Dr. Paul J. Kenny – James L. McGaugh Distinguished Seminar
James L. McGaugh Distinguished Seminar Series
Friday, March 8th, 2024
11:00AM – 12:00PM
The seminar will be live streamed via Zoom and In-Person.
“A master regulator of opioid reward in ventral prefrontal cortex”
Paul J. Kenny, Ph.D.
Ward-Coleman Professor and Chair, Nash Family Department of Neuroscience
Director, Drug Discovery Institute (DDI), Icahn School of Medicine at Mount Sinai
Intrinsic rewarding properties of opioids have contributed to an alarming surge in overdose-related fatalities in the United States due to their widespread misuse. Opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. Here, I will describe data from whole-brain activity mapping experiments showing that neurons in the dorsal peduncular nucleus (DPn), a relatively unexplored territory in ventral prefrontal cortex (vPFC), are highly responsive to the opioid analgesic oxycodone. Using single-cell connectomic profiling, we found that DPn neurons innervate the parabrachial nucleus and other brain regions known to regulate physiological and behavioral responses to opioids. Using FosTRAP2 mice, we found that optically stimulating opioid-regulated DPn neurons or their terminals in the PBn induced an aversive behavioral state that was reversible by oxycodone. Spatial and single-nuclei transcriptomics resolved a unique population of PBn-projecting pyramidal neurons restricted to the DPn that express μ-opioid receptors (μORs). Disrupting μOR signaling in these neurons switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings suggest that DPn neurons are important substrates for the abuse liability of opioids.