Research

Overview

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. 

Projects

1) Medial Habenula GABA Regulates 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.

2) Epigenetic Regulation in Medial Habenula Contributes to Relapse. 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.

3) Identification of Medial Habenula Cell Populations that Contribute to Relapse. We are identifying the specific medial habenula cell populations that drive relapse-like behavior. Using spatial transcriptomics, we are mapping gene expression across anatomically defined subregions of the medial habenula to determine which neuronal and non-neuronal cell types show relapse-associated transcriptional changes. These studies allow us to link molecular signatures to precise anatomical locations, providing a high-resolution framework for understanding how distinct medial habenula cell populations contribute to drug seeking. Candidate cell populations identified through these approaches will be tested using targeted viral strategies, activity measurements, and behavioral assays to determine their causal role in relapse vulnerability. 

4) Medial Habenula Circuit Activity During Drug Seeking and Relapse. Another line of research examines how neural activity in medial habenula circuits changes across drug taking, abstinence, and relapse. Using fiber photometry in genetically defined cell populations, we measure real-time activity in the medial habenula during behavioral models of addiction to determine how specific neuronal signals track motivational state and relapse vulnerability. These studies allow us to link molecular and genetic findings to circuit-level function, providing insight into how changes in gene expression and epigenetic regulation alter neural activity to drive drug seeking. By combining photometry with targeted viral manipulations, we aim to identify the activity patterns that causally promote relapse and define circuit mechanisms that may serve as therapeutic targets. 

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.