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Abstract
Methamphetamine (METH) is a potent stimulant that induces a euphoric state but also causes cognitive impairment, neurotoxicity and neurodevelopmental deficits. Yet, the molecular mechanisms by which METH causes neurodevelopmental defects have remained elusive. Here we utilized human cerebral organoids and single-cell RNA sequencing (scRNA-seq) to study the effects of prenatal METH exposure on fetal brain development. We analyzed 20,758 cells from eight untreated and six METH-treated cerebral organoids and found that the organoids developed from embryonic stem cells contained a diverse array of glial and neuronal cell types. We further identified transcriptionally distinct populations of astrocytes and oligodendrocytes within cerebral organoids. Treatment of organoids with METH-induced marked changes in transcription in multiple cell types, including astrocytes and neural progenitor cells. METH also elicited novel astrocyte-specific gene expression networks regulating responses to cytokines, and inflammasome. Moreover, upregulation of immediate early genes, complement factors, apoptosis, and immune response genes suggests a neuroinflammatory program induced by METH regulating neural stem cell proliferation, differentiation, and cell death. Finally, we observed marked METH-induced changes in neuroinflammatory and cytokine gene expression at the RNA and protein levels. Our data suggest that human cerebral organoids represent a model system to study drug-induced neuroinflammation at single-cell resolution.
Highlights
Methamphetamine (METH) is a stimulant which induces a temporary state of intense euphoria; studies have shown that METH commonly leads to psychosis, depression, and attenuated immune systems [1, 2]
We propose the use of cerebral organoid models, which are composed of neural progenitor cells, glial and neuronal cell types grown in a 3D selforganizing manner, to study the effect of METH on the human brain
Embryoid bodies were generated from human embryonic stem cells and differentiated into self-organizing three-dimensional cerebral organoids in bioreactors
Summary
Methamphetamine (METH) is a stimulant which induces a temporary state of intense euphoria; studies have shown that METH commonly leads to psychosis, depression, and attenuated immune systems [1, 2]. We propose the use of cerebral organoid models, which are composed of neural progenitor cells, glial and neuronal cell types grown in a 3D selforganizing manner, to study the effect of METH on the human brain. Astrocytes, dynamically interact with neuronal cells to modulate many of these functions that contribute to METH pathogenesis [22]. Further studies into the roles of glial cells, and astrocytes, during METH pathogenesis and addiction may elucidate novel neuronal–glial interactions. We utilized cerebral organoids and scRNA-seq to study the effects of prenatal METH exposure and evaluate glial cell diversity within organoids with single-cell resolution. ScRNA-seq identified differentially expressed genes and novel gene co-expression networks regulating the cortical astrocyte response to cytokines, neuroinflammation, inflammasome activation, and cell cycle regulation induced by METH treatment. We present a platform for studying both the effects of drugs on the human brain as well as human glial cell biology and function with single-cell resolution in vitro
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