The role of a novel cortical circuit in opioid reward

The National Institute on Drug Abuse awarded Icahn School of Medicine at Mount Sinai $100,228 on October 8, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to support research on opioid reward mechanisms.

The award funds a project investigating the functional role of a novel cortical circuit connecting the dorsal peduncular nucleus to the ventral tegmental area in mediating opioid reward. The research employs barcoded anatomy resolved by sequencing combined with spatial transcriptomics to generate connectomic and transcriptional profiles at single-cell resolution, patch-clamp electrophysiology paired with single-cell transcriptional profiling to characterize postsynaptic neurons, and intersectional genetics with mouse behavioral assays to determine the circuit's contribution to opioid reward. The work addresses the incomplete understanding of how mu opioid receptors in the ventral tegmental area mediate opioid reward and opioid use disorder risk.

Performance occurs in New York, New York 10029, with a period of performance from October 8, 2026 through June 30, 2028. This is a Project Grant, the standard assistance type for NIDA basic and translational research. The Drug Use and Addiction Research Programs supports basic, clinical, translational, and implementation research to develop prevention, diagnosis, and treatment approaches for drug use, misuse, addiction, and overdose.

Abstract

Misuse of opioids to obtain their rewarding effects remains a significant public health concern due to high risk of developing opioid use disorder (OUD) and overdose-induced death. MU opioid receptors (μors) in the ventral tegmental area (VTA) are regarded as key substrates for opioid reward. Opioids are thought to act in the VTA by stimulating μors expressed by inhibitory gabaergic inputs to dopamine neurons, thereby disinhibiting mesolimbic dopamine transmission to enhance reward-related behavioral states. However, direct evidence supporting this mechanism is limited, and the specific population of ΜOR-expressing neurons in the VTA that mediate opioid reward remains undefined. The kenny laboratory has shown that vesicular glutamate transporter 2-expressing cortical neurons in the dorsal peduncular nucleus (DPNVGLUT2 neurons) mediate the rewarding effects of opioids. IT was also shown that DPNVGLUT2 neurons express μors and project to the VTA, but the role of the DPNVGLUT2ÀVTA circuit in opioid reward is unknown. The goals of this proposal are to define the functional organization of the DPNVGLUT2ÀVTA circuit and test the hypothesis that ΜOR-mediated silencing of the terminals of DPNVGLUT2 inputs to the VTA contributes to opioid reward. These goals will be accomplished through the following specific aims: in aim 1, i will use barcoded anatomy resolved by sequencing (barseq) in combination with the xenium-5K spatial transcriptomics platform to generate connectomic and transcriptional profiles of DPNVGLUT2ÀVTA neurons with single-cell resolution. In aim 2, i will use patch-SEQ, which combines patch-clamp whole cell electrophysiological recordings with single-cell transcriptional profiling, to define the transcriptional identity of postsynaptic VTA neurons targeted by DPNVGLUT2 inputs. In aim 3, i will use an intersectional genetics approach and mouse behavioral assays to determine the role of the DPNVGLUT2ÀVTA circuit in opioid reward. This highly innovative and multidisciplinary program of research promises to deliver new insights into the neurobiological circuits regulating opioid reward. Importantly, the proposed project supported by the icahn school of medicine at mount sinai will provide an excellent training opportunity, spanning multiple disciplines in neurobiological research methods, that will facilitate professional development, mentorship, and technical repertoire expansion to facilitate my career progression to an independent academic research scientist.