Determining if Activity in Specific Lateral Habenula Output Pathways Motivates Avoidance of Synthetic Opioid Withdrawal or Cue Induced Reinstatement

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Project Summary Opioid abuse has reached epidemic proportions in the United States and is responsible for more than 40,000 overdose deaths each year 1. In particular, synthetic opioid addiction has proven to be extremely difficult to combat, in part because it generates powerful opponent processes in the user. Each dose of synthetic opioid produces rapid and potent euphoria that is strongly associated to drug cues, while withdrawal and abstinence from synthetic opioids induce severe distress. Avoidance of withdrawal and subsequent exposure to drug cues are key deterrents to long-term abstinence. The Lateral Habenula (LHb) is an exciting target for studying neuronal facilitation of relapse, as LHb activity is correlated with both stress evasion and the encoding of motivational value 6. LHb activity during acute withdrawal may motivate relapse via stress avoidance mechanisms, while during abstinence cues that are normally paired with drugs go unrewarded, inducing activity in the LHb. This activity may motivate drug seeking via a process akin to reward prediction error. Under the primary mentorship of Drs. John Neumaier, Michael Bruchas, Paul Phillips, and Charles Chavkin, this K99/R00 Pathway to Independence award will allow me to obtain training in cutting edge in-vivo calcium imaging and optogenetics, and oral self-administration model development. This training will allow me to elucidate the roles of the major LHb output pathways in motivating avoidance of fentanyl withdrawal and cued reinstatement. During the mentored phase of this grant I will be trained to use GCaMP6-based in-vivo calcium imaging to record LHb neurons that project specifically to the ventral tegmental area (VTA), the rostromedial tegmentum (RMTg), or the dorsal raphe nucleus (DRN) during naloxone-precipitated withdrawal, conditioned place aversion testing, and fentanyl reinstatement. I will also be trained to combine in-vivo calcium imaging with red-shifted optogenetic inhibition in order to leverage simultaneous circuit imaging and recording, and test causal relationships between neural pathway activity and behavior. Finally, I will be trained in novel oral fentanyl self-administration (SA) model development, which will be invaluable to my independent research career as a behavioral neuroscientist. During the independent phase of the award, I will combine this training with my prior expertise to determine if activity in each LHb pathway is necessary for expression of withdrawal related negative affect, withdrawal induced CPA, or cued reinstatement to fentanyl seeking. I will do so by simultaneously inhibiting LHb projections and recording from each LHb target region (VTA, RMTg, or DRN) to determine the effect of inhibition on behavior and monoaminergic nucleus activity. In summary, the research proposed in this Pathway to Independence Award will elucidate the role of individual LHb pathways in motivating avoidance of withdrawal and cued reinstatement, as well as their role in the expression of negative affect. This award will provide training in new technical tools, grant writing, lab management, mentorship, and other skills necessary to establish an independent research program capable of producing high impact studies and training the next generation of scientists.