Characterization of transcriptional profiles associated with stress-induced neuronal activation in Arc-TRAP mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE240573 | GEO | 2023/08/14
REPOSITORIES: GEO
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2016-07-30 | E-GEOD-85005 | biostudies-arrayexpress
Project description:An animal’s ability to cope with or succumb to deleterious effects of chronic psychological stress may be rooted in the brain’s immune responses manifested in microglial activity. Mice subjected to chronic social defeat (CSD) were categorized as susceptible (CSD-S) or resilient (CSD-R) based on behavioral phenotyping, and their microglial RNAs were isolated and analyzed by global gene expression microarrays. Microglia transcriptome from CSD-S mice was enriched for pathways that describe phases of CNS healing to sterile injury including, inflammation, oxidative stress, debris clearance, and wound resolution. Histochemical experiments confirmed the array predictions: CSD-S microglia showed elevated phagocytosis and oxidative stress, and the brains of CSD-S but not CSD-R or HC mice showed vascular leakage of intravenously injected fluorescent tracers. The results suggest that the inflammatory profile of CSD-S microglia may be precipitated by leakage of blood-born substances into brain parenchyma. We hypothesize that these CNS-centric responses contribute to the stress-susceptible behavioral phenotype.
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Project description:Chronic social defeat (CSD) in mice has been increasingly employed in experimental resilience research. Particularly, the degree of CSD-induced social avoidance is used to classify animals into resilient (socially non-avoidant) versus susceptible (avoidant). Inspired by human data pointing to threat-safety discrimination and responsiveness to extinction training of aversive memories as characteristics of resilient individuals, we here describe a translationally informed stratification which identified three phenotypic subgroups of mice following CSD: the Discriminating-avoiders, characterised by successful social threat-safety discrimination and successful extinction of social avoidance; the Indiscriminate-avoiders, showing fear generalisation, and the Non-avoiders (absence of social avoidance) displaying impaired conditioned learning. Furthermore, and supporting the biological validity of our approach, we uncovered subgroup-specific transcriptional signatures in classical fear conditioning and anxiety-related brain regions. Our reconceptualisation of resilience in mice refines the currently used dichotomous classification and contributes to advancing future translational approaches.
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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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Project description:ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins.
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Project description:Susceptibility to depression-like behavioral abnormalities in mice is studied with a well-established social defeat stress model. Responses to social defeat are associated with widespread transcriptomic changes in several brain regions. Here we present the first study of genome-wide cytosine methylation patterns of mice susceptible to social defeat stress using whole-genome bisulfite sequencing on DNA from the nucleus accumbens, a key brain reward region implicated in depression. We find a greater proportion of CpG hypermethylation than hypomethylation in susceptible mice compared to controls, with an opposite trend in the CHG and CHH contexts. Among the genes with the largest extent of differential methylation we find several which have been identified in earlier studies of gene expression changes related to social defeat, including estrogen receptor alpha (encoded by Esr1) and the deleted in colorectal cancer (Dcc) gene. Genes exhibiting differential methylation are enriched in GO terms of nervous system development, neurogenesis and structure development, which associated with learning memory and stress response. Our data provide a new evidence of the association of DNA methylation profiles and susceptibility to chronic stress.
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Project description:Depression is a complex and heterogeneous disorder and a leading contributor to the global burden of of disease. Most previous research has focused on individual brain regions and individual genes that contribute to depression. However, emerging evidence in both humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here we use a bioinformatics approach intersecting differential expression analysis with weighted gene co-expression network analysis to identify transcriptional networks that regulate susceptibility to depressive-like symptoms in mice. We performed RNA-sequencing on multiple brain regions from control animals and those either susceptible or resilient to chronic social defeat stress (CSDS) at multiple time points after defeat. We bioinformatically identified several transcriptional networks that regulate depression susceptibility, and in vivo manipulations of these networks confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our findings reveal novel transcriptional networks that control stress susceptibility and offer fundamentally new leads for antidepressant drug discovery.
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