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Molecular profiling in the Habenula of Rat Chronic Restaint Stress Model

ABSTRACT: Chronic stressful situations contribute to the risk of developing depression. Using Genome-wide gene expression analysis, we analyzed the habenula transcriptome of rats exposed to chronic restraint stress for 14 days. We selected 379 differentially expressed genes (DEGs) affected by chronic stress. From 379 DEGs, neuroactive ligand-receptor interaction, cAMP signaling pathway, circadian entrainment and synaptic signaling on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, response to corticosteroid, positive regulation of lipid transport, anterograde trans-synaptic signaling, chemical synapse transmission on Gene Ontology (GO) pathway analysis was identified as significantly enriched pathways. We made a protein-protein interaction network of DEGs and analyzed subclusters, and neuroactive ligand-receptor interaction, circadian entrainment, and cholinergic synapse-related clusters were identified. To validate the findings, quantitative RT-PCR was done for significant genes. Identified DEGs and pathways could be important factors modulating habenular response to stress and lead to behavioral change. These data identify key molecular targets involved in chronic stress-induced depression within habenula and provides a valuable resource for future study.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE183386 | GEO | 2022/05/26

REPOSITORIES: GEO

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Project description:Despite depression being one of the most prevalent and debilitating disorders worldwide, it has been difficult to understand its pathophysiology and to develop more effective treatments. Maladaptive transcriptional regulation within limbic neural circuits, including reward processing regions such as the nucleus accumbens (NAc), in response to chronic stress is thought to be a major contributor to the development of the syndrome. Epigenetic events?in particular, histone writers and erasers?that alter chromatin structure to regulate programs of gene expression have increasingly been associated with depression-related behavioral abnormalities in animal models and in depressed humans examined postmortem. However, very little is known about the ATP-dependent chromatin remodelers that control nucleosome positioning and the packing state of chromatin. Here we show that the ACF complex, part of the ISWI family of chromatin remodelers, is persistently and selectively upregulated in the NAc of mice that are susceptible to chronic social stress, as well as in the NAc of depressed human. We further establish that ACF induction is both necessary and sufficient for susceptibility to stress-induced depressive-like behaviors. Using ChIP-seq, we demonstrate that altered ACF binding after chronic stress is strongly correlated with altered nucleosome positioning, in particular, around the transcriptional start sites of affected genes. These alterations in ACF binding and nucleosome repositioning are associated with repressed expression of a subset of genes in animals that are susceptible to chronic stress. Together, these findings establish that active ATP-dependent chromatin remodeling by the ACF complex is a key regulator in the repression of genes that mediate susceptibility to social stress, and provide novel candidate targets for improved therapeutics of depression and other stress-related disorders. c57bl/6 mice underwent chronic social defeat stress (CSDS), and social interaction test was used to separate animals into control, susceptible and resilient groups. Nucleus accumbens (NAc) tissue was collected 48 hours after the last defeat session, and then Acf1, SNF2H ChIP-seq or H3 MNase-seq were performed based on the control, susceptible, and resilient groups. Three sequencing replicates were performed on each group.

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Molecular profiling in the Habenula of Rat Chronic Restaint Stress Model

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