Mechanistic studies of opiate withdrawal-induced sleep disturbances

PROJECT SUMMARY The majority of patients with Opioid Use Disorder (OUD) report sleep problems such as insomnia. Sleep disruption commonly occurs during opiate withdrawal and has been considered as a major factor that contributes to relapse. However, little is known about the underlying mechanisms, and the circuits/neurons/genes that are

involved. One of major component of both the opioid withdrawal and arousal circuitry resides in the monoaminergic nuclei—the locus coeruleus (LC), which is known to abundantly express µ-opioid receptors, mediates opioid withdrawal symptoms, and promote wakefulness. In the proposed project, we will combine

activity-dependent labelling and intersectional strategies to specifically target the wake-active populations of LC noradrenergic (LCNE-Wake) neurons and determine whether they are critical for morphine withdrawal-induced sleep disturbances. In Aim 1, using cutting-edge systems neuroscience tools, we will determine whether

spontaneous withdrawal from chronic morphine administration disrupts the neuronal activity and membrane properties of LCNE-Wake neurons, and functionally and molecularly characterize these dysfunctional neurons. In Aim 2, we will further evaluate the functional role of major presynaptic inputs of LC, gigantocellular reticular

nucleus (Gi) of medulla in withdrawal-induced sleep disturbances, test whether activation of GABAergic neurons in Gi can sufficiently mitigate the dysregulated sleep, and lastly map the spatial transcriptomic signatures of Gi-LC neurobiological pathway during morphine withdrawal. Successful completion of these aims will advance

our understanding of the circuit mechanisms underlying OUD-associated sleep disturbances, potentially leading to the development of effective therapies.