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. 2021 Jun 22;26(12):7760–7783. doi: 10.1038/s41380-021-01189-9

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — a, b Statistically unsupervised analysis of treatment-induced metabolites. The metabolome of dorsal forebrain organoids exposed to our narcotic and neuropsychiatric-related treatments were first analyzed and in a statistically unsupervised format. This involved unbiased clustering of the metabolomic profiles of all samples (a). In addition, a statistically unsupervised principal components analysis was also conducted to visualize the distinctness of our various treatments within human-derived dorsal forebrain organoids (b). Note, the ordering of groups for presentation purposes are presented differ here due to the hierarchical relationships present between samples in these statistically-unsupervised clustering/principal components analyses. c, d Metabolomic Log2FC alterations visualized as split-axis volcano plots. Metabolic factors were next analyzed as a function of both their Log2FC and statistical significance. This yielded a global metabolite profile for all treatment conditions (see global volcano plot in (c)). Differential metabolite expression was subsequently split as a function of treatment group and was visualized as group-specific volcano plots that had been statistically compared against the metabolite profile of vehicle-treated controls (d). e Metabolome convergence and divergence across narcotic and neuropsychiatric-related risk factors in dorsal forebrain organoids. Further analysis of metabolomes revealed both common and unique metabolite alterations between human-derived dorsal forebrain organoids exposed to our different treatment conditions. This included differential expression of L-Phenylalanine in all treatment groups. The neurodevelopment-related metabolite Guanosine Triphosphate (GTP) was also differentially expressed in all treatment groups except those exposed to WIN 55,212-2. Because WIN 55,212-2 exhibited no further commonalities with our other groups, only the remaining 5 narcotic and neuropsychiatric-related treatment conditions were visualized (e). As discussed in-text, further analysis revealed that treatment of human-derived dorsal forebrain organoids with IL17a altered pyruvic acid expression, cortisol altered N-Acetylglutamine, nicotine altered D-Ribose 5-Phosphate and Acetylcysteine, and ethanol treatment yielded altered succinic acid, guanosine monophosphate, and inosine. Further discussion of metabolite data is provided in-text. Note that (a) and (b) share the same group legend, which is presented in (b). For all panels, each donor sample was treated with all experimental compounds. This yielded n = 5 iPSC donors x n = 7 treatment groups for a total n of = 35 experimental samples for LC/MS analysis.