Dynorphin counteracts excitatory co-transmission in a lateral hypothalamus–locus coeruleus circuit underlying stress-induced anxiety

Anxiety disorders are highly prevalent, yet the circuit mechanisms linking stress to pathological anxiety remain incompletely understood. The locus coeruleus (LC), the brain’s primary noradrenaline source, receives dense innervation from the lateral hypothalamus (LH). Here, we investigate the LH prodynorphin→LC noradrenergic (LHdyn→LCNA) pathway in stress-induced anxiety.

We find that restraint stress activates LHdyn neurons, which form monosynaptic connections onto LCNA neurons. In male mice, chemogenetic activation of this pathway promotes anxiety-like behavior—an effect attenuated by intra-LC orexin receptor blockade but exacerbated by kappa opioid receptor antagonism, indicating that co-released dynorphin acts as an intrinsic anxiolytic brake. Conversely, chemogenetic inhibition is anxiogenic in naïve male mice yet anxiolytic after chronic restraint stress.

Using genetically encoded sensors, we show that dynorphin and glutamate are co-released in the LC, and that elevating dynorphin tone suppresses LCNA hyperactivity and reduces anxiety. These findings reveal a push–pull mechanism wherein excitatory transmission is intrinsically balanced by co-released dynorphin, offering a framework for understanding stress-related psychopathology. We thank Professor Cheng Xiao and Professor Hongxing Zhang for their help with experiments, and the Public Experimental Research Center of Xuzhou Medical University for technical services.

This work was supported by grants from the National Natural Science Foundation of China (82571724, 81901369 to M.-J.J.; 32271010 to C.L.), the Jiangsu Province Specially-Appointed Professor Fund (to C.L.), the Starting Grant for Excellent Talents at Xuzhou Medical University (to M.-J.J and C.L), and the Innovative Youth Team Project at Xuzhou Medical University (TD202203 to M.-J.J.). These authors contributed equally: Yin-Yin Yang, Huanyao Tang, Ke-Xue Li. Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, School of Anesthesiology, Xuzhou Medical University, Xuzhou, China Yin-Yin Yang, Huanyao Tang, Xiang Cao, Yu-Tong Cheng, Chenhao Tian, Chao Liu & Miao-Jin Ji Department of Anesthesiology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China Department of Physiology, School of Basic Medical Science, Xuzhou Medical University, Xuzhou, China Correspondence to Chao Liu or Miao-Jin Ji.

The authors declare no competing interests. During the preparation of this work, the authors used ChatGPT and DeepSeek in order to improve language and readability. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.