Abstract
Opioid use disorder (OUD) is a chronic, relapsing disease characterized by compulsive drug-taking and the inability to stop despite negative consequences. OUD is an urgent economic, estimated to cost the US economy $1.021T in 2017, and public health crisis with annual opioid deaths quadrupling to 81,606 in the decade from 2012 to 2022. While historical advances in the field of OUD research have focused mostly on neuron-to-neuron interactions, more recent findings have raised the possibility that activation of glial cells, particularly microglia, could regulate the behavioral and emotional aspects of OUD, such as drug craving. However, the transcriptional and epigenetic mechanisms of opioid-induced microglial activation remain poorly understood. Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining brain homeostasis as well as aiding in CNS development. Their ability to modulate the CNS environment stems from their pleiotropic nature, which is regulated in part by epigenetic mechanisms. Histone 3 lysine 27 trimethylation (H3K27me3) is transcriptionally repressive and is known to be deposited on genes that produce pro-inflammatory cytokines associated with microglial activation and, its erasure by histone lysine demethylase 6b (Kdm6b) promotes microglial activation and in chronic scenarios, neuroinflammation. Indeed, H3K27me3 and the dynamics of other histone post-translational modifications (hPTMs), such as acetylation of H3K27 and H3K9, and methylation of H3K4, are well characterized in infectious diseases and certain cancers; however, our understanding of their contributions to OUD are still emerging. By analyzing the behavioral, transcriptional, and epigenetic changes that occur in microglia across different phases of morphine use, this thesis sought to characterize the dynamics of histone PTMs (hPTMs) and the role of an epigenetic switch for pro-inflammatory microglial activation, contributing to drug maintenance, seeking and relapse in OUD.