Regulation of neuronal activity in the paraventricular thalamus by chronic morphine

项目总结

Project Summary High rates of opioid abuse and overdose deaths represent a substantial public health issue in the United States. Avoidance of withdrawal symptoms is a primary driver of continued opioid use and overdose. Understanding the neuroadaptations induced by chronic opioid exposure holds great promise for the identification of novel and efficacious therapeutics. The paraventricular thalamic nucleus (PVT), located in the dorsal midline thalamus, encodes behavioral states relevant to drug addiction, including arousal, hunger, reward-seeking, and aversion. Recent studies have pointed a critical role of the PVT and its projections in regulating many behavioral effects of opioids. The Mu-opioid receptor (MOR) is expressed in many brain regions, which collectively mediate many cellular and behavioral effects of opioids. It remains unknown to what extent the MOR in the PVT contributes to morphine withdrawal-induced somatic signs. In addition, several important questions remain poorly understood. How is the MOR is activated in the PVT? How does chronic morphine exposure and subsequent withdrawal affect the action potential firing—the final output—of PVT neurons? To what extent do the changes in neuronal activity contribute to morphine withdrawal-induced somatic signs? Two Specific Aims are proposed to address these questions. In Aim I, I will determine the extent to which activation and desensitization of the MOR alters neuronal output of PVT neurons following morphine withdrawal. Slice electrophysiology and in vivo Ca2+ imaging with fiber photometry will be employed to address this question. In Aim II, I will use Cre-LoxP technique to selectively delete the MOR in the PVT and examine its impact on withdrawal-induced somatic signs. Additionally, I will test whether blocking withdrawal- induced increase in excitability in PVT neurons affects the aversive behavioral effects of morphine withdrawal. Completion of this project is expected to provide excellent training opportunities to learn a wide range of powerful techniques, including ex vivo slice electrophysiology, in vivo fiber photometry, in situ hybridization, immunohistochemistry, viral microinjection, pharmacology, and animal behavior assays. Further, the proposed research will deepen our understanding of cellular and circuit mechanisms underlying adverse effects of opioid withdrawal.