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Somatostatin neurons in the central amygdala mediate anxiety by disinhibition of the central sublenticular extended amygdala

Molecular Psychiatry volume 28, pages 4163–4174 (2023)Cite this article

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Abstract

Fear and anxiety are two defensive emotional states evoked by threats in the environment. Fear can be initiated by either imminent or future threats, but experimentally, it is typically studied as a phasic response initiated by imminent danger that subsides when the threats is removed. In contrast, anxiety is a sustained response, initiated by imagined or potential threats. The central amygdala (CeA) is a key structure active during both fear and anxiety but thought to engage different neural systems. Fear responses are triggered by activation of somatostatin (SOM) expressing neurons in the lateral division of the CeA (CeL), and downstream projections from the medial division. Anxiety responses engage the central extended amygdala that includes the CeA, central sublenticular extended amygdala (SLEAc) and bed nucleus of the stria terminalis, but the nature of connections between these regions is not understood. Here using a combination of tract tracing, electrophysiology, and behavioral analysis in mice, we show that a population of SOM+ neurons in the CeL project to the SLEAc where they inhibit local GABAergic interneurons. Optogenetic activation of this input to the SLEAc has no effect on movement, but is anxiogenic in both open field and elevated plus maze. Our results define the inhibitory connections between CeL and SLEAc and establish a specific CeL to SLEAc projection as a circuit element in mediating anxiety.

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Fig. 1: Somatostatin neurons in the CeL project to the SLEAc.
Fig. 2: CeL input to the SLEAc is disinhibitory.
Fig. 3: Somatostatin expressing neurons in the CeL project to GABAergic neurons in the SLEAc.
Fig. 4: Activation of CeL neurons projecting to the SLEAc is anxiogenic.
Fig. 5: Projection-specific excitation of CeL SOM+ afferents in the SLEAc is anxiogenic.

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Acknowledgements

We thank A. Woodruff for comments on our paper and the Sah Laboratory for feedback on the experiments. This work was funded by grants from the Australian National Health and Medical Research Council of Australia and the Australian Research Council. Imaging was performed at the Queensland Brain Institute’s Advanced Microscopy Facility.

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  1. These authors contributed equally: Yajie Sun, Lei Qian

Authors and Affiliations

  1. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia

    Yajie Sun, Lei Qian, Li Xu, Sarah Hunt & Pankaj Sah

  2. School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

    Lei Qian

  3. Brain Research Centre and Department of Biology, Southern University of Science and Technology, Nanshan District, Shenzhen, Guangdong Province, PR China

    Pankaj Sah

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Contributions

PS designed, supervised all of the experiments, and wrote paper. YS designed experiments, carried out most experiments, analyzed data, and wrote paper. SH did experiments and analyzed data. LX made virus for injections. LQ designed and did behavioral experiments, analyzed data, and wrote paper.

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Correspondence to Pankaj Sah.

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Sun, Y., Qian, L., Xu, L. et al. Somatostatin neurons in the central amygdala mediate anxiety by disinhibition of the central sublenticular extended amygdala. Mol Psychiatry 28, 4163–4174 (2023). https://doi.org/10.1038/s41380-020-00894-1

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