Distinct serotonergic pathways to the amygdala underlie separate behavioral features of anxiety

Xiao-Dan Yu; Yi Zhu; Qi-Xin Sun; Fei Deng; Jinxia Wan; Di Zheng; Wankun Gong; Shi-Ze Xie; Chen-Jie Shen; Jia-Yu Fu; Huiqian Huang; Hsin-Yi Lai; Jin Jin; Yulong Li; Xiao-Ming Li

doi:10.1038/s41593-022-01200-8

Distinct serotonergic pathways to the amygdala underlie separate behavioral features of anxiety

Nat Neurosci. 2022 Dec;25(12):1651-1663. doi: 10.1038/s41593-022-01200-8. Epub 2022 Nov 29.

Authors

Xiao-Dan Yu^{1

2

3}, Yi Zhu^{1

2}, Qi-Xin Sun², Fei Deng⁴, Jinxia Wan⁴, Di Zheng², Wankun Gong⁵, Shi-Ze Xie², Chen-Jie Shen², Jia-Yu Fu², Huiqian Huang¹, Hsin-Yi Lai^{1

3

6

7}, Jin Jin⁸, Yulong Li⁴, Xiao-Ming Li^{9

10

11}

Affiliations

¹ Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
³ Department of Neurology of the Second Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
⁴ State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China.
⁵ Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ College of Biomedical Engineering and Instrument Science, Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, China.
⁷ Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁸ The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
⁹ Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. lixm@zju.edu.cn.
¹⁰ NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China. lixm@zju.edu.cn.
¹¹ Center for Brain Science and Brain-Inspired Intelligence, Research Units for Emotion and Emotion Disorders, Chinese Academy of Medical Sciences/Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China. lixm@zju.edu.cn.

PMID: 36446933
DOI: 10.1038/s41593-022-01200-8

Abstract

Anxiety-like behaviors in mice include social avoidance and avoidance of bright spaces. Whether these features are distinctly regulated is unclear. We demonstrate that in mice, social and anxiogenic stimuli, respectively, increase and decrease serotonin (5-HT) levels in basal amygdala (BA). In dorsal raphe nucleus (DRN), 5-HT∩vGluT3 neurons projecting to BA parvalbumin (DRN^{5-HT∩vGluT3}-BA^PV) and pyramidal (DRN^{5-HT∩vGluT3}-BA^Pyr) neurons have distinct intrinsic properties and gene expression and respond to anxiogenic and social stimuli, respectively. Activation of DRN^{5-HT∩vGluT3}→BA^PV inhibits 5-HT release via GABA_B receptors on serotonergic terminals in BA, inducing social avoidance and avoidance of bright spaces. Activation of DRN^{5-HT∩vGluT3}→BA neurons inhibits two subsets of BA^Pyr neurons via 5-HT1A receptors (HTR1A) and 5-HT1B receptors (HTR1B). Pharmacological inhibition of HTR1A and HTR1B in BA induces avoidance of bright spaces and social avoidance, respectively. These findings highlight the functional significance of heterogenic inputs from DRN to BA subpopulations in the regulation of separate anxiety-related behaviors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amygdala
Animals
Anxiety
Anxiety Disorders*
Basolateral Nuclear Complex*
Mice
Receptors, GABA-B
Serotonin*

Substances

Receptors, GABA-B
Serotonin