Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice
Xinyi Zhou1,2 • Bifeng Wu3 • Wenhao Liu1,4 • Qian Xiao1 • Wei He5 • Ying Zhou6 • Pengfei Wei1,2 • Xu Zhang7 • Yue Liu2,8 • Jie Wang2,8 • Jufang He9,10 • Zhigang Zhang1 • Weidong Li7 • Liping Wang1,2 • Jie Tu1,2
1 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, the Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain ScienceShenzhen Fundamental Research Institutions, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055 Shenzhen, China
2 University of Chinese of Academy of Sciences, Beijing 100049, China
3 Department of Information Technology and Electrical Engineering, Zurich Swiss Federal Institute of Technology Zurich, 8092 Zurich, Switzerland
4 Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong
5 Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
6 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta 30322, USA
7 Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai 200240, China
8 Center of Brain Science, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, National Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, 430071 Wuhan, China
9 Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
10 City University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China
Abstract
A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-NTM) mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze (EPM) and showed reduced social preference in a threechamber social interaction test. Following EPM tests, c-Fos expression levels indicated that the nucleus accumbens (NAc) was associated with risk-avoidance behavior in DISC1-NTM mice. In addition, in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons (FS) in the NAc were significantly lower in DISC1-NTM mice than in wildtype (WT) mice. In addition, in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV)neurons in the NAc of DISC1-NTM mice than in WT controls. The impairment of risk avoidance in DISC1-NTM mice was rescued using optogenetic tools that activated NAcPV neurons. Finally, inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the riskavoidance impairment found in DISC1-NTM mice during tests on the elevated zero maze. Taken together, our findings confirm an impairment in risk avoidance in DISC1-NTM mice and suggest that reduced excitability of NAcPV neurons is responsible.
Keywords
DISC1; Risk avoidance; Parvalbumin; Nucleus accumbens
