Transcriptional reprogramming of drug-associated memories in the nucleus accumbens

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Project Summary Substance use disorder (SUD) is characterized by recurrent drug-taking behaviors that often resemble the renewal-induced relapse after a successful extinction-based therapy. This inability of transferring the learned extinction as the subjects are re-exposed to the original drug context (i.e., their homes) is associated with deficits in neural regions such as the nucleus accumbens (NAc), which regulates the extinction of drug-associated memories and its ability to maintain voluntary abstinence. For instance, addicts developing addiction in a particular context “A” may extinguish the responses for drug-associated cues in a clinical context “B”, but when re-exposed to the same cues in context “A”, fail to transfer the learned extinction to suppress the context-induced renewal/relapse. Thus, because the ability to cease drug-seeking relies on overcoming drug-associated memories, extinction represents a preclinical opportunity to characterize and manipulate the molecular substrates underlying drug-seeking behavior to overcome the renewal-associated relapse. While drug self-administration (SA) leads to numerous neuroplasticity changes in the reward circuit, little is known about the impact of extinction training in reprogramming the addiction-relevant behavioral and transcriptomic codes/outcomes of the brain reward circuit. Together, these research questions pose a platform to delineate my current personal and professional training plan, which will be applied as I transition to a faculty position. Under the tutelage of my primary mentors (Drs. Eric Nestler: sponsor and Paul Kenny: co-sponsor) and my mentoring committee (Drs. Mary Kay Lobo, Yavin Shaham, Li Shen and Fabricio Do Monte), I will use RNA-sequencing of NAc subregions (core and shell) of rats receiving cocaine-SA and contextual extinction (AAA vs ABA) or withdrawal (no extinction) procedures, to characterize the drug-associated memories (phenotypes; renewal vs. extinction), at the transcriptional level (Aim 1). Subsequently, to manipulate the resulting behaviors, I will be targeting the transcriptome of NAc subregions and cell types. Specifically, I will design novel viral vectors to perform viral-mediated gene transfer to manipulate a top hub gene (i.e., transcription factor) previously proven or newly deduced as a main driver of renewal-induced relapse (failure of extinction transfer) in a subregion and cell-specific manner in NAc. As for the cell-specific manipulations, I will be utilizing the novel transgenic rat model expressing Cre-recombinase in dopamine D1 or D2 medium spiny neurons (MSNs) (Aim 2). Purposely, because life situations involving conflict between abstaining from or taking a drug due to adverse consequences are a key feature of relapse, I will test the impact of extinction training on restoring adaptive decisions in a conflict-based model (Aim 3), where drug seeking leads to punishable outcomes (i.e., footshocks), to delve deeper into the neurobiology of extinction/renewal that is most relevant to people.