Molecular Mechanisms of Opioid Use Disorder in Human Brain Models

Author

Emily MendezFollow

Author ORCID Identifier

0000-0002-8046-6905

Date of Graduation

5-2024

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Consuelo Walss-Bass

Committee Member

Fabricio Do Monte

Committee Member

Ruth Heidelberger

Committee Member

Scott Lane

Committee Member

Antonio Teixeira

Abstract

Opioid use disorder (OUD) is a national and global public health crisis with no end in sight. While studies from animal models hint at widespread epigenetic and transcriptomic alterations of opioid drugs, the molecular consequences of long-term exposure to opioid drugs in human brain is still unclear, and human-centered translational models are necessary to discern the human cell type-specific effects of OUD.

Using postmortem brain Brodmann area 9 (BA9) from the UTHealth Brain Collection for Research on Psychiatric Disorders, I identified angiogenic gene networks perturbed in the RNA and protein of OUD subjects, as well as downregulation of many neuron-correlated synaptic genes. Using single-nuclei RNA sequencing, I found global suppression of cell-cell signaling networks across all cell types, particularly involved in synaptic and growth factor signaling. Finally, using a novel postmortem fibroblast-derived induced pluripotent stem cell model of neuronal morphine exposure, I identify gene expression caused by chronic morphine exposure and compare these expression signatures to the source subjects’ brain.

Integrating results from all studies, I propose a hypothesis whereby opioid use disorder convergently dysregulates both synaptogenesis and angiogenesis through perturbation of the PI3K/Akt and MAPK/Erk second messenger systems and dysregulation of immediate early genes. The mechanistic insights from these human models may aid the discovery of novel pharmaceutical targets to treat OUD or prevent long-term consequences of drug exposure.

Keywords

Opioid Use Disorder, Postmortem, Overdose, RNAseq, Proteomics, Polygenic Risk Score, iPSC, snRNAseq, Transcriptomics