Mechanistic interrogation of the medial habenula's role in regulating drug-induced behaviors - Recovery from Substance Use Disorder (SUD) is endangered by a lifelong risk of relapse. Exposure to drug- associated environments or cues can trigger relapse, and these memories can be extremely long lasting. This persistence is attributed to changes in neural circuit pathways that enable long-lasting cellular and behavioral changes that remodel the brain’s reward circuits. The roles of brain regions such as the ventral tegmental area (VTA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) have been extensively studied in the context of substance misuse, particularly in the reinforcing properties of these drugs. However, given that reinstatement is distinct from drug-evoked reward behaviors, it is likely that distinct circuit elements are recruited selectively during the reinstatement of drug-seeking behaviors, and engage neural circuits involved in drug seeking. This proposal focuses on the role of the medial habenula (MHb) in the reinstatement (relapse related behavior) of drug-seeking behaviors. Although not nearly as well characterized as the well-studied lateral habenula, the MHb has been shown to regulate aspects of reward and drug-seeking behavior. The lateral and medial habenula complex is thought to form part of the neural basis that all vertebrates, including humans, use to adapt their behavior to rewards, stress, fear, and other motivating factors. However, the MHb remains vastly understudied, even though it is likely a major component of the reward circuitry. Previous work from our labs shows that the MHb appears to be selectively engaged during reinstatement of cocaine-induced conditioned place preference, suggesting a key role for the MHb in reinstatement. Chemogenetic induction of the MHb results in reinstatement of CPP, and new preliminary fiber photometry data show the MHb is highly active specifically during reinstatement of CPP as well. Together, these CPP data suggest the MHb may be a key regulator of reinstatement. Indeed, preliminary data show that chemogenetically activating MHb ChAT (choline acetyltransferase) cells drives reinstatement of intravenous self-administration (gold standard for modeling volitional drug taking) of cocaine. In contrast, perturbations that reduce the activity of MHb ChAT cells nearly abolish reinstatement. These preliminary data support the main hypothesis that the MHb is highly active during reinstatement and, and altering its level of activity can bi-directionally control reinstatement. Furthermore, data from past studies from our labs indicate that the MHb may be driving reinstatement via increasing the activity of a select subpopulation of VTA dopaminergic cells, which would provide a substrate by which MHb ChAT cells facilitate reinstatement. We address these open questions with three aims combining cutting-edge genetic, viral and behavioral approaches. Together, our studies will illuminate the activity of MHbChAT cells in reinstatement of SUD-related behavior, unambiguously define the causative role these cells play, and reveal the downstream connections and circuit elements that are engaged by MHb ChAT cells and facilitate drug-induced behaviors, particularly reinstatement.
