Resilience and susceptibility in a mouse model of immune-mediated neurodevelopmental disorders
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE150481 | GEO | 2020/10/12
REPOSITORIES: GEO
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Project description:Background: Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development remains unclear. Methods: We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing. Results: Early MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation. Conclusions: Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.
2021-06-18 | GSE178403 | GEO
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: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:Individuals in a population respond differently to stressful situations. While resilient individuals recover efficiently, others are susceptible to the same stressors. Most existing information regarding the factors regulating stress resilience in vertebrates is from specific areas of the brain from adult rodents or humans. In order to study resilience during development, we established a new paradigm to identify resilience in zebrafish larvae. Using this assay, we identified resilient and susceptible subsets of zebrafish larvae at 6 days post fertilization and performed gene expression analysis on whole larvae.
2023-01-05 | GSE193433 | 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: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
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:Background: The present study investigated a role of proteins from BET family (epigenetic readers) in schizophrenia-like abnormalities in MAM-E17 model of schizophrenia. Methods: An inhibitor of BET proteins, JQ1, was given during adolescence in postnatal days (P) 23-P30, and behavioral response (sensorimotor gating, recognition memory) and prefrontal cortex (mPFC) function (long-term potentiation (LTP), molecular and proteomic studies) were performed in adult males and females. Results: Deficits in sensorimotor gating and recognition memory were observed only in MAM-treated males. However, adolescent JQ1 treatment affected control, but MAM-treated groups in both sexes. Electrophysiological study showed an LTP impairment only in male MAM-treated animals, and JQ1 did not have any effect on LTP in the mPFC. In contrast, MAM did not affect immediate early gene expression (markers of neuronal and synaptic activity), but JQ1 altered them in both sexes. Proteomic study revealed alterations in MAM-treated groups only in males, while JQ1 affected both sexes. Conclusions: Prenatal MAM administration induced schizophrenia-like abnormalities only in males. In contrast, adolescent JQ1 treatment affected both sexes and induced behavioral changes in control groups, altered a markers of neuronal and synaptic activity and proteomic landscape in the mPFC of both groups (VEH- and MAM-treated). Thus, adolescent inhibition of BET family might change neuroplasticity in the mPFC.
2021-09-07 | PXD027050 | Pride