Yuanyuan Tian: Department of Psychiatry of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
Junqiang Zheng: Department of Psychiatry of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
Xiao Zhu: Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou 310027, China.
Xue Liu: Department of Psychiatry of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
Haoyang Li: Department of Psychiatry of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
Jun Wang: Department of Psychiatry of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
Qian Yang: Department of Psychiatry of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
Ling-Hui Zeng: Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China.
Zhiguo Shi: College of Information Science and Electronic Engineering, Zhejiang University, Hangzhou 310027, China.
Mengyuan Gong: Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou 310027, China.
Yuzheng Hu: Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou 310027, China.
Han Xu: Department of Psychiatry of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
The medial prefrontal cortex (mPFC) has been implicated in the pathophysiology of social impairments, including social fear. However, the precise subcortical partners that mediate mPFC dysfunction on social fear behaviour have not been identified. Using a social fear conditioning paradigm, we induced robust social fear in mice and found that the lateral habenula (LHb) neurons and LHb-projecting mPFC neurons are activated synchronously during social fear expression. Moreover, optogenetic inhibition of the mPFC-LHb projection significantly reduced social fear responses. Importantly, consistent with animal studies, we observed an elevated prefrontal-habenular functional connectivity in subclinical individuals with higher social anxiety characterized by heightened social fear. These results unravel a crucial role of the prefrontal-habenular circuitry in social fear regulation and suggest that this pathway could serve as a potential target for the treatment of social fear symptoms often observed in many psychiatric disorders.
