Dynamic epigenomic landscape of opioid abuse following early-life adversity

PROJECT SUMMARY The last decade has seen a devastating epidemic of opioid addiction in the U.S with the fatal opioid overdose incidence doubling in 10 years. Genetic factors clearly contribute to addiction vulnerability, but they alone cannot account for this rise. Therefore, environmental factors must also play role, and their enduring effects would be maximal during sensitive/critical periods early in life. Indeed, early life adversity (ELA) is associated with opioid addiction vulnerability, and in experimental models, it promotes such vulnerability. Although the responsible mechanisms have yet to be elucidated, the enduring nature of changes set in motion by ELA strongly suggest that epigenetic mechanisms may underlie these stable changes. The epigenome is a signal integration platform superimposed on the genome, which is modified by both ELA and drugs of abuse, and which also encodes aspects of sex differences. Epigenetic mechanisms are known to establish stable changes in cell function (via coordinating gene regulation) that give rise to persistently altered behaviors, including drug use and drug seeking behaviors. Thus, understanding epigenetic and transcriptional changes associated with addiction propensity following ELA may answer several key questions about the causes and mechanisms of opioid use disorder (OUD). For example, how is ELA epigenetically encoded, thereby increasing risk for opioid abuse and relapse- associated behaviors? Does heroin differentially affect the epigenome and transcriptome in those with ELA history, promoting this vulnerability? These questions will be addressed here using robust rat models of ELA and of heroin self-administration and relapse. Capitalizing on our findings that ELA augments heroin vulnerability and relapse in a sex-divergent manner4, consistent with human data20-23, we will test the driving hypothesis that both ELA and initial heroin use regulate epigenomic processes, and these, in turn, coordinate gene regulation that ultimately affects cellular signaling, and OUD-like behaviors. The epigenomic and transcriptomic changes induced by ELA and heroin will be determined by employing both bulk- and single-cell multi-omics in selected brain regions at different points in the OUD trajectory. They will be complemented by sampling of CSF and blood extracellular vesicle (EV) miRNA profiles to enable potential development of predictive markers of OUD risk and/or progression. Using state of the art sequencing and analysis methods, we will uncover gene regulatory networks associated with ELA, initial heroin use, and heroin abuse/relapse in females and males. This approach will allow us to identify novel targets for OUD prevention and intervention in vulnerable individuals.