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  • The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons.

The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons.

Molecular psychiatry (2021-05-16)
Hongsheng Wang, Wanpeng Cui, Wenbing Chen, Fang Liu, Zhaoqi Dong, Guanglin Xing, Bin Luo, Nannan Gao, Wen-Jun Zou, Kai Zhao, Hongsheng Zhang, Xiao Ren, Zheng Yu, Heath L Robinson, Zhipeng Liu, Wen-Cheng Xiong, Lin Mei
ABSTRACT

Dopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Tyrosine Hydroxylase Antibody, clone LNC1, ascites fluid, clone LNC1, Chemicon®
Sigma-Aldrich
PP1 Analog II, 1NM-PP1, PP1 Analog II, CAS 221244-14-0, is a cell-permeable PP1 analog that acts as a potent, reversible, selective, ATP-competitive inhibitor of mutant over wild-type kinases.
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture