Stress resilience is established during development and is regulated by complement factors
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE193433 | GEO | 2023/01/05
REPOSITORIES: GEO
Similar Datasets
Project description:Here we show that ?-catenin mediates pro-resilient and anxiolytic effects in mice in the nucleus accumbens (NAc), a key brain reward region, an effect that is mediated by ?-catenin signaling in D2-type medium spiny neurons (MSNs) specifically. Conversely, blocking ?-catenin function in NAc promotes susceptibility to chronic stress, and we show evidence of robust suppression of ?-catenin transcriptional activity in the NAc both of depressed humans examined postmortem as well as of mice that display a susceptible phenotype after chronic stress, with a converse upregulation in mice that are stress resilient. Using ChIP-seq, we demonstrate a global, genome-wide enrichment of ?-catenin in the NAc of resilient mice, and specifically identify Dicer1—important in small RNA (e.g., microRNA [miRNA]) biogenesis—as a critical ?-catenin target gene involved in mediating a resilient phenotype. Small RNA-seq after excising ?-catenin from the NAc in the context of chronic stress reveals dynamic ?-catenin-dependent miRNA regulation associated with resilience. Control: 2 samples, Resilient: 2 samples, Susceptible: 2 samples; DNA input: 1 sample.
2014-11-13 | E-GEOD-61294 | biostudies-arrayexpress
Project description:Here we show that ?-catenin mediates pro-resilient and anxiolytic effects in mice in the nucleus accumbens (NAc), a key brain reward region, an effect that is mediated by ?-catenin signaling in D2-type medium spiny neurons (MSNs) specifically. Conversely, blocking ?-catenin function in NAc promotes susceptibility to chronic stress, and we show evidence of robust suppression of ?-catenin transcriptional activity in the NAc both of depressed humans examined postmortem as well as of mice that display a susceptible phenotype after chronic stress, with a converse upregulation in mice that are stress resilient. Using ChIP-seq, we demonstrate a global, genome-wide enrichment of ?-catenin in the NAc of resilient mice, and specifically identify Dicer1—important in small RNA (e.g., microRNA [miRNA]) biogenesis—as a critical ?-catenin target gene involved in mediating a resilient phenotype. Small RNA-seq after excising ?-catenin from the NAc in the context of chronic stress reveals dynamic ?-catenin-dependent miRNA regulation associated with resilience. GFP_Control: 12 samples, GFP_Resilient: 12 samples, GFP_Susceptible: 4 samples; CRE_Control: 12 samples, CRE_Susceptible: 8 samples.
2014-11-13 | E-GEOD-61295 | biostudies-arrayexpress
Project description:Chronic social isolation (CSIS), an animal model of depression, generates two stress-response phenotypes: CSIS-resilient and CSIS-susceptible. However, the molecular mechanism underlying resilience to CSIS remains unclear. We aimed to investigate the prefrontal cortical synaptoproteome profile between CSIS-resilient, CSIS-susceptible and control rats in order to identify predictive proteins for the resilience phenotype. Comparison of CSIS-resilient versus CSIS-susceptible rats revealed downregulated glycolysis intermediate Aldoc and upregulated Cltc, Cam2a, Syn and Fasn proteins involved in neuronal transmission, synaptic vesicle trafficking and fatty acid synthesis. Comparison of CSIS-resilient and control rats revealed downregulated mitochondrial proteins Atp5f1b and Cs, and upregulated Prkcg, Slc17a7, and Sv2a proteins involved in signal transduction and synaptic trafficking. These proteins make the animal groups linearly separable, and 100% validation accuracy is achieved by standard machine learning models. In addition, we identified the most significant proteins for discriminating CSIS-resilient vs. CSIS-susceptible or control rats by using Support Vector Machine with greedy forward search and Random Forest, resulting in four panels of discriminative proteins. Proteomics-data-driven machine learning algorithms can provide a platform for accessing predictive features and provide additional insight into the molecular mechanisms of synaptic neurotransmission involved in stress resilience.
2024-04-23 | PXD047159 | Pride
Project description:Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nucleus transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid load. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GRIA3, KCNMA1, and STXBP1. This putative cell type has been implicated in resilience in previous studies on bulk RNA-seq tissue, but our single-nucleus and cross-species approach identifies particular resilience-associated gene signatures in these cells. These novel resilience candidate genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Based on these gene signatures, we identified several potential mechanisms of resilience, including regulation of synaptic plasticity, axonal and dendritic development, and neurite vesicle transport along microtubules that are potentially targetable by available therapeutics. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.
2023-12-23 | GSE221702 | GEO
Project description:Chronic social isolation (CSIS) generates two stress-related phenotypes, resilience and susceptibility. Although brain energy metabolism is important in regulating social behaviors, the molecular mechanisms underlying CSIS resilience remain unclear. To identify protein changes and altered biochemical pathways and processes for resilience to CSIS, prefrontal cortical cytosolic proteomic profiling was performed comparing CSIS-resilient with CSIS-susceptible and control rats. Potential predictive proteins discriminating between the CSIS-resilient and CSIS-susceptible groups were identified by support vector machine-based sequential feature selection and random forest-based feature importance scores. Predominantly decreased levels of glycolytic enzymes, G protein-coupled receptor proteins, Ras subfamily of GTPase proteins, and antioxidant proteins were found in CSIS-resilient vs. CSIS-susceptible groups. Altered levels of Gapdh and proteins involved in microtubule and cytoskeletal organization, and calcium-binding proteins were identified between the two phenotypes. These dynamic changes were accompanied by increased levels of proteins involved in GABA synthesis, the proteasome system, nitrogen metabolism, and chaperone-mediated protein folding. The overall ratio of significantly up- and down-regulated cytosolic proteins suggests adaptive cellular alterations as part of the stress-coping process specific for the CSIS-resilient phenotype.
2024-04-23 | PXD048641 | Pride
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.
2023-02-28 | GSE161726 | GEO
Project description:Understanding the mechanisms involved in cognitive resilience in Alzheimer’s disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. Here, by performing a transcriptomic analysis of the prefrontal cortex of demented and resilient Tg2576 mice, we have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, Cd4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience and interestingly, we have found a negative correlation between CD4 mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. All of this, highlights the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4+ cells in the brain as a key player of cognitive dysfunction in AD.
2023-09-19 | GSE180968 | GEO
Project description:Here we show that β-catenin mediates pro-resilient and anxiolytic effects in mice in the nucleus accumbens (NAc), a key brain reward region, an effect that is mediated by β-catenin signaling in D2-type medium spiny neurons (MSNs) specifically. Conversely, blocking β-catenin function in NAc promotes susceptibility to chronic stress, and we show evidence of robust suppression of β-catenin transcriptional activity in the NAc both of depressed humans examined postmortem as well as of mice that display a susceptible phenotype after chronic stress, with a converse upregulation in mice that are stress resilient. Using ChIP-seq, we demonstrate a global, genome-wide enrichment of β-catenin in the NAc of resilient mice, and specifically identify Dicer1—important in small RNA (e.g., microRNA [miRNA]) biogenesis—as a critical β-catenin target gene involved in mediating a resilient phenotype. Small RNA-seq after excising β-catenin from the NAc in the context of chronic stress reveals dynamic β-catenin-dependent miRNA regulation associated with resilience.
2014-11-13 | GSE61295 | GEO
Project description:Here we show that β-catenin mediates pro-resilient and anxiolytic effects in mice in the nucleus accumbens (NAc), a key brain reward region, an effect that is mediated by β-catenin signaling in D2-type medium spiny neurons (MSNs) specifically. Conversely, blocking β-catenin function in NAc promotes susceptibility to chronic stress, and we show evidence of robust suppression of β-catenin transcriptional activity in the NAc both of depressed humans examined postmortem as well as of mice that display a susceptible phenotype after chronic stress, with a converse upregulation in mice that are stress resilient. Using ChIP-seq, we demonstrate a global, genome-wide enrichment of β-catenin in the NAc of resilient mice, and specifically identify Dicer1—important in small RNA (e.g., microRNA [miRNA]) biogenesis—as a critical β-catenin target gene involved in mediating a resilient phenotype. Small RNA-seq after excising β-catenin from the NAc in the context of chronic stress reveals dynamic β-catenin-dependent miRNA regulation associated with resilience.
2014-11-13 | GSE61294 | GEO
Project description:Stress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.
2019-08-22 | GSE118317 | GEO