PREreviews of A neuropeptide-specific signaling pathway for state-dependent regulation of the mesolimbic dopamine system | PREreview

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A neuropeptide-specific signaling pathway for state-dependent regulation of the mesolimbic dopamine system

by Mollie X. Bernstein, Omar Koita, Marta Trzeciak, Andrew Fan, Daniel T. McAuley, Seung-Woo Jin, and Larry S. Zweifel

Posted: July 22, 2025
Server: bioRxiv
DOI: 10.1101/2025.07.17.665396

Abstract

Dopamine (DA)-producing neurons of the ventral tegmental area (VTA) regulate consummatory behavior in a state-dependent manner (e.g. when hungry or thirsty). The mechanisms by which and extent to which DA neurons are regulated by these interoceptive signals are poorly understood. Here, we identify transient receptor potential canonical type 6 (TRPC6) channels as selective mediators of neuropeptide receptor-induced calcium signaling in VTA-DA neurons. These channels regulate DA neuron activity and consummatory behavior in a state-dependent manner. We find that TRPC6 channels regulate distinct aspects of neuropeptide-induced calcium signals in DA neurons but make little contribution to calcium dynamics associated with metabotropic neurotransmitter receptor signaling. We further show that TRPC6 channels regulate scalable reward valuation and consummatory behavior in hungry but not thirsty mice. These findings demonstrate that neuropeptide-and neurotransmitter-activated G-protein coupled receptors (GPCRs) regulate cellular calcium dynamics through distinct mechanisms, and that TRPC6 channels are important determinants of how animals respond to different homeostatic demands.

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PREreview by Theresa Haunold et al. of HHMI Transparent and Accountable Peer Review Training Program

Authored by Theresa Haunold and Yue Yu of HHMI Transparent and Accountable Peer Review Training Program

Bernstein et al. investigate the role of neuropeptide signaling in ventral tegmental dopamine neurons (VTA_DA), a population implicated in both natural and drug rewards. Using CRISPR-Cas9 mutagenesis in mice, they knock down transient receptor potential canonical type 6 (TRPC6) channels, which are…

Read the PREreview by Theresa Haunold et al. of HHMI Transparent and Accountable Peer Review Training Program
PREreview by Yue Yu et al. of HHMI Transparent and Accountable Peer Review Training Program

Authored by Yue Yu and 1 other author of HHMI Transparent and Accountable Peer Review Training Program

Review for “A neuropeptide-specific signaling pathway for state-dependent regulation of the mesolimbic dopamine system”

Yue Yu, Theresa Haunold
…
Read the PREreview by Yue Yu et al. of HHMI Transparent and Accountable Peer Review Training Program