Mechanistic description of tolerance/withdrawal from opioids in the paraventricular nucleus of the thalamus

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Project Summary The paraventricular nucleus of the thalamus (PVT) is a critical node between ascending nociceptive information and goal directed behavior. Lesions, chemogenetic and optogenetic inhibition of the PVT reduces an animal’s ability to complete goal-directed behaviors. Studies have suggested NAc-projecting PVT neurons are necessary for mediating opioid dependence, or opioid use disorder. Chronic opiate use induces opioid dependence, a complex disease whose components including tolerance, drug seeking or craving, and physical dependence characterized by withdrawal avoidance behavior. The PVT is rich with all 4 opioid receptors, particularly the mu-opioid receptor (MOR) – the primary target of analgesic drugs like morphine and fentanyl. Interestingly, activity-driven expression of the immediate early gene c-fos indicates increased excitation of the PVT in response to opioid withdrawal. Given the growing body of evidence that the PVT is involved in the expression of opioid dependence, I will examine the effects of acute and chronic opioid administration on PVT neurons. Thus, Aim 1 is dedicated to characterizing the acute actions of opioids on MORs pre- and postsynaptic to the PVT and the role of phosphorylation in the process of acute desensitization in the PVT. Phosphorylation of sites on the C-terminus of MORs results in the induction of acute desensitization which is thought to be a precursor for the development of long-term tolerance. Tolerance, or a diminished responsiveness has been well described in hindbrain regions such as the locus coeruleus (LC) yet less is known about how tolerance shapes circuits that mediate goal directed behavior. Since phosphorylation of MOR is thought to be the initial step in the development of tolerance, I have characterized these mechanisms in the PVT. Sequential work will determine long-term adaptations that lead to withdrawal to multiple opioids including, morphine, fentynal, and bupinorphine in the PVT; as well as presynaptic adaptations of MOR (+) inputs to the PVT. The overall goal of this proposal is to characterize the adaptations of MORs in PVTs seen after chronic opioid treatment. Additionally, this work stands as the foundation of what I aim to achieve in science and bring to my post-doctoral fellowship. In Aim 2, I propose to identify a post-doctoral mentor with expertise in mood disorders, chronic stress, and/or addiction who can utilize my electrophysiology expertise and train me in rigorous experimental design and data analysis for in-vivo imaging and behavioral assays. The broad, long term goal is to build the skill set required to dissect a circuit molecularly and follow these adaptations to awake and moving animals. This proposal seeks to address the BRAIN Initiative’s Scientific Review and High Priority Research Area for using multimodal methods to monitor neural activity. My electrophysiological foundation will serve well to seize the challenge of recording dynamic neuronal activity from both complete neural networks and single cells; informing us about dynamic networks with molecular precision.