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Chronic opioid treatment arrests neurodevelopment and alters synaptic activity in human midbrain organoids

ABSTRACT: Chronic opioid treatment arrests neurodevelopment and alters synaptic activity in human midbrain organoids

PROVIDER: PRJNA1082742 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28198719_1.fastq.gz	Fastqsanger.gz
	SRR28198719_2.fastq.gz	Fastqsanger.gz
	SRR28198720_1.fastq.gz	Fastqsanger.gz
	SRR28198720_2.fastq.gz	Fastqsanger.gz
	SRR28198721_1.fastq.gz	Fastqsanger.gz

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Chronic opioid treatment arrests neurodevelopment and alters synaptic activity in human midbrain organoids

Project description:Understanding the impact of long-term opioid exposure on the embryonic brain is critical due to the surging number of pregnant mothers with opioid dependency, but has been limited by human brain inaccessibility and cross-species differences in animal models. Here we establish a human midbrain model that uses hiPSC-derived midbrain organoids and apply it to assess cell-type-specific responses to acute and chronic fentanyl treatment and fentanyl withdrawal. Single-cell mRNA sequencing of 25,510 cells from organoids in different treatment groups indicated that chronic fentanyl treatment arrests neuronal subtype specification during early midbrain development and alters synaptic activity and neuron projection. In contrast, acute fentanyl treatment increases dopamine release but does not significantly alter gene expression related to cell lineage development. These results provide the first examination of the effects of opioid exposure on human midbrain development at the single cell level.

2024-03-05 | GSE260711 | GEO

Single Nucleus Transcriptomes from the Ventral Midbrain of Opioid Overdose Cases and Controls

Project description:Dynamic interactions of neurons and glia in the ventral midbrain (VM) mediate reward and addiction behavior. We studied gene expression in 212,713 VM single nuclei from 95 human opioid overdose cases and drug-free controls. Chronic exposure to opioids left numerical proportions of VM glial and neuronal subtypes unaltered, while broadly affecting glial transcriptomes, involving 9.5 - 6.2% of expressed genes within microglia, oligodendrocytes, and astrocytes, with prominent activation of the immune response including interferon, NFkB signaling, and cell motility pathways, sharply contrasting with down-regulated expression of synaptic signaling and plasticity genes in VM non-dopaminergic neurons. VM transcriptomic reprogramming in the context of opioid exposure and overdose included 325 genes with genetic variation linked to substance use traits in the broader population, thereby pointing to heritable risk architectures in the genomic organization of the brain’s reward circuitry.

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Transcriptional alterations in dorsolateral prefrontal cortex and nucleus accumbens implicate neuroinflammation and synaptic remodeling in opioid use disorder

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Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment

Project description:Individuals with Williams syndrome (WS), a multisystemic neurodevelopmental disorder, characteristically portray a hypersocial phenotype. WS is caused by the hemizygous loss of 26-28 genes at chromosomal locus 7q11.23, one of which is GTF2I. Copy number variations and mutations in GTF2I are associated with altered sociality and have been proposed to underlie the hypersocial expression of WS. However, the contribution of GTF2I to human neurodevelopment remains poorly understood. Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, were differentiated from CRISPR-Ca9-edited GTF2I-knockout (GTF2I-KO) pluripotent stem cells (hiPSCs) to investigate the role of GTF2I in human neurodevelopment. Compared to controls, GTF2I-KO progenitors exhibited an increased proliferation rate and an altered cell cycle profile. Cortical organoids and neurons demonstrated increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity on a multi-electrode array. Overall, our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.

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'Single nucleus transcriptomes from the ventral midbrain of opioid overdose cases and controls'

Project description:'Single nucleus transcriptomes from the ventral midbrain of opioid overdose cases and controls'

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'Single nucleus transcriptomes from the ventral midbrain of opioid overdose cases and controls'

Project description:'Single nucleus transcriptomes from the ventral midbrain of opioid overdose cases and controls'

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Single Nucleus Transcriptomes from the Ventral Midbrain of Opioid Overdose Cases and Controls

Project description:Single Nucleus Transcriptomes from the Ventral Midbrain of Opioid Overdose Cases and Controls

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Uncovering diurnal rhythm disruptions of synaptic proteome signaling in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Project description:This article presents a study that examines the proteomic alterations associated with opioid use disorder (OUD) in the human brain. The study investigates the interplay between pro-inflammatory signaling, extracellular matrix (ECM) remodeling, and synaptic plasticity in the corticostriatal circuitry associated with OUD. The findings reveal differential alterations in the synaptic proteomes across the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC), indicating that changes in certain synaptic subtypes are unique to each brain region. The proteomic alterations associated with OUD in DLPFC are mainly in glutamatergic, serotonergic, dopaminergic, and oxytocin signaling, while altered adrenergic signaling is enriched in NAc. The study also identifies alterations in proteins involved in circadian entrainment specifically in synaptic enrichments in both DLPFC and NAc of OUD subjects. These findings provide new evidence linking disrupted molecular rhythms in the regulation of distinct synaptic subtypes altered by opioids.

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Chronic alcohol drinking modulates synchrony between midbrain gene transcription and long-lasting changes in dopamine terminal and opioid function in macaques

Project description:Alcohol use disorder is marked by disrupted behavioral and emotional states which can persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired ex vivo voltammetry in nucleus accumbens slices with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and dynorphin release – all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. Therefore, the long-lasting synaptic impact of alcohol use suggests that assessment of transcript-function relationships may provide avenues for precision therapeutics targeted to specific synaptic pathophysiologies.

2024-04-16 | GSE244557 | GEO

Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment

Project description:Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment

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