{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:54:28Z","timestamp":1782280468413,"version":"3.54.5"},"posted":{"date-parts":[[2025,4,9]]},"group-title":"Neuroscience","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Nociceptin\/orphanin FQ (N\/OFQ), an endogenous opioid neuropeptide, and its G-protein coupled receptor NOPR have been implicated in motivation, feeding behaviors, and aversion. Stress-induced dysfunction in these states is central to the development of numerous psychiatric disorders, and the N\/OFQ-NOPR system\u2019s role in reward- and stress-related responses has driven broad interest in NOPR as a therapeutic target for anxiety and depression. However, the impact of stress on N\/OFQ signaling in the context of its influence on discrete midbrain reward circuitry remains unknown. To this end, we focused on a possible candidate population of N\/OFQ neurons in the paranigral ventral tegmental area (pnVTA\n                  <jats:sup>PNOC<\/jats:sup>\n                  ) that have been shown to act locally on NOPR-containing VTA dopamine neurons to suppress motivation. Here we report and characterize pnVTA\n                  <jats:sup>PNOC<\/jats:sup>\n                  sensitivity to stress exposure and identify a functional excitatory and inhibitory afferent input to this subpopulation from the lateral hypothalamus (LH). Our results indicate that pnVTA\n                  <jats:sup>PNOC<\/jats:sup>\n                  neurons become recruited during exposure to a range of acute stressor types, whereas the GABAergic input from the LH to this population is suppressed by predator odor stress, providing a mechanism for disinhibition of these neurons. These findings suggest that this N\/OFQ population in the pnVTA could act as a critical bridge between stress and motivation through interactions with upstream hypothalamic circuitry.\n                <\/jats:p>","DOI":"10.1101\/2025.04.08.647881","type":"posted-content","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T04:45:21Z","timestamp":1744173921000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification of a stress-sensitive endogenous opioid-containing neuronal population in the paranigral ventral tegmental area"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8171-3464","authenticated-orcid":false,"given":"Carrie","family":"Stine","sequence":"first","affiliation":[{"name":"Center for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, WA, USA"},{"name":"Molecular and Cellular Biology, University of Washington School of Medicine, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Marcus","sequence":"additional","affiliation":[{"name":"Center for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0196-4827","authenticated-orcid":false,"given":"Amanda L.","family":"Pasqualini","sequence":"additional","affiliation":[{"name":"Center for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3573-2873","authenticated-orcid":false,"given":"Ananya S.","family":"Achanta","sequence":"additional","affiliation":[{"name":"Center for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph C.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Center for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjana","family":"Jadhav","sequence":"additional","affiliation":[{"name":"Center for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4713-7816","authenticated-orcid":false,"given":"Michael R.","family":"Bruchas","sequence":"additional","affiliation":[{"name":"Center for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041203341917000_2025.04.08.647881v1.1","doi-asserted-by":"publisher","DOI":"10.15288\/jsa.1995.56.538"},{"key":"2026041203341917000_2025.04.08.647881v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301574"},{"key":"2026041203341917000_2025.04.08.647881v1.3","doi-asserted-by":"publisher","DOI":"10.3109\/00952998609083739"},{"key":"2026041203341917000_2025.04.08.647881v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyu038"},{"key":"2026041203341917000_2025.04.08.647881v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.brat.2017.08.003"},{"key":"2026041203341917000_2025.04.08.647881v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2017.07.010"},{"key":"2026041203341917000_2025.04.08.647881v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2019.08.022"},{"key":"2026041203341917000_2025.04.08.647881v1.8","doi-asserted-by":"publisher","DOI":"10.1097\/YCO.0000000000000122"},{"key":"2026041203341917000_2025.04.08.647881v1.9","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2015_391"},{"key":"2026041203341917000_2025.04.08.647881v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2015.26"},{"key":"2026041203341917000_2025.04.08.647881v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2013.03.019"},{"key":"2026041203341917000_2025.04.08.647881v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03286.x"},{"key":"2026041203341917000_2025.04.08.647881v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2011.04.012"},{"key":"2026041203341917000_2025.04.08.647881v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(00)00188-3"},{"key":"2026041203341917000_2025.04.08.647881v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-024-02818-x"},{"key":"2026041203341917000_2025.04.08.647881v1.16","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2008.08081201"},{"key":"2026041203341917000_2025.04.08.647881v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpsc.2019.05.012"},{"key":"2026041203341917000_2025.04.08.647881v1.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0209361"},{"key":"2026041203341917000_2025.04.08.647881v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.coemr.2022.100388"},{"key":"2026041203341917000_2025.04.08.647881v1.20","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2019.00078"},{"key":"2026041203341917000_2025.04.08.647881v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2015.10.022"},{"key":"2026041203341917000_2025.04.08.647881v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2016.165"},{"key":"2026041203341917000_2025.04.08.647881v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2020.112986"},{"key":"2026041203341917000_2025.04.08.647881v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0203-4"},{"key":"2026041203341917000_2025.04.08.647881v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.034"},{"key":"2026041203341917000_2025.04.08.647881v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10154"},{"key":"2026041203341917000_2025.04.08.647881v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704806"},{"key":"2026041203341917000_2025.04.08.647881v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2021.170548"},{"key":"2026041203341917000_2025.04.08.647881v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.04.035"},{"key":"2026041203341917000_2025.04.08.647881v1.30","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2588-12.2013"},{"key":"2026041203341917000_2025.04.08.647881v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49712-0"},{"key":"2026041203341917000_2025.04.08.647881v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00898-2"},{"key":"2026041203341917000_2025.04.08.647881v1.33","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.86183"},{"key":"2026041203341917000_2025.04.08.647881v1.34","doi-asserted-by":"publisher","DOI":"10.1101\/2022.06.30.498327"},{"key":"2026041203341917000_2025.04.08.647881v1.35","doi-asserted-by":"publisher","DOI":"10.3791\/3769"},{"key":"2026041203341917000_2025.04.08.647881v1.36","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18247"},{"key":"2026041203341917000_2025.04.08.647881v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.12.024"},{"key":"2026041203341917000_2025.04.08.647881v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2013.151"},{"key":"2026041203341917000_2025.04.08.647881v1.39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232437"},{"key":"2026041203341917000_2025.04.08.647881v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.10.047"},{"key":"2026041203341917000_2025.04.08.647881v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0657-z"},{"key":"2026041203341917000_2025.04.08.647881v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.017"},{"key":"2026041203341917000_2025.04.08.647881v1.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0219522"},{"key":"2026041203341917000_2025.04.08.647881v1.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1909340117"},{"key":"2026041203341917000_2025.04.08.647881v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0369-5"},{"key":"2026041203341917000_2025.04.08.647881v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.11.005"},{"key":"2026041203341917000_2025.04.08.647881v1.47","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abc2590"},{"key":"2026041203341917000_2025.04.08.647881v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.10.011"},{"key":"2026041203341917000_2025.04.08.647881v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2018.01.001"},{"key":"2026041203341917000_2025.04.08.647881v1.50","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2018.00731"},{"key":"2026041203341917000_2025.04.08.647881v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.348"},{"issue":"12","key":"2026041203341917000_2025.04.08.647881v1.52","first-page":"727","article-title":"[Changes and significance of orphanin and serotonin in patients with postpartum depression]","volume":"38","year":"2003","journal-title":"Zhonghua Fu Chan Ke Za Zhi"},{"issue":"13","key":"2026041203341917000_2025.04.08.647881v1.53","first-page":"916","article-title":"[Plasma levels of nociceptin\/orphanin FQ in patients with bipolar disorders and health adults]","volume":"89","year":"2009","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"2026041203341917000_2025.04.08.647881v1.54","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-017-4676-8"},{"key":"2026041203341917000_2025.04.08.647881v1.55","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-017-4677-7"},{"key":"2026041203341917000_2025.04.08.647881v1.56","doi-asserted-by":"publisher","DOI":"10.1037\/0735-7044.110.4.727"},{"key":"2026041203341917000_2025.04.08.647881v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-022-01493-0"},{"key":"2026041203341917000_2025.04.08.647881v1.58","doi-asserted-by":"publisher","DOI":"10.1152\/jn.91111.2008"},{"key":"2026041203341917000_2025.04.08.647881v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.01.016"},{"key":"2026041203341917000_2025.04.08.647881v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/nature04071"},{"key":"2026041203341917000_2025.04.08.647881v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2013.07.008"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.04.08.647881","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:02:05Z","timestamp":1782277325000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.04.08.647881"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,9]]},"references-count":61,"URL":"https:\/\/doi.org\/10.1101\/2025.04.08.647881","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41386-025-02292-z","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,4,9]]},"subtype":"preprint"}}