Unraveling Molecular Mechanisms Underlying Heroin-induced Mitochondrial Perturbations

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

Project Summary/Abstract The opioid epidemic has continued to be a major public health issue within the United States, contributing to ~100,000 overdose deaths. Opioid abuse contributes to more than just the more often focused addiction related behaviors. Long-term heroin exposure has recently been linked to the acceleration of neurodegenerative disease-like changes. Utilizing bulk RNA sequencing, we measured the gene expression signature within the dorsal striatum in human heroin users and aged matched controls. In addition to replicating previous findings relevant to behaviors related to the effects of opioids, we also identified a large set of genes that were altered related to mitochondrial oxidative phosphorylation and the electron transport chain. These genes, which were predominantly downregulated, were also enriched in KEGG ontology pathways related to several neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. My project aims to investigate the casual role heroin self-administration has on the mitochondrial transcriptional profile in the rodent dorsal striatum following heroin exposure using RNA sequencing. Additionally, I will use in-vivo and in-vitro models to elucidate the impact of opioid exposure on mitochondrial morphology and function. To that end, I will leverage immunohistochemistry to visualize perturbations on the mitochondrial network and use Seahorse assay to measure changes in oxygen consumption rate of mitochondria in cells to assess ATP production efficiency. Lastly, leveraging immunohistochemistry and functional strategies used in my cell culture and rodent model, I will assess mitochondria characteristics in post-mortem dorsal striatum tissue of heroin users. Altogether, this project will allow me to gain significant training in bioinformatics, RNA sequencing, metabolic assays, immunohistochemistry, and behavioral assays that will provide a significant foundation for my future development as an independent researcher to answer questions that might start from studies of the human brain to subsequently interrogate underlying neurobiological mechanisms and behavior in translational models.