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

• Published in: Nature neuroscience 2022-12, Vol.25 (12), p.1651-1663
• Main Authors: Yu, Xiao-Dan, Zhu, Yi, Sun, Qi-Xin, Deng, Fei, Wan, Jinxia, Zheng, Di, Gong, Wankun, Xie, Shi-Ze, Shen, Chen-Jie, Fu, Jia-Yu, Huang, Huiqian, Lai, Hsin-Yi, Jin, Jin, Li, Yulong, Li, Xiao-Ming
• Format: Article
• Language: English
• Subjects: 631/378/1457; 631/378/3920; Amygdala; Animal Genetics and Genomics; Animals; Anxiety; Anxiety Disorders; Avoidance; Basolateral Nuclear Complex; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Dorsal raphe nucleus; Gene expression; Mice; Molecular modelling; Neurobiology; Neurons; Neurosciences; Parvalbumin; Pyramidal cells; Raphe nuclei; Receptors; Receptors, GABA-B; Serotonin; Serotonin S1 receptors; Social behavior; Stimuli; Subpopulations; γ-Aminobutyric acid B receptors
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-022-01200-8

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. Yu et al. show that at least two distinct serotonergic DRN-to-BA pathways are involved in different aspects of anxiety-related behaviors via different molecular mechanisms.