Relapse remains the central barrier to the successful treatment of substance use disorders (SUD), driven by maladaptive drug-associated memories that are formed during drug use and persist long after abstinence. My research program investigates a brain region called the medial habenula (MHb) as a relapse-specific regulator of cocaine-seeking behavior, with a focus on epigenetic and molecular mechanisms that shape neuronal activity and relapse vulnerability. Epigenetic modulations, including gene regulation via altered chromatin structure and DNA methylation, may function as a persistent “molecular memory” that encodes drug experience and drives vulnerability to relapse.
Building on prior work demonstrating that MHb cholinergic neurons are selectively engaged during relapse, my studies use chemogenetic activation, fiber photometry, and single-nucleus RNA sequencing (snRNAseq) to uncover molecular changes linked to reinstatement of cocaine self-administration. Gene network analysis of snRNAseq data revealed converging hub genes related to GABA receptor subunits, strongly implicating GABAergic signaling as a key mechanism linking MHb cellular activity to relapse. Ongoing work in my new laboratory is aimed at causally testing MHb GABA subunit genes as regulators of relapse, using viral tools, qPCR assays, activity readouts (photometry), and behavioral testing in rodent models of addiction.
Complementing this mechanistic work, a parallel line of research examines persistent DNA methylation signatures as predictors of relapse, using reduced representation bisulfite sequencing and machine learning approaches to identify changes in methylation that persist through all phases of our addiction model and accurately predict relapse behavior. These epigenetic signatures will pinpoint novel transcriptional targets and long-lasting regulatory mechanisms underlying drug-seeking behavior.
Together, these projects advance a unifying hypothesis: experience-dependent epigenetic regulation within the MHb alters gene expression, neuronal activity, and ultimately relapse behavior. By combining behavioral neuroscience with transcriptomics, epigenetic profiling, and targeted gene manipulation, my research program establishes the MHb as a molecular entry point for therapeutic intervention in SUD.
In the long term, this framework extends to stress, aversion, and early-life adversity, which are highly comorbid with SUD. My lab will investigate MHb transcriptomic and epigenetic signatures following stress and adversity, testing whether the MHb integrates these processes to drive susceptibility to relapse. These studies will lay the foundation for targeted, mechanistic interventions to prevent relapse, leveraging the MHb as a key hub for translational discovery.