---
OA_place: publisher
OA_type: hybrid
_id: '22913'
abstract:
- lang: eng
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.
acknowledged_ssus:
- _id: M-Shop
- _id: PreCl
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.
article_number: e2536560123
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Hüseyin C
full_name: Önal, Hüseyin C
id: 4659D740-F248-11E8-B48F-1D18A9856A87
last_name: Önal
orcid: 0000-0002-2771-2011
- first_name: Peter
full_name: Koppensteiner, Peter
id: 3B8B25A8-F248-11E8-B48F-1D18A9856A87
last_name: Koppensteiner
orcid: 0000-0002-3509-1948
- first_name: Mary W
full_name: Muhia, Mary W
id: ab7ed20f-09f7-11eb-909c-d5d0b443ee9d
last_name: Muhia
- first_name: Elodie
full_name: Le Monnier, Elodie
id: 3B59276A-F248-11E8-B48F-1D18A9856A87
last_name: Le Monnier
- first_name: Ryuichi
full_name: Shigemoto, Ryuichi
id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
last_name: Shigemoto
orcid: 0000-0001-8761-9444
citation:
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.
Proceedings of the National Academy of Sciences of the United States of America.
2026;123(36). doi:10.1073/pnas.2536560123
apa: Önal, C., Koppensteiner, P., Muhia, M. W., 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. National Academy of Sciences. https://doi.org/10.1073/pnas.2536560123
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.” Proceedings of the National Academy of Sciences
of the United States of America. National Academy of Sciences, 2026. https://doi.org/10.1073/pnas.2536560123.
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,”
Proceedings of the National Academy of Sciences of the United States of America,
vol. 123, no. 36. National Academy of Sciences, 2026.
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.
mla: Önal, Cihan, et al. “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, vol. 123, no. 36, e2536560123, National Academy
of Sciences, 2026, doi:10.1073/pnas.2536560123.
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).
corr_author: '1'
das_tickbox: '1'
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).
date_created: 2026-09-13T22:01:52Z
date_published: 2026-09-08T00:00:00Z
date_updated: 2026-09-16T09:55:16Z
day: '08'
ddc:
- '570'
department:
- _id: RySh
- _id: PreCl
doi: 10.1073/pnas.2536560123
ec_funded: 1
external_id:
pmid:
- '42673459'
file:
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checksum: 8efe98c02ba79b9a3d76b7d6c1edbfbc
content_type: application/pdf
creator: dernst
date_created: 2026-09-16T09:09:58Z
date_updated: 2026-09-16T09:09:58Z
file_id: '22936'
file_name: 2026_PNAS_Oenal.pdf
file_size: 7496942
relation: main_file
success: 1
file_date_updated: 2026-09-16T09:09:58Z
fulldoi: https://doi.org/10.1073/pnas.2536560123
has_accepted_license: '1'
intvolume: ' 123'
issue: '36'
keyword:
- medial habenula
- GABAB receptor
- asymmetry
- fear conditioning
- mouse
language:
- iso: eng
month: '09'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 92503f6e-16d5-11f0-9cad-8c571927f3b7
grant_number: PAT 5720324
name: New regime of presynaptic release regulation
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '665385'
name: International IST Doctoral Program
publication: Proceedings of the National Academy of Sciences of the United States
of America
publication_identifier:
eissn:
- 1091-6490
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
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record:
- id: '22704'
relation: research_data
status: public
researchdata_availability: yes
scopus_import: '1'
status: public
supplementarymaterial: yes
title: Asymmetrical modulation of fear expression via GABAB receptors in the mouse
medial habenula
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: journal_article
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volume: 123
year: '2026'
...