A novel cellular and circuit target for opioids

About This Grant

Opioid use disorder (OUD) is a public health crisis that affects millions of individuals in the United States and results in profound economic, social, and individual harm. While increasing use of potent opioids like fentanyl and heroin have driven a dramatic rise in overdose deaths in the past decade, available treatments for OUD are often unsuccessful, highlighting the need for a better understanding of opioid actions. In the brain, a key region called the nucleus accumbens serves as a hub for opioid signaling, and plays an essential role in the rewarding and reinforcing properties of opioids. However, the specific cell population (or populations) in the nucleus accumbens that mediate this effect is not clear. Our group has recently generated high-resolution cell atlases of this structure, enabling a comprehensive identification of transcriptionally distinct neuronal populations in a rat model system that have also been confirmed in studies with human brains. These atlases identified expression of the mu opioid receptor (encoded by the Oprm1 gene, a primary target of abused opioids), in several neuronal populations. Unexpectedly, we identified a transcriptionally distinct yet uncharacterized neuronal population that expressed the highest levels of Oprm1. This cell population was marked by nearly exclusive expression of Chst9, a carbohydrate sulfotransferase, and formed clustered islands along the ventral and medial boundary of the nucleus accumbens. Although groundbreaking evidence has revealed that this unique cell population is conserved from mice to humans, almost nothing is known about its role in opioid reward and withdrawal. Using novel model organisms and gene editing tools that we developed to allow labeling and manipulation of this population, we will test the overarching hypothesis that these cells are necessary and sufficient for opioid reward, and will examine the impact of opioid experience on the molecular composition of this population to identify targets for pharmacological and therapeutic intervention. Specific Aim 1 of this proposal will define the functional effects of opioids, opioid seeking, and opioid withdrawal on the activity of these neurons. Specific Aim 2 will test the role of these neurons (and opioid receptors in these neurons) in opioid reward and relapse. Finally, Specific Aim 3 defines the impact of opioid consumption and withdrawal on transcriptional properties of this unique population. Together, these studies will reveal fundamental new mechanisms by which opioids act in the brain to promote opioid reward and relapse, and generate novel datasets to identify potential therapeutic targets in opioid use disorder.