Hedgehog-interacting protein acts in the habenula to regulate nicotine intake

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dc.contributor.authorCaligiuri, Stephanie P. B.en
dc.contributor.authorHowe, William M.en
dc.contributor.authorWills, Laurenen
dc.contributor.authorSmith, Alexander C. W.en
dc.contributor.authorLei, Yeen
dc.contributor.authorBali, Purvaen
dc.contributor.authorHeyer, Mary P.en
dc.contributor.authorMoen, Janna K.en
dc.contributor.authorAbles, Jessica L.en
dc.contributor.authorElayouby, Karim S.en
dc.contributor.authorWilliams, Mayaen
dc.contributor.authorFillinger, Clementineen
dc.contributor.authorOketokoun, Zainaben
dc.contributor.authorLehmann, Vanessa E.en
dc.contributor.authorDiFeliceantonio, Alexandra G.en
dc.contributor.authorJohnson, Paul M.en
dc.contributor.authorBeaumont, Kristinen
dc.contributor.authorSebra, Robert P.en
dc.contributor.authorIbanez-Tallon, Inesen
dc.contributor.authorKenny, Paul J.en
dc.date.accessioned2024-02-06T17:59:29Zen
dc.date.available2024-02-06T17:59:29Zen
dc.date.issued2022-11-08en
dc.description.abstractHedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.en
dc.description.versionPublished versionen
dc.format.extent12 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN e2209870119 (Article number)en
dc.identifier.doihttps://doi.org/10.1073/pnas.2209870119en
dc.identifier.eissn1091-6490en
dc.identifier.issn0027-8424en
dc.identifier.issue46en
dc.identifier.orcidDiFeliceantonio, Alexandra [0000-0002-7155-6060]en
dc.identifier.pmid36346845en
dc.identifier.urihttps://hdl.handle.net/10919/117873en
dc.identifier.volume119en
dc.language.isoenen
dc.publisherNational Academy of Sciencesen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36346845en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectnicotineen
dc.subjecthabenulaen
dc.subjectsingle-cell RNA sequencingen
dc.subjecthedgehog signalingen
dc.subjectchronic obstructive pulmonary diseaseen
dc.subject.meshHabenulaen
dc.subject.meshAnimalsen
dc.subject.meshMiceen
dc.subject.meshLung Diseasesen
dc.subject.meshNicotineen
dc.subject.meshReceptors, Nicotinicen
dc.subject.meshHedgehog Proteinsen
dc.subject.meshCholinergic Neuronsen
dc.titleHedgehog-interacting protein acts in the habenula to regulate nicotine intakeen
dc.title.serialProceedings of the National Academy of Sciences of the United States of Americaen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen
pubs.organisational-group/Virginia Tech/Science/School of Neuroscienceen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTCen

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