ErbB4 knockdown in serotonergic neurons in the dorsal raphe induces anxiety-like behaviors

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Abstract

There is a close relationship between serotonergic (5-HT) activity and anxiety. ErbB4, a receptor tyrosine kinase, is expressed in 5-HT neurons. However, whether ErbB4 regulates 5-HT neuronal function and anxiety-related behaviors is unclear. Here, using transgenic and viral approaches, we show that mice with ErbB4 deficiency in 5-HT neurons exhibit heightened anxiety-like behavior and impaired fear extinction, possibly due to an increased excitability of 5-HT neurons in the dorsal raphe nucleus (DRN). Notably, the chemogenetic inhibition of 5-HT neurons in the DRN of ErbB4 mutant mice rescues anxiety-like behaviors. Altogether, our results unravel a previously unknown role of ErbB4 signaling in the regulation of DRN 5-HT neuronal function and anxiety-like behaviors, providing novel insights into the treatment of anxiety disorders.

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Fig. 1: Sert-Cre;ErbB4loxp/loxp mice show anxiety-like behaviors and fear extinction impairment.
Fig. 2: Specific interference of ErbB4 expression in DRN 5-HT neurons is sufficient to produce anxiety-like behaviors and fear extinction impairment.
Fig. 3: ErbB4 overexpression in the DRN rescues the behavioral phenotypes of Sert-Cre;ErbB4loxp/loxp mice.
Fig. 4: Increased excitability of DRN-5-HT neurons from Sert-Cre;ErbB4loxp/loxp and ErbB4 knockdown mice.
Fig. 5: Chemogenetic inhibition of 5-HT neurons in the DRN of Sert-Cre;ErbB4loxp/loxp mice can rescue heightened anxiety-like behaviors and impaired fear extinction.

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Acknowledgements

We thank Dr. Minmin Luo (National Institute of Biological Sciences, China) for providing the Sert-Cre mice. We also thank Dr. Lin Mei (Case Western Reserve University, USA) for providing the ErbB4::CreERT2;Rosa::LSL-tdTomato mice.

Funding and disclosure

This work was supported by grants from the National Natural Science Foundation of China (31430032, 31830033, 81671356), the Program for Changjiang Scholars and Innovative Research Team in University (IRT_16R37), the Science and Technology Program of Guangdong (2018B030334001) and Science and Technology Program of Guangzhou (201707020027). The authors declare no competing interests.

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Correspondence to Tian-Ming Gao.

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Zhang, S., Wu, J., Chen, H. et al. ErbB4 knockdown in serotonergic neurons in the dorsal raphe induces anxiety-like behaviors. Neuropsychopharmacol. (2020) doi:10.1038/s41386-020-0601-7

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