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  3. Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice

Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice

  • Neurosci Bull. 2021 Sep;37(9):1325-1338. doi: 10.1007/s12264-021-00731-7.
Xinyi Zhou  # 1 2,  Bifeng Wu  # 3,  Wenhao Liu  # 1 4,  Qian Xiao 1,  Wei He 5,  Ying Zhou 6,  Pengfei Wei 1 2,  Xu Zhang 7,  Yue Liu 2 8,  Jie Wang 2 8,  Jufang He 9 10,  Zhigang Zhang 1,  Weidong Li 7,  Liping Wang 1 2,  Jie Tu 11 12
Affiliations

Affiliations

  • 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 Science-Shenzhen 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.
  • 11 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 Science-Shenzhen Fundamental Research Institutions, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China. jie.tu@siat.ac.cn.
  • 12 University of Chinese of Academy of Sciences, Beijing, 100049, China. jie.tu@siat.ac.cn.
  • # Contributed equally.
PMID: 34143365 DOI: 10.1007/s12264-021-00731-7
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 three-chamber 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 wild-type (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 risk-avoidance 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; Nucleus accumbens; Parvalbumin; Risk avoidance.

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