Co-methylation Networks Associated with Cognition and Structural Brain Development During Adolescence
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE284550 | GEO | 2024/12/20
REPOSITORIES: GEO
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Project description:Adolescence is a critical period in cognitive and emotional development, characterized by high levels of social interaction and increases in risk-taking behavior including binge drinking. Adolescent exposure to social stress and binge ethanol have individually been associated with the development of social, emotional, and cognitive deficits, as well as increased risk for alcohol use disorder. Disruption of cortical development by early life social stress and/or binge drinking may partly underlie these enduring emotional, cognitive, and behavioral effects. The study goal is to implement a novel neighbor housing environment to identify the effects of adolescent neighbor housing and/or binge ethanol drinking on (1) a battery of emotional and cognitive tasks (2) adult ethanol drinking behavior, and (3) the nucleus accumbens and prefrontal cortex transcriptome. Adolescent male and female C57BL/6J mice were single or neighbor housed with or without access to intermittent ethanol. One cohort underwent behavioral testing during adulthood to determine social preference, expression of anxiety-like behavior, cognitive performance, and patterns of ethanol intake. The second cohort was sacrificed in late adolescence and brain tissue was used for transcriptomics analysis. As adults, single housed mice displayed decreased social interaction, deficits in the novel object recognition task, and increased anxiety-like behavior, relative to neighbor-housed mice. There was no effect of housing condition on adolescent or adult ethanol consumption. Adolescent ethanol exposure did not alter adult ethanol intake. Transcriptomics analysis revealed that adolescent housing condition and ethanol exposure resulted in differential expression of genes related to synaptic plasticity in the nucleus accumbens and genes related to methylation, the extracellular matrix and inflammation in the prefrontal cortex. The behavioral results indicate that social interaction during adolescence via the neighbor housing model may protect against emotional, social, and cognitive deficits. In addition, the transcriptomics results suggest that these behavioral alterations may be mediated in part by dysregulation of transcription in the frontal cortex or the nucleus accumbens
2023-09-18 | GSE242910 | GEO
Project description:Background: Adolescent cannabis use leads to long-lasting behavioral changes involving cognitive and reward processes. However, the underlying molecular mechanisms are not well understood. To address this limitation, we performed gene network analyses using transcriptomic data from mice exposed during adolescence to Δ-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. Methods: We injected vehicle or THC in female and male mice during the entire adolescence period. Two weeks following the last exposure, we measured recognition memory, social interaction and anxiety-related behaviors. We generated 120 RNA-seq datasets from 5 brain regions for each mouse. We performed differential gene expression analysis and constructed co-expression networks to identify THC-induced transcriptional alterations at the level of individual genes, gene networks, biological pathways, and cellular specificity. Further, we integrated THC-correlated gene networks with human traits from genome-wide association studies and performed key driver analysis to identify potential regulators of disorder-associated networks. Results: THC impaired cognitive behaviors of mice, with memory being more impacted in females, which coincided with larger transcriptional alterations in the female brain. Gene network analyses identified brain region-, cell type- and sex- specific co-expressed genes (“modules”) dysregulated by THC. THC-induced memory deficits in females were correlated with disruption of gene networks involved in endocannabinoid signaling and inflammation. Additional THC-correlated modules in both sexes involved converging pathways related to dopamine signaling and addiction processes. Moreover, the connectivity map of THC-correlated modules uncovered intra- and inter-region molecular circuitries influenced by THC. Further, modules altered by THC treatment were enriched in genes relevant for human cognition and schizophrenia. Conclusions: These findings provide novel insights concerning the genes, cell types, and pathways underlying persistent behavioral deficits induced by adolescent exposure to THC in a sex-specific manner, and highlight the connection between adolescent cannabis use and neuropsychiatric disorders in humans.
2021-12-06 | GSE189821 | GEO
Project description:Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant structural changes to the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively-transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesize that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. To investigate this at the molecular level, ethanol (4g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA- and ChIP-sequencing were then performed within the same tissue to determine gene expression changes and identify genes and loci where H3K36me3 was disrupted by ethanol. We further assessed ethanol-induced changes at the transcription level with differential exon-use and cryptic transcription analysis – a hallmark of decreased H3K36me3. Here, we found ethanol-induced changes to the gene expression and H3K36me3-regulation of synaptic-related genes in all our analyses. Notably, H3K36me3 was differentially trimethylated between ethanol and control conditions at synaptic-related genes, and Snap25 and Cplx1 showed evidence of cryptic transcription in males and females treated with ethanol during adolescence. Our results provide preliminary evidence that ethanol-induced changes to H3K36me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level, which may explain the reported ethanol-induced changes to PFC synaptic function.
2023-02-21 | GSE220742 | GEO
Project description:Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant structural changes to the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively-transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesize that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. To investigate this at the molecular level, ethanol (4g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA- and ChIP-sequencing were then performed within the same tissue to determine gene expression changes and identify genes and loci where H3K36me3 was disrupted by ethanol. We further assessed ethanol-induced changes at the transcription level with differential exon-use and cryptic transcription analysis – a hallmark of decreased H3K36me3. Here, we found ethanol-induced changes to the gene expression and H3K36me3-regulation of synaptic-related genes in all our analyses. Notably, H3K36me3 was differentially trimethylated between ethanol and control conditions at synaptic-related genes, and Snap25 and Cplx1 showed evidence of cryptic transcription in males and females treated with ethanol during adolescence. Our results provide preliminary evidence that ethanol-induced changes to H3K36me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level, which may explain the reported ethanol-induced changes to PFC synaptic function.
2023-02-21 | GSE220745 | GEO
Project description:Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.
2023-10-03 | GSE242892 | GEO
Project description:Circadian rhythm disturbances have long been associated with the development of psychiatric disorders, including mood and substance use disorders. Adolescence is a particularly vulnerable time for the onset of psychiatric disorders and for circadian rhythm and sleep disruptions. Preclinical studies have found that circadian rhythm disruption (CRD) impacts the brain and behavior, but this research is largely focused on adult disruptions. Here, we sought to determine the long-term behavioral and neurobiological effects of CRD during early adolescence by exposing mice to 12 h shifts in the light/dark cycle. We hypothesized that adolescent CRD would have a greater effect on psychiatric-related behaviors, relative to adult disruption. To identify possible mechanisms, we also measured gene expression in brain regions relevant to circadian rhythms, mood and reward. We found that disruption during early adolescence, but not adulthood, persistently increased exploratory drive (risk-taking behavior) and cocaine preference when tested later in life. Interestingly, we found sex differences when intravenous cocaine self-administration was tested. While female mice with a history of adolescent CRD had a greater propensity to self-administer cocaine, as well as increased motivation and cue-induced reinstatement, male adolescent CRD mice had reduced motivation and extinction responding. Overall, adolescent CRD in mice caused persistent increases in risky behavior, cocaine reward and cocaine self-administration, which suggests that CRD during adolescence may predispose individuals towards substance use disorders. Importantly, we found that many transcripts were affected by adolescent CRD and these were largely distinct across sex and brain region. Future research is required to elucidate how adolescent CRD affects behaviors relevant to mood- and substance use-related disorders across the 24-hour day, as well as to identify intervention strategies to alleviate disruption during adolescence and novel therapeutic approaches once symptoms have begun.
2024-11-25 | GSE282275 | GEO
Project description:Adolescent cannabis use has been associated with long-term cognitive dysfunction attributed to action of the main cannabis ingredient, delta-9-tetrahydrocannabinol (Δ9-THC), on the cannabinoid receptor 1 (CNR1). However, not all marijuana users develop cognitive impairment, suggesting a genetic vulnerability to adverse effects of cannabis. As both neurons and glial cells express CNR1, genetic vulnerability could influence Δ9-THC-induced signaling in a cell type-specific manner. Here we use an animal model of inducible expression of dominant-negative Disrupted-In-Schizophrenia-1 (DN-DISC1) selectively in astrocytes to evaluate the molecular mechanisms whereby an astrocyte genetic vulnerability could synergistically interact with adolescent Δ9-THC exposure to impair recognition memory in adulthood. We report that selective expression of DN-DISC1 in astrocytes and adolescent treatment with Δ9-THC synergistically affected recognition memory in adult mice. Similar deficits in recognition memory were observed following knockdown of endogenous Disc1 in hippocampal astrocytes in mice treated with Δ9-THC during adolescence. At the molecular level, DN-DISC1 and Δ9-THC synergistically activated the NF-kB-COX-2 (encoded by Ptgs2 gene) pathway in astrocytes and decreased immunoreactivity of parvalbumin-positive pre-synaptic inhibitory boutons around pyramidal neurons of the CA3 area of the hippocampus. The cognitive abnormalities were prevented in DN-DISC1 mice exposed to Δ9-THC by simultaneous adolescent treatment with the COX-2 inhibitor, NS389. Our data demonstrate that individual vulnerability to cannabis can be exclusively mediated by astrocytes. Results of this work suggest that genetic predisposition within astrocytes can exaggerate Δ9-THC-produced cognitive impairments via convergent inflammatory signaling, suggesting possible targets for preventing adverse effects of cannabis within susceptible individuals.
2018-12-31 | GSE116813 | GEO
Project description:The incidence of neural tube defects (NTDs) declined by about 40% in Canada with the introduction of national folic acid (FA) fortification programs. However, NTDs persist despite the fact that few Canadians currently exhibit folate deficiency. FA fortification may have aided in reducing NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate replete population may also occur in the context of compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain and muscle were collected from 19 control, 22 spina bifida and 15 anencephaly fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array. No difference in repetitive element DNAm was noted. Using a false discovery rate <0.05 and average group difference in DNAm >0.05, differentially methylated array sites were only identified in (i) the comparison of anencephaly to controls in chorionic villi (n=4 sites) and (ii) the comparison of spina bifida to controls in kidney (n=3,342 sites). We suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect. Although other studies have provided data to support altered DNAm in NTDs, this was not a major feature of British Columbian cases on a genome-wide or site specific level.
2016-01-23 | GSE69502 | GEO
Project description:Adolescence is a time of experimentation with cannabis. We evaluated whether adolescent exposure to the drug's psychotropic consituent, delta-9-tetrahydrocannabidiol (THC), might persistently alter microglia function and brain immune responses to lipopolysaccaride administration.
2022-09-22 | GSE213734 | GEO
Project description:To elucidate the impact of androgen exposure in fetal life on adolescent sheep, fetuses were exposed to either a vehicle control or testosterone propionate. Sheep were then reared to adolescence, and RNA was extracted from the liver to assess the impact of hormone exposure during fetal development.
2019-12-31 | E-MTAB-8032 | biostudies-arrayexpress