{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T19:16:41Z","timestamp":1788203801711,"version":"build-2803163510"},"reference-count":75,"publisher":"National Academy of Sciences","issue":"36","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:p>\n                    The medial habenula (MHb) is implicated in regulating emotional responses to aversive events. Studies in zebrafish have identified a remarkable morphological left\u2013right asymmetry in the dorsal habenula (zebrafish equivalent of mammalian MHb)-interpeduncular nucleus (IPN) pathway and its asymmetrical roles in behavior. However, there is little evidence for structural or functional lateralization in the mammalian MHb-IPN pathway. Here, we investigated the synaptic properties of left- and right-MHb afferents to the IPN and their roles in the expression of conditioned fear in mice. We found that each IPN neuron receives inputs from both left and right MHb, but the left MHb-originating synapses exhibit lower release probability and higher \u03b3-aminobutyric acid type B receptor (GABA\n                    <jats:sub>B<\/jats:sub>\n                    R)-mediated potentiation compared to the right MHb-originating synapses. Interestingly, these asymmetrical properties persist in the inversus visceral mutant mice with normal internal organ laterality (situs solitus), but nearly disappear in those with reversed internal organ laterality (situs inversus). Behaviorally, chemogenetic inhibition of cholinergic neurons and conditional deletion of GABA\n                    <jats:sub>B<\/jats:sub>\n                    R in the left, but not the right, MHb significantly attenuated cue-dependent fear recall. Our results demonstrate functional asymmetry of the MHb under partial influence of the nodal flow in mice, revealing a predominant role of GABA\n                    <jats:sub>B<\/jats:sub>\n                    R-mediated signaling in the left MHb-IPN pathway in modulating fear memories. These findings suggest that lateralized MHb pathways could represent a fundamental principle in the neural regulation of emotion across species but that they develop differently in zebrafish and mice.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2536560123","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T19:03:24Z","timestamp":1788203004000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Asymmetrical modulation of fear expression via GABA\n                    <sub>B<\/sub>\n                    receptors in the mouse medial habenula"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2771-2011","authenticated-orcid":false,"given":"Cihan","family":"\u00d6nal","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gnh5541","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Science and Technology Austria","place":["Klosterneuburg, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3509-1948","authenticated-orcid":false,"given":"Peter","family":"Koppensteiner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gnh5541","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Science and Technology Austria","place":["Klosterneuburg, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3463-512X","authenticated-orcid":false,"given":"Mary","family":"Muhia","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gnh5541","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Science and Technology Austria","place":["Klosterneuburg, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2539-4373","authenticated-orcid":false,"given":"Elodie","family":"Le Monnier","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gnh5541","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Science and Technology Austria","place":["Klosterneuburg, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8761-9444","authenticated-orcid":false,"given":"Ryuichi","family":"Shigemoto","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gnh5541","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Science and Technology Austria","place":["Klosterneuburg, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.23.1.155"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1535"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1944"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3339"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30381-6"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.24.1.897"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-23-08410.2003"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1364.007"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2654"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2866"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.20913"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313103110"},{"key":"e_1_3_4_13_2","first-page":"931","article-title":"The medial habenula: Still neglected","volume":"7","author":"Viswanath H.","year":"2013","unstructured":"H. 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Le Monnier C. \u00d6nal Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula. ISTA REx 2026. https:\/\/doi.org\/10.15479\/AT-ISTA-22704. Deposited 13 August 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2536560123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T19:04:07Z","timestamp":1788203047000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2536560123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":75,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2026,9,8]]}},"alternative-id":["10.1073\/pnas.2536560123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2536560123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]},"assertion":[{"value":"2025-12-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2536560123"}}