects. Here, we develop a harmonized framework for comparative structural neuroimaging and apply this to systematically profile SCD effects on regional brain anatomy in both humans and mice by contrasting groups with SCT (XXY and XYY) vs. XY controls. We show that total brain size is substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Controlling for global effects reveals robust and spatially convergent effects of XXY and XYY on regional brain volume in humans, but not mice. However, mice do show subtle effects of XXY and XYY on regional volume, although there is not a general spatial convergence in these effects within mice or between species. Notwithstanding this general lack of conservation in SCT effects, we detect several brain regions that show overlapping effects of XXY and XYY both within and between species (cerebellum, parietal, and orbitofrontal cortex) - thereby nominating high priority targets for future translational dissection of SCD effects on the mammalian brain. Our study introduces a generalizable framework for comparative neuroimaging in humans and mice and applies this to achieve a cross-species comparison of SCD effects on the mammalian brain through the lens of SCT. HighlightsO_LIParallel structural neuroimaging in humans and mice with sex chromosome trisomies C_LIO_LIDivergent X- and Y-chromosome effects on human brain size, but convergent effects on regional anatomy C_LIO_LIMuted impact of additional X or Y on mouse brain, but subtle regional effects evident C_LIO_LIEvidence for conserved cross-species impact of X and Y on fronto-parietal cortices and cerebellum C_LI

neuroscience↗

bioRxiv2022

Sex differences in NK cells mediated by the X-linked epigenetic regulator UTX

Viral infection outcomes are sex-biased, with males generally more susceptible than females. Paradoxically, the numbers of anti-viral natural killer (NK) cells are increased in males compared to females. Using samples from mice and humans, we demonstrate that while numbers of male NK cells are increased compared to females, they display impaired production of the anti-viral cytokine IFN-{gamma}. These sex differences were not due solely to divergent levels of gonadal hormones, since these differences persisted in gonadectomized mice. Instead, these differences can be attributed to lower male expression of X-linked Kdm6a (UTX), an epigenetic regulator which escapes X inactivation in female NK cells. NK cell-specific UTX deletion in females phenocopied multiple features of male NK cells, which include increased numbers and reduced IFN-{gamma} production. Integrative ATAC-seq and RNA-seq analysis revealed a critical role for UTX in the regulation of chromatin accessibility and gene expression at loci important in NK cell homeostasis and effector function. Consequently, NK cell-intrinsic UTX levels are critical for optimal anti-viral immunity, since mice with NK cell-intrinsic UTX deficiency show increased lethality to mouse cytomegalovirus (MCMV) challenge. Taken together, these data implicate UTX as a critical molecular determinant of NK cell sex differences and suggest enhancing UTX function as a new strategy to boost endogenous NK cell anti-viral responses.

immunology↗

bioRxiv2021

Gonadal hormones and sex chromosome complement differentially contribute to ethanol intake, preference, and relapse-like behavior in Four Core Genotypes mice

Alcohol use and high-risk alcohol drinking behaviors among women are rapidly rising. In rodent models, females typically consume more ethanol (EtOH) than males. Here, we used the Four Core Genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviors. FCG mice were given access to escalating concentrations of EtOH in a two-bottle, 24-h continuous access drinking paradigm to assess consumption and preference. Relapse-like behavior was measured by assessing escalated intake following repeated cycles of deprivation and re-exposure. Twenty-four hour EtOH consumption was greater in mice with ovaries (Sry-), relative to those with testes, and in mice with the XX chromosome complement, relative to those with XY sex chromosomes. EtOH preference was higher in XX vs. XY mice. Escalated intake following repeated cycles of deprivation and re-exposure emerged only in XX mice (vs. XY). Mice with ovaries (Sry-FCG mice and C57Bl/6J females) were also found to consume more water than mice with testes. These results demonstrate that aspects of EtOH drinking behavior may be independently regulated by sex hormones and chromosomes and inform our understanding of the neurobiological mechanisms which contribute to EtOH dependence in male and female mice. Future investigation of the contribution of sex chromosomes to EtOH drinking behaviors is warranted.

neuroscience↗

bioRxiv2019

Reversal learning performance in the XY* mouse model of Klinefelter and Turner Syndromes

Klinefelter syndrome (KS; 47, XXY) and Turner syndrome (TS; 45, XO) are caused by two relatively common sex chromosome aneuploidies. These conditions are associated with an increased odds of neuropsychiatric disorders, including attention deficit/hyperactivity disorder (ADHD), as well as impairments in cognition that include learning delays, attentional dysfunction and impulsivity. We studied cognitive functions in the XY* mouse model, which allows comparison of XXY to XY males (KS model), and XO to XX females (TS model). We evaluated adult mice with and without gonads, using a version of an operant reversal-learning task (RLT) that can be used to measure various facets of learning, impulsivity and attention. In the KS model, only one measure related to impulsivity - perseverative responding under reversal conditions - reliably discriminated gonadally intact XXY and XY mice. In contrast, a fundamental learning impairment (more trials to criterion in acquisition phase) in XXY mice, as compared to XY, was observed in gonadectomized subjects. No other task measures showed differences consistent with KS. In the TS mouse model, XO mice did not show a pattern of results consistent with TS, similar to past observations. Thus, the application of this RLT to these XY* models reveals only limited behavioral impairments relevant to KS.

animal behavior and cognition↗

bioRxiv2019

Single cell profiling of the VMH reveals a sexually dimorphic regulatory node of energy expenditure

Estrogen signaling in the central nervous system promotes weight loss by increasing thermogenesis and physical activity in the ventromedial hypothalamus (VMH), but the precise neuronal populations regulating these aspects of energy expenditure remain unclear. Here we define the molecular and functional heterogeneity of the VMH using single cell RNA sequencing, in situ hybridization, chemogenetic activation, and targeted gene knockdown. We describe six molecularly distinct neuron clusters in the VMH. In females, estrogen receptor alpha (ER) is restricted to neurons expressing tachykinin-1 (Tac1) or reprimo (Rprm). Further, Tac1 and Rprm expression is enriched in females, a sex difference that is established by permanent effects of gonadal hormones early in life. Finally, while Tac1 ablation selectively impairs movement, here we show that silencing Rprm selectively dysregulates temperature without affecting physical activity. Together this work provides a novel architectural framework whereby distinct and sexually differentiated neuron populations within the VMH mediate sex-specific aspects of metabolic homeostasis.

neuroscience↗