Summary The synthetic opioid fentanyl is a major contributor to the current opioid addiction crisis. We report that claustral neurons projecting to the frontal cortex limit oral fentanyl self-administration in mice. We found that fentanyl transcriptionally activates frontal-projecting claustrum neurons. These neurons also exhibit a unique suppression of Ca 2+ activity upon initiation of bouts of fentanyl consumption. Optogenetic stimulation of frontal-projecting claustral neurons, intervening in this suppression, decreased bouts of fentanyl consumption. In contrast, constitutive inhibition of frontal-projecting claustral neurons in the context of a novel, group-housed self-administration procedure increased fentanyl bout consumption. This same manipulation also sensitized conditioned-place preference for fentanyl and enhanced the representation of fentanyl experience in the frontal cortex. Together, our results indicate that claustrum neurons exert inhibitory control over frontal cortical neurons to restrict oral fentanyl intake. Upregulation of activity in the claustro-frontal projection may be a promising strategy for reducing human opioid addiction. Graphical abstract Highlights • Claustrum neurons are transiently repressed during bouts of fentanyl consumption • Fentanyl bout consumption is limited by optogenetic activity of claustrum neurons • Suppressing claustro-frontal projections increases fentanyl seeking and consumption • Fentanyl drives enhanced activity of frontal neurons following claustrum suppression Terem and Fatal et al. study the claustrum’s impact on opioid consumption. They discover that transient reductions in the activity of claustral neurons projecting to the frontal cortex are necessary for fentanyl bout consumption. Inhibition of these neurons disinhibits the frontal cortex and leads to prolonged consumption bouts of fentanyl.
【저자키워드】 opioids, transcriptomics, fentanyl, photometry, Self-administration, orbitofrontal cortex, Claustrum, Optogenetics, anterior cingulate cortex, conditioned-place preference, constitutive silencing, home-cage behavior, neuropixels,