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Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

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  • Yan Yang

    (Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang University
    Mental Health Center, School of Medicine, Zhejiang University)

  • Yihui Cui

    (Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang University
    Mental Health Center, School of Medicine, Zhejiang University)

  • Kangning Sang

    (Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang University
    Mental Health Center, School of Medicine, Zhejiang University)

  • Yiyan Dong

    (Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang University)

  • Zheyi Ni

    (Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang University)

  • Shuangshuang Ma

    (Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang University)

  • Hailan Hu

    (Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang University
    Mental Health Center, School of Medicine, Zhejiang University)

Abstract

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the ‘anti-reward center’, the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.

Suggested Citation

  • Yan Yang & Yihui Cui & Kangning Sang & Yiyan Dong & Zheyi Ni & Shuangshuang Ma & Hailan Hu, 2018. "Ketamine blocks bursting in the lateral habenula to rapidly relieve depression," Nature, Nature, vol. 554(7692), pages 317-322, February.
    • Handle: RePEc:nat:nature:v:554:y:2018:i:7692:d:10.1038_nature25509
    DOI: 10.1038/nature25509
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    Cited by:

    1. Francis Kei Masuda & Emily A. Aery Jones & Yanjun Sun & Lisa M. Giocomo, 2023. "Ketamine evoked disruption of entorhinal and hippocampal spatial maps," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Soo Hyun Yang & Esther Yang & Jaekwang Lee & Jin Yong Kim & Hyeijung Yoo & Hyung Sun Park & Jin Taek Jung & Dongmin Lee & Sungkun Chun & Yong Sang Jo & Gyeong Hee Pyeon & Jae-Yong Park & Hyun Woo Lee , 2023. "Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Jing Huang & Weijun Huang & Junzhe Yi & Yiwen Deng & Ruijie Li & Jieying Chen & Jiahao Shi & Yuan Qiu & Tao Wang & Xiaoyong Chen & Xiaoran Zhang & Andy Peng Xiang, 2023. "Mesenchymal stromal cells alleviate depressive and anxiety-like behaviors via a lung vagal-to-brain axis in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Yan Zhang & Jiayi Shen & Famin Xie & Zhiwei Liu & Fangfang Yin & Mingxiu Cheng & Liang Wang & Meiting Cai & Herbert Herzog & Ping Wu & Zhi Zhang & Cheng Zhan & Tiemin Liu, 2024. "Feedforward inhibition of stress by brainstem neuropeptide Y neurons," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. Radhika Rawat & Elif Tunc-Ozcan & Tammy L. McGuire & Chian-Yu Peng & John A. Kessler, 2022. "Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Can Tao & Guang-Wei Zhang & Wen-Jian Sun & Junxiang J. Huang & Li I. Zhang & Huizhong Whit Tao, 2024. "Excitation-inhibition imbalance in medial preoptic area circuits underlies chronic stress-induced depression-like states," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Wang, Xianjun & Gu, Huaguang & Jia, Yanbing, 2023. "Nonlinear mechanism for enhanced and reduced bursting activity respectively induced by fast and slow excitatory autapse," Chaos, Solitons & Fractals, Elsevier, vol. 166(C).
    8. Shannon Trombley & Jackson Powell & Pavithran Guttipatti & Andrew Matamoros & Xiaohui Lin & Tristan O’Harrow & Tobias Steinschaden & Leann Miles & Qin Wang & Shuchao Wang & Jingyun Qiu & Qingyang Li &, 2023. "Glia instruct axon regeneration via a ternary modulation of neuronal calcium channels in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Jeroen P. H. Verharen & Johannes W. Jong & Yichen Zhu & Stephan Lammel, 2023. "A computational analysis of mouse behavior in the sucrose preference test," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Muran Wang & Peijun Li & Zewen Li & Beatriz S. Silva & Wu Zheng & Zhenghua Xiang & Yan He & Tao Xu & Cristina Cordeiro & Lu Deng & Yuwei Dai & Mengqian Ye & Zhiqing Lin & Jianhong Zhou & Xuzhao Zhou &, 2023. "Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    11. Zhang, Xu & Min, Fuhong & Dou, Yiping & Xu, Yeyin, 2023. "Bifurcation analysis of a modified FitzHugh-Nagumo neuron with electric field," Chaos, Solitons & Fractals, Elsevier, vol. 170(C).

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