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Daswani, Rishika Rajender

University of British Columbia

Opioid addiction, particularly to fentanyl, presents significant public health challenges, necessitating a deeper understanding of its neurobiological underpinnings. This study employs a multiomics approach to elucidate brain circuitry changes resulting from fentanyl self-administration in rats. Over a 15-day self-administration period, with 10 days of continuous access followed by 5 days of intermittent access, we observed notable alterations in specific neuronal populations and gene expression profiles. The single-nuclei RNA sequencing (snRNA-seq) data revealed an increase in GABAergic neurons expressing the Megf11 gene and a decrease in glutamatergic neurons expressing the Hox5b gene in fentanyl-exposed rats. Fentanyl significantly downregulated genes in Cerebellar Granule Glutamatergic (CB Granule Glut) neurons including Cx3cr1, Ets1, and Dock8, and upregulated genes such as Prckg and Nudt7. In the Cerebellar Cortex Purkinje GABAergic (CBX Purkinje Gaba) neurons, we identified mostly mitochondrial genes being upregulated. Using both single-nuclei ATAC-seq (snATAC-seq) and SnRNA-seq analysis, we identified genes that were both differentially regulated and expressed, particularly Skap2, Arhgap15, Slc25a13, and Akap13. Pathway analysis revealed that fentanyl upregulates the Signal transduction of S1P receptor pathway in CB Granule Glut neurons. Additionally, spatial analysis using the NanoString CosMx Spatial Molecular Imager highlighted spatially variable genes such as Ttr and Malat1 and identified ten spatially resolved clusters. Our study is the first to utilize a multiomics approach to investigate fentanyl's impact on brain circuitry, providing a detailed map of molecular changes associated with chronic fentanyl exposure. These findings contribute to the growing body of knowledge on the neural mechanisms of opioid addiction, offering potential targets for therapeutic intervention. Future directions include exploring sex-specific differences, validating findings through gene knockouts, and exploring behavioral consequences in confirmatory studies. Such efforts will enhance our understanding of the functional roles of identified genes and aid in developing targeted treatments for opioid use disorder.

Text

2024-08-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88978

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/