Tet1 in nucleus accumbens regulates stress responses
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76977 | GEO | 2017/09/06
SECONDARY ACCESSION(S): PRJNA309167
REPOSITORIES: GEO
Similar Datasets
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.
2015-09-21 | E-GEOD-54263 | biostudies-arrayexpress
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. BAZ1B (WSTF) ChIP-seq of mouse. Cocaine vs Saline, 3 biological replicates. In social defeat model: Normal control vs Susceptible vs Resilient, 3 biological replicates.
2016-07-30 | E-GEOD-85005 | biostudies-arrayexpress
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.
2016-07-30 | GSE85005 | GEO
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.
2019-03-16 | GSE126955 | GEO
Project description:Background: Examining transcriptional regulation by existing antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Further, given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine (14 daily injections), and a rapidly acting, experimental, non-monoamine-based antidepressant, ketamine (single injection), in mice subjected to chronic social defeat stress, a validated model of depression, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results: We identified approximately equal numbers of responder and non-responder mice following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus than other brain regions; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in ketamine and imipramine responders were most similar in PFC, where the least transcriptional regulation occurred for each drug. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptible associated transcriptional changes as well as induced resilient associated transcription in PFC, with effects varying by drug and brain region studied. Conclusions: We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility and inducing resilience associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine. mRNA profiles of susceptibility to chronic social defeat stress as well as treatment response were generated across 4 separate brain regions, with a sample size of 3-5 per group.
2016-07-27 | E-GEOD-81672 | biostudies-arrayexpress
Project description:Background: Depression is the leading cause of disability which produces enormous health and economic burdens. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activities of D1- or D2-type medium spiny neurons (MSNs). Methods: To separate D1- or D2-MSN specific transcriptomes in the NAc, RiboTag (RT) mice were crossed with D1- or D2-Cre lines and subjected to chronic social defeat stress. The cell-type specifically tagged ribosome-mRNA complex was pulled down by anti-HA antibody, and purified RNAs were subjected to RNA sequencing. Sequencing data were analyzed and defined differentially expressed genes (DEGs) were validated with RNAscope and viral overexpression in vivo. Results: Both MSN subtypes express distinct gene expression profiles according to stress groups. The DEGs are correlated with depression relevant gene ontology terms. Behavioral susceptibility and resilience are also correlated with subsets of DEGs, especially in D1-MSNs. Conclusions: Distinct subsets of genes are modulated in a cell-type specific manner in the NAc of depressed mice. Here we provided valuable transcriptome data sets for future studies on depression.
2021-07-09 | GSE147640 | GEO
Project description:Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, and show aberrant transcription across several limbic brain regions. The nucleus accumbens (NAc) in particular shows unique susceptible versus resilient phenotypes at the transcriptional, neuroanatomical, and physiological levels. Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in NAc have not yet been investigated. Here, we examined long-lasting changes in histone modifications induced in NAc by ELS and studied their underlying mechanisms in mediating heightened lifelong stress susceptibility in male and female mice. We identify methylation of lysine 79 of histone H3 (H3K79me) and the enzymes that control this modification, selectively in D2-type medium spiny neurons, as crucial for the expression of ELS-induced stress susceptibility, and reveal the transcriptional networks regulated by this mechanism. Finally, we demonstrate the potential clinical viability of this approach by showing that systemic delivery of a small molecule inhibitor of H3K79me reverses ELS-induced behavioral deficits.
2020-12-09 | GSE133889 | GEO
Project description:Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets.
2018-02-16 | GSE110725 | GEO
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.
2016-05-12 | GSE72343 | GEO
Project description:While stressful life events are an important cause of psychopathology such as Post-Traumatic Stress Disorder (PTSD) and Major Depressive Disorder (MDD), most individuals exposed to chronic stress remain psychologically unperturbed. The molecular mechanisms such variations in stress resilience remain to be explored. Utilizing a mouse social defeat paradigm as a model for chronic social stress exposure, we segregated socially defeated c57bl/6J mice into Susceptible and Unsusceptible groups based on scores of social avoidance, and these groups differ along multiple behavioral and physiological domains. To explore neuroplastic changes within the mesolimbic dopamine circuit that may explain variations in susceptibility, we examined global patterns of gene expression within the VTA (ventral tegmental area) and the NAc (nucleus accumbens). Tissue punches of NAc and VTA were obtained from either non-defeated control, Susceptible and Unsusceptible mice approximately 48 hours after the cessation of social defeat stress. Data from Illumina sentrix gene expression microarrays revealed three main findings: (1) the total number of genes significantly up or downregulated was considerably higher within the NAc, (2) the Unsusceptible phenotype was associated with the regulation of a much higher number of genes, and (3) as compared to the NAc, the VTA displayed far fewer genes that were identically regulated in both Susceptible and Unsusceptible groups. Taken together, these data strongly suggest that the VTA is an important substrate for transcriptional changes that can be correlated with variations in Susceptibility. In addition, they suggest that changes in anxiety (found in both Susceptible and Unsusceptible groups) versus changes in reward behavior (found only in Susceptilbe mice) can be explained by gene expression changes within the mesolimbic dopamine circuit. Keywords: neural stress response
2007-09-01 | GSE8870 | GEO