Opioid actions on the habenulo-peduncular circuit

PROJECT SUMMARY Withdrawal is a major obstacle in overcoming opioid dependence and addiction. Identifying the neural circuits involved and how opioids modulate the activity of those circuits is essential for developing new therapeutic approaches to prevent or treat opioid use disorder. The medial habenula (MHb) projects primarily to the interpeduncular nucleus (IPN) and has long been known to express high levels of the Mu-opioid receptor (MOR). Activity in this circuit has been associated with expression of fear and anxiety; and repeatedly implicated in mediating aversive qualities of nicotine and nicotine dependence. Emerging evidence also supports a role for MHb projections to IPN in the somatic and affective symptoms of opioid withdrawal. Despite this, there is remarkably little information on what cell types in both MHb and IPN express MOR, how MOR signaling influences this circuit, and whether chronic MOR signaling induces physiological changes in this circuit that contribute to withdrawal. In this proposal we propose experiments to inform each of these questions using a combination of molecular, physiological, and behavioral approaches to investigate MOR-expressing neurons in both MHb and IPN of mice. Based on prior literature and preliminary data we posit an important role for excitatory neurons in lateral MHb and inhibitory neurons in rostral IPN in mediating aversive qualities of opioid dependence that contribute to withdrawal and relapse.