A self-limiting orexin-habenula circuit for stress resilience

Yang, S. H.; Yang, E.; Jung, J. T.; Lee, J.; Pyeon, G. H.; Jo, Y. S.; Park, H. S.; Moon, J. W.; Park, J.-Y.; Boo, K.-J.; Lee, D.; Chun, S.; Yoo, H.; Lee, H. W.; Kim, H.

doi:10.64898/2026.05.07.722567

bioRxiv · 10.64898/2026.05.07.722567

A self-limiting orexin-habenula circuit for stress resilience

Yang, S. H.·Yang, E.·Jung, J. T.·Lee, J.·Pyeon, G. H.·Jo, Y. S.·Park, H. S.·Moon, J. W.·Park, J.-Y.·Boo, K.-J.·Lee, D.·Chun, S.·Yoo, H.·Lee, H. W.·Kim, H.

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Abstract

Resilience requires neural systems that mobilise active coping during stress while limiting its persistence to preserve homeostasis under sustained challenge1-4. Here we identify a self-limiting orexin-habenula circuit in which lateral hypothalamic orexin neurons engage aromatic L-amino acid decarboxylase-expressing D-neurons (encoded by Ddc) in the lateral habenula via orexin receptor type 2 (OX2R)5-7. Activation of this pathway increased nucleus accumbens dopamine and promoted active coping and positive valence. Optotagging revealed rapid stress-evoked recruitment followed by post-stress suppression. In lateral habenula neurons, orexin peptides exerted dissociable effects: orexin-A engaged an OX2R-dependent inhibitory programme superimposed on a parallel inward current, whereas orexin-B did not reproduce this inhibitory profile and instead exerted a distinct membrane effect. Chronic stress disrupted this buffering system through coordinated inflammatory activation, promoter methylation and erosion of D-neuron identity and orexin responsiveness. Restoring orexin-A reversed behavioural and molecular deficits through OX2R-dependent suppression of nuclear factor kappa B signalling, preservation of Tet2 expression, and demethylation-linked maintenance of the Ddc programme. Together, these findings define a self-limiting orexin-habenula resilience circuit that enables adaptive coping while constraining stress-induced vulnerability.

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Yang, S. H., Yang, E., Jung, J. T., Lee, J., Pyeon, G. H., Jo, Y. S., Park, H. S., Moon, J. W., Park, J.-Y., Boo, K.-J., Lee, D., Chun, S., Yoo, H., Lee, H. W., Kim, H.. 2026-05-09. A self-limiting orexin-habenula circuit for stress resilience. https://doi.org/10.64898/2026.05.07.722567

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