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Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus [Illumina]

ABSTRACT: Preclinical work has long focused only on male animals, even though sexual divergence in both baseline behaviors and drug responses clearly impact treatment outcomes in patients. Psychiatric disorders are notably divergent, with males showing higher prevalence of ADHD and ASD, and females GAD and MDD. This divergence is reflected in quantitative differences in subclincal behaviors. The Noradrenergic neurotransmitter system is targeted by many psychiatric drugs, but is relatively uncharacterized at a molecular level. We developed a mouse to profile these neurons, defining their both a baseline transcriptome, including druggable receptors, and their molecular response to stimulation. We also discovered a remarkable sexual divergence in their gene expression, including functionally increased expression of the EP3 receptor in females – a difference that can be used to modulate stress-induced anxiety in a sex specific manner. These findings underscore the need to conduct preclinical studies in a manner balanced for sex, and suggest that baseline differences in noradrenergic neurons could underlay sexually divergent behaviors.

ORGANISM(S): Mus musculus

PROVIDER: GSE100004 | GEO | 2018/04/30

REPOSITORIES: GEO

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Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus [Affymetrix]

Project description:Preclinical work has long focused only on male animals, even though sexual divergence in both baseline behaviors and drug responses clearly impact treatment outcomes in patients. Psychiatric disorders are notably divergent, with males showing higher prevalence of ADHD and ASD, and females GAD and MDD. This divergence is reflected in quantitative differences in subclincal behaviors. The Noradrenergic neurotransmitter system is targeted by many psychiatric drugs, but is relatively uncharacterized at a molecular level. We developed a mouse to profile these neurons, defining their both a baseline transcriptome, including druggable receptors, and their molecular response to stimulation. We also discovered a remarkable sexual divergence in their gene expression, including functionally increased expression of the EP3 receptor in females – a difference that can be used to modulate stress-induced anxiety in a sex specific manner. These findings underscore the need to conduct preclinical studies in a manner balanced for sex, and suggest that baseline differences in noradrenergic neurons could underlay sexually divergent behaviors.

2018-04-30 | GSE100002 | GEO

Cocaine self-administration induces divergent protein expression in the nucleus accumbens of male and female mice to eliminate basal sex differences

Project description:Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by long-lasting alterations in the neural circuitry regulating reward and motivation. Substantial work has focused on characterizing the molecular substrates which underlie these persistent changes in neural function and behavior; however, this work has overwhelmingly focused on male subjects, despite mounting clinical and preclinical evidence that females demonstrate dissimilar progression to SUD and responsivity to drugs of abuse, such as cocaine. Here, we show that sex is a critical biological variable that defines drug-induced plasticity in the NAc. Using quantitative mass spectrometry, we assessed the protein expression patterns altered by cocaine self-administration and demonstrate unique molecular profiles between males and females. We show that 1. Cocaine self-administration induces non-overlapping protein expression patterns in males and females and 2. Cocaine specifically acts on baseline sexual dimorphisms to exert these effects. Critically, we find that cocaine administration blunts not only basal sex-differences in the accumbens proteome, but also the pre-existing sex differences in behavior for natural rewards. Together, these data suggest that chronic cocaine is capable of rewriting baseline proteomic function to maintain cocaine-specific behaviors.

2021-09-09 | PXD022832 | Pride

Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing

Project description:Background There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established. Methods In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n=22-24 per group/region). Findings We found over 3,000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in Astrocytes, Drd3+MSNs and Oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS). Interpretation Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross- disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS.

2021-03-10 | GSE168599 | GEO

RNA-Seq of the different life history stages in Bostrychia moritziana (male gametophyte, female gametophyte, tetrasporophyte)

Project description:Diverse sex determination mechanisms have been reported in eukaryotes, but little is known about the genetic pathways leading to sex determination in red algae. Sex-specific genes that could be involved in sex determination and sexual differentiation were investigated in a red alga Bostrychia moritziana by analyzing the transcriptomes of various phases including males, females and tetrasporophytes. Sex-dominantly-expressed genes which shows >10 fold difference between sexes were isolated using comparative RNA-seq analysis. We found 19 gene homologues, 10 from males and 9 from females, that were found only in one sex in genomic amplification. This suggests that these divergent homologues are on non-recombining, possibly different, chromosomes in their respective sexes. Most of the sex-specific genes are involved in important cellular processes including chromosome segregation, nucleo-cytoplasmic protein shuttling or tRNA modification. Quantitative PCR analysis also showed that some sex-specific genes were differently regulated during critical events of sexual reproduction like fertilization and carposporophyte development. We could also localize the expression of a male-specific gene in spermatia before and after gamete binding using RNA in situ hybridization. Another set of transcripts were found that were sex-dominantly-expressed, but not sex-specific. 19 out of 39 sex-dominantly-expressed transcripts were annotated to transposable elements, but none of them was sex-specific. Our results suggest that sexual differentiation in B. moritziana may be achieved by multi-level regulation of cellular processes, both from genes present only in one sex and differential expression of shared genes.

2020-09-01 | GSE155429 | GEO

Spenito-dependent metabolic sexual dimorphism intrinsic to fat storage cells

Project description:Metabolism in males and females is distinct. Differences are usually linked to sexual reproduction, with circulating signals (e.g. hormones) playing major roles. By contrast, sex differences prior to sexual maturity and intrinsic to individual metabolic tissues are less understood. We analyzed Drosophila melanogaster larvae and find that males store more fat than females, the opposite of the sexual dimorphism in adults. We show that metabolic differences are intrinsic to the major fat storage tissue, including many differences in the expression of metabolic genes. Our previous work identified fat storage roles for Spenito (Nito), a conserved RNA-binding protein and regulator of sex determination. Nito knockdown specifically in the fat storage tissue abolished fat differences between males and females. We further show that Nito is required for sex-specific expression of the master regulator of sex determination, Sex-lethal (Sxl). “Feminization” of fat storage cells via tissue-specific overexpression of a Sxl target gene made larvae lean, reduced the fat differences between males and females, and induced female-like metabolic gene expression. Altogether, this study supports a model in which Nito autonomously controls sexual dimorphisms and differential expression of metabolic genes in fat cells in part through its regulation of the sex determination pathway.

2023-04-25 | GSE229991 | GEO

Flower development and sex determination in Vernicia fordii

Project description:To further elucidate the molecular mechanism underling sex determination at the divergence stage of male and female flowers, the comparative transcriptome analysis was performed. In total, 56,065 unigenes were generated 24,567 transcripts were identified. Among 608 differential expression genes (DEGs), 310 DEGs showed significant expression in males and 298 DEGs in females. The data showed that the sexual dimorphism of female flowers was affected by jasmonic acid, transcription factors and some genes related with activity of floral meristem, which were considered as the candidate sex determination genes. In this study, interesting information will be provided in understanding the development of unisexual flower and the regulatory networks hidden the sex determination in V. fordii, which is useful for the practice of improving its yield.

2017-05-09 | GSE98631 | GEO

Semen of gibel carp - Distinct sperm nucleus behaviors between genotypic and temperature-dependent sex determination males are associated with replication and expression-related pathways in a gynogenetic fish

Project description:In our study, differential male nucleus events and development behaviors were revealed from the fertilized eggs in response to the sperm from males of genotypic sex determination (GSD) and temperature-dependent sex determination (TSD) in gibel carp. When the eggs of maternal fish were fertilized by the sperm from males of GSD, the fertilized egg encountered similar sexual reproduction events and behaviors. However, when the eggs of maternal fish were fertilized by the sperm from males of TSD, a typical process of gynogenesis was observed. To reveal the underlying molecular mechanism of differential sperm nucleus development behaviors in the fertilized eggs, iTRAQ-based quantitative semen proteomics were performed on three semen samples from three males of GSD and three semen samples from three males of TSD respectively.

2018-06-14 | PXD008919 | Pride

Sex differences in the ventral tegmental area and nucleus accumbens proteome at baseline and following nicotine exposure

Project description:Sex differences in behaviors relevant to nicotine addiction have been observed in rodent models and human subjects. Behavioral, imaging and epidemiological studies also suggest underlying sex differences in mesolimbic dopamine signaling pathways. In this study we evaluated the proteome in the ventral tegmental area (VTA) and nucleus accumbens (NAc) shell in male and female mice. Experimental groups included two mouse strains (C3H/HeJ and C57BL/6J) at baseline, a sub-chronic, rewarding regimen of nicotine in C3H/HeJ mice, and chronic nicotine administration and withdrawal in C57BL/6J mice. Isobaric labeling with a TMT 10-plex system, sample fractionation, and tandem mass spectrometry were used to quantify changes in protein abundance. Similar or greater numbers of differentially regulated proteins were found between sexes at baseline in C3H/HeJ or C57BL/6J mice than within sexes following their respective regimen of nicotine administration. Despite differences by sex, strain, and nicotine exposure parameters, glial fibrillary acidic protein (GFAP) and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32, Ppp1r1b) were repeatedly identified as significantly altered proteins, especially in the VTA. Further, network analyses showed sex- and nicotine-dependent regulation of a number of signaling pathways, including dopaminergic signaling. Sub-chronic nicotine exposure in female mice increased proteins related to dopaminergic signaling in the NAc shell but decreased them in the VTA, whereas the opposite pattern was observed in male mice. In contrast, dopaminergic signaling pathways were similarly upregulated in both male and female VTA after chronic nicotine and withdrawal. Overall, this study identifies significant sex differences in the proteome of the mesolimbic system, at baseline and after nicotine reward or withdrawal, which may help explain differential trajectories and susceptibility to nicotine addiction in males and females.

2021-06-28 | PXD023859 | Pride

Transcriptomics and proteomics revealed sex differences in human pulmonary microvascular endothelial cells

Project description:There is marked sexual dimorphism displayed in the onset and progression of pulmonary hypertension (PH). Females more commonly develop pulmonary arterial hypertension (PAH), however, females with PAH and other types of PH have better survival than males. Pulmonary microvascular endothelial cells play a crucial role in the pulmonary vascular remodelling and increased pulmonary vascular resistance of PH. Given this background, we hypothesized that there are sex differences in the pulmonary microvascular endothelium basally and in response to hypoxia that are independent of the sex hormone environment.

2024-01-03 | PXD046787 | Pride

Role of sex chromosome complement in autosomal gene expression

Project description:It has generally been assumed that most differences between males and females are due to developmental and hormonal differences between the sexes. Here we investigate the contribution of sex chromosomal complement to such sexual dimorphisms. These genome-wide transcription profiling showed that the expression of hundreds of autosomal genes was sensitive to sex chromosome complement, rather than gender. The existence of such differences between males and females holds important implications for understanding sexual dimorphisms in physiology and disease hitherto attributed solely to gender or hormonal effects.

2010-10-02 | GSE21822 | GEO

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