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

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

PROVIDER: PRJNA708353 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13920163_1.fastq.gz	Fastqsanger.gz
	SRR13920163_2.fastq.gz	Fastqsanger.gz
	SRR13920164_1.fastq.gz	Fastqsanger.gz
	SRR13920164_2.fastq.gz	Fastqsanger.gz
	SRR24463613_1.fastq.gz	Fastqsanger.gz

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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.

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Sex specific gene expression patterns in cortico-limbic structures associate with psychiatric disorders

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:MicroRNAs have been implicated in the pathology not only of cancer, but also of psychiatric diseases, such as bipolar disorder and schizophrenia. As several psychiatric disorders share the same risk genes, we hypothesized that this microRNA could also be associated with attention-deficit/hyperactivity disorder (ADHD) and that this association to psychiatric disorders might be due to the variable number of tandem repeats (VNTR) polymorphism within the internal miR-137 (Imir137) promoter (PMID 18316599; PMID 25154622). To further understand the role of the microRNA 137 in the brain a knock-down of miR-137 expression in SH-SY5Y neuroblastoma cells was performed followed by expression analysis using a microarray.

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