Sex specific gene expression patterns in cortico-limbic structures associate with psychiatric disorders
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ABSTRACT:
PROVIDER: PRJNA681830 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13174900_1.fastq.gz | Fastqsanger.gz | |||
| SRR13174900_2.fastq.gz | Fastqsanger.gz | |||
| SRR13175000_1.fastq.gz | Fastqsanger.gz | |||
| SRR13175000_2.fastq.gz | Fastqsanger.gz | |||
| SRR13174901_1.fastq.gz | Fastqsanger.gz |
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Project description:In humans there are sex-specific differences in the prevalence and symptomology of psychiatric disorders. However, preclinical animal models have primarily used males. As such, the molecular mechanisms underlying sex-specific differences in mental illness are not well established. 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. We found a considerable number of differentially expressed genes (DEGs) between males and females across all brain regions. However, 84.9% of all DEGs were found in the NAcS (> 5000 genes; p < 0.01, FDR < 0.01). Relating these DEGs to genome wide association studies (GWAS) revealed an enrichment for loci associated with major depressive disorder (Psychiatric Genomics Consortium 2019). We compared the DEGs in the NAcS to an analgous human dataset (Labonte, 2017), and found 587 common DEGs which were enriched for genes associated with both anxiety (neuro genetics study, 2016) and broad depression (UK biobank, 2018). Our data provide comprehensive evidence of sex molecular profiles in the NAcS. Importantly these differences associate with anxiety and depression, suggesting an intrinsic molecular basis for sex-based differences in disease prevalence and presentation.
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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.
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Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.
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