[{"fulldoi":"https://doi.org/10.1073/pnas.2536560123","project":[{"grant_number":"PAT 5720324","_id":"92503f6e-16d5-11f0-9cad-8c571927f3b7","name":"New regime of presynaptic release regulation"},{"grant_number":"665385","name":"International IST Doctoral Program","call_identifier":"H2020","_id":"2564DBCA-B435-11E9-9278-68D0E5697425"}],"year":"2026","supplementarymaterial":"yes","issue":"36","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_type":"original","acknowledged_ssus":[{"_id":"M-Shop"},{"_id":"PreCl"}],"dataavailabilitystatement":"All numerical data regarding electrophysiological recordings, calcium imaging, image analysis and behavioral tracking included in the article and/or SI Appendix have been deposited and are publicly available at ISTA REx (https://doi.org/10.15479/AT-ISTA-22704).","type":"journal_article","related_material":{"record":[{"id":"22704","relation":"research_data","status":"public"}]},"month":"09","publication":"Proceedings of the National Academy of Sciences of the United States of America","OA_place":"publisher","external_id":{"pmid":["42673459"]},"oa":1,"article_processing_charge":"Yes (in subscription journal)","publisher":"National Academy of Sciences","corr_author":"1","acknowledgement":"We thank Bernhard Bettler for GABAB1 floxed mice. This project has received funding from the Austrian Science Fund (10.55776/PAT5720324) to R.S., and the Marie Skłodowska-Curie Grant Agreement No. 665385 to C.Ö. We thank Todor Asenov from the ISTA machine shop for preparing the custom part and the ISTA preclinical facility for animal care. SI Appendix, Fig. S7 was created in BioRender under the following license [Onal, C.(2026) https://BioRender.com/wuyvshe]. For open access purposes, the author has applied a CC BY-NC-ND public copyright license to any author-accepted manuscript version arising from this submission.","has_accepted_license":"1","ddc":["570"],"day":"08","volume":123,"publication_identifier":{"eissn":["1091-6490"]},"scopus_import":"1","abstract":[{"text":"The medial habenula (MHb) is implicated in regulating emotional responses to aversive events. Studies in zebrafish have identified a remarkable morphological left–right 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 γ-aminobutyric acid type B receptor (GABABR)-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 GABABR 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 GABABR-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.","lang":"eng"}],"OA_type":"hybrid","keyword":["medial habenula","GABAB receptor","asymmetry","fear conditioning","mouse"],"file":[{"file_name":"2026_PNAS_Oenal.pdf","access_level":"open_access","file_id":"22936","content_type":"application/pdf","file_size":7496942,"date_updated":"2026-09-16T09:09:58Z","checksum":"8efe98c02ba79b9a3d76b7d6c1edbfbc","relation":"main_file","success":1,"date_created":"2026-09-16T09:09:58Z","creator":"dernst"}],"pmid":1,"author":[{"first_name":"Hüseyin C","id":"4659D740-F248-11E8-B48F-1D18A9856A87","last_name":"Önal","orcid":"0000-0002-2771-2011","full_name":"Önal, Hüseyin C"},{"full_name":"Koppensteiner, Peter","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","last_name":"Koppensteiner","orcid":"0000-0002-3509-1948","first_name":"Peter"},{"last_name":"Muhia","id":"ab7ed20f-09f7-11eb-909c-d5d0b443ee9d","first_name":"Mary W","full_name":"Muhia, Mary W"},{"full_name":"Le Monnier, Elodie","first_name":"Elodie","last_name":"Le Monnier","id":"3B59276A-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Shigemoto, Ryuichi","orcid":"0000-0001-8761-9444","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi"}],"publication_status":"published","date_published":"2026-09-08T00:00:00Z","file_date_updated":"2026-09-16T09:09:58Z","das_tickbox":"1","title":"Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula","doi":"10.1073/pnas.2536560123","language":[{"iso":"eng"}],"ec_funded":1,"oa_version":"Published Version","status":"public","department":[{"_id":"RySh"},{"_id":"PreCl"}],"citation":{"ieee":"C. Önal, P. Koppensteiner, M. W. Muhia, E. Le Monnier, and R. Shigemoto, “Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 123, no. 36. National Academy of Sciences, 2026.","mla":"Önal, Cihan, et al. “Asymmetrical Modulation of Fear Expression via GABAB Receptors in the Mouse Medial Habenula.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 123, no. 36, e2536560123, National Academy of Sciences, 2026, doi:<a href=\"https://doi.org/10.1073/pnas.2536560123\">10.1073/pnas.2536560123</a>.","ama":"Önal C, Koppensteiner P, Muhia MW, Le Monnier E, Shigemoto R. Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2026;123(36). doi:<a href=\"https://doi.org/10.1073/pnas.2536560123\">10.1073/pnas.2536560123</a>","ista":"Önal C, Koppensteiner P, Muhia MW, Le Monnier E, Shigemoto R. 2026. Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula. Proceedings of the National Academy of Sciences of the United States of America. 123(36), e2536560123.","short":"C. Önal, P. Koppensteiner, M.W. Muhia, E. Le Monnier, R. Shigemoto, Proceedings of the National Academy of Sciences of the United States of America 123 (2026).","chicago":"Önal, Cihan, Peter Koppensteiner, Mary W Muhia, Elodie Le Monnier, and Ryuichi Shigemoto. “Asymmetrical Modulation of Fear Expression via GABAB Receptors in the Mouse Medial Habenula.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2026. <a href=\"https://doi.org/10.1073/pnas.2536560123\">https://doi.org/10.1073/pnas.2536560123</a>.","apa":"Önal, C., Koppensteiner, P., Muhia, M. W., Le Monnier, E., &#38; Shigemoto, R. (2026). Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2536560123\">https://doi.org/10.1073/pnas.2536560123</a>"},"article_number":"e2536560123","quality_controlled":"1","date_updated":"2026-09-16T09:55:16Z","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","short":"CC BY-NC-ND (4.0)"},"_id":"22913","intvolume":"       123","researchdata_availability":"yes","date_created":"2026-09-13T22:01:52Z"},{"_id":"13173","tmp":{"short":"CC BY-NC (4.0)","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","image":"/images/cc_by_nc.png","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode"},"date_updated":"2026-10-21T08:33:44Z","day":"29","date_created":"2023-06-29T13:16:42Z","abstract":[{"text":"GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity-dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1-fold increase in readily releasable vesicle pool (RRP) size and a 3.5-fold increase of docked synaptic vesicles at the presynaptic active zone (AZ). Strikingly, tonic and phasic release exhibit distinct coupling distances and are selectively affected by deletion of synaptoporin (SPO) and Ca2+-dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short-term plasticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. Double pre-embedding immunolabeling confirmed the co-localization of CAPS2 and SPO inside the same terminal. The cytosolic protein CAPS2 showed a synaptic vesicle (SV)-associated distribution similar to the vesicular transmembrane protein SPO. A newly developed “Flash and Freeze-fracture” method revealed the release of SPO-associated vesicles in both tonic and phasic modes and activity-dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2-associated SVs, contributing to a persistent RRP increase. Thus, we discovered structural and molecular mechanisms underlying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals.","lang":"eng"}],"corr_author":"1","publisher":"Institute of Science and Technology Austria","ddc":["571"],"has_accepted_license":"1","status":"public","citation":{"ieee":"R. Shigemoto, “Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals.” Institute of Science and Technology Austria, 2023.","ama":"Shigemoto R. Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals. 2023. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:13173\">10.15479/AT:ISTA:13173</a>","ista":"Shigemoto R. 2023. Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:13173\">10.15479/AT:ISTA:13173</a>.","mla":"Shigemoto, Ryuichi. <i>Transition from Tonic to Phasic Neurotransmitter Release by Presynaptic GABAB Receptor Activation in Medial Habenula Terminals</i>. Institute of Science and Technology Austria, 2023, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:13173\">10.15479/AT:ISTA:13173</a>.","short":"R. Shigemoto, (2023).","chicago":"Shigemoto, Ryuichi. “Transition from Tonic to Phasic Neurotransmitter Release by Presynaptic GABAB Receptor Activation in Medial Habenula Terminals.” Institute of Science and Technology Austria, 2023. <a href=\"https://doi.org/10.15479/AT:ISTA:13173\">https://doi.org/10.15479/AT:ISTA:13173</a>.","apa":"Shigemoto, R. (2023). Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:13173\">https://doi.org/10.15479/AT:ISTA:13173</a>"},"article_processing_charge":"No","oa":1,"department":[{"_id":"RySh"}],"month":"07","related_material":{"record":[{"id":"15084","status":"public","relation":"used_in_publication"}]},"oa_version":"Published Version","type":"research_data","doi":"10.15479/AT:ISTA:13173","file_date_updated":"2024-02-06T07:21:43Z","title":"Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals","keyword":["medial habenula","GABAB receptor","vesicle release","Flash and Freeze","Flash and Freeze-fracture"],"author":[{"id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","orcid":"0000-0001-8761-9444","first_name":"Ryuichi","full_name":"Shigemoto, Ryuichi"}],"date_published":"2023-07-29T00:00:00Z","file":[{"file_name":"Raw data for Koppensteiner et al.zip","access_level":"closed","file_id":"13174","file_size":542873672,"content_type":"application/x-zip-compressed","relation":"main_file","description":"After review an updated version of the data is provided","date_updated":"2023-11-17T14:30:44Z","checksum":"ed59170869ba621f89f7c1894092192f","creator":"shigemot","title":"Outdated Version","date_created":"2023-06-29T13:11:22Z"},{"file_name":"11-17-23 Updated Koppensteiner et al. raw data.xlsx","access_level":"open_access","file_id":"14550","file_size":915079,"content_type":"application/vnd.openxmlformats-officedocument.spreadsheetml.sheet","date_updated":"2023-11-17T14:13:02Z","checksum":"c07860eb82b4d367245f1b589fe5c250","relation":"main_file","success":1,"date_created":"2023-11-17T14:13:02Z","creator":"patrickd"},{"file_id":"14942","access_level":"open_access","file_name":"EM_Images.zip","success":1,"date_created":"2024-02-06T07:21:43Z","creator":"dernst","date_updated":"2024-02-06T07:21:43Z","checksum":"abf84b1699edac4349dc3a92d466fb7b","relation":"main_file","file_size":544868924,"content_type":"application/x-zip-compressed"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","license":"https://creativecommons.org/licenses/by-nc/4.0/","year":"2023","fulldoi":"https://doi.org/10.15479/AT:ISTA:13173"}]