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Research Articles, Neurobiology of Disease

Neuronal Nitric Oxide Synthase in Nucleus Accumbens Specifically Mediates Susceptibility to Social Defeat Stress through Cyclin-Dependent Kinase 5

Chun-Yu Yin, Shu-Ying Huang, Ling Gao, Yu-Hui Lin, Lei Chang, Hai-Yin Wu, Dong-Ya Zhu and Chun-Xia Luo
Journal of Neuroscience 17 March 2021, 41 (11) 2523-2539; DOI: https://doi.org/10.1523/JNEUROSCI.0422-20.2021
Chun-Yu Yin
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
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Shu-Ying Huang
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
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Ling Gao
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
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Yu-Hui Lin
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
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Lei Chang
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
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Hai-Yin Wu
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
2Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 211166, China
3Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, 510515, China
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Dong-Ya Zhu
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
2Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 211166, China
3Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, 510515, China
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Chun-Xia Luo
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
2Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 211166, China
3Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, 510515, China
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Abstract

Stress-induced depression is common worldwide. NAc, a “reward” center, is recently reported to be critical to confer the susceptibility to chronic social defeat stress (CSDS) and the depression-related outcome. However, the underlying molecular mechanisms have not been well characterized. In this study, we induced depression-like behaviors with CSDS and chronic mild stress in male mice to mimic social and environmental factors, respectively, and observed animal behaviors with social interaction test, tail suspension test, and sucrose preference test. To determine the role of neuronal nitric oxide synthase (nNOS) and its product nitric oxide (NO), we used brain region-specifically nNOS overexpression and stereotaxic injection of NO inhibitor or donor. Moreover, the downstream molecular cyclin-dependent kinase 5 (CDK5) was explored by conditional KO and gene mutation. We demonstrate that nNOS-implicated mechanisms in NAc shell (NAcSh), including increased cell number, increased protein expression levels, and increased specific enzyme activity, contribute the susceptibility to social defeat and the following depression-like behaviors. NAcSh nNOS does not directly respond to chronic mild stress but facilitates the depression-like behaviors. The increased NAcSh nNOS expression after CSDS leads to the social avoidance and depression-like behaviors in defeated mice, which is dependent on the nNOS enzyme activity and NO production. Moreover, we identify the downstream signal in NAcSh. S-nitrosylation of CDK5 by NO contributes to enhanced CDK5 activity, leading to depression-related behaviors in susceptible mice. Therefore, NAcSh nNOS mediates susceptibility to social defeat stress and the depression-like behaviors through CDK5.

SIGNIFICANCE STATEMENT Stress-induced depression is common worldwide, and chronic exposure to social and psychological stressors is important cause of human depression. Our study conducted with chronic social defeat stress mice models demonstrates that nNOS in NAcSh is crucial to regulate the susceptibility to social defeat stress and the following depression-like behaviors, indicating NAcSh nNOS as the responding molecule to social factors of depression. Moreover, we discover the downstream mechanism of NAcSh nNOS in mediating the susceptibility is NO and S-nitrosylation of CDK5. Thus, NAcSh nNOS mediates susceptibility to social defeat stress through CDK5 is a potential mechanism for depression, which may interpret how the brain transduces social stress exposure into depression.

  • CDK5
  • depression
  • NAc
  • nNOS
  • social defeat

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The Journal of Neuroscience: 41 (11)
Journal of Neuroscience
Vol. 41, Issue 11
17 Mar 2021
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Neuronal Nitric Oxide Synthase in Nucleus Accumbens Specifically Mediates Susceptibility to Social Defeat Stress through Cyclin-Dependent Kinase 5
Chun-Yu Yin, Shu-Ying Huang, Ling Gao, Yu-Hui Lin, Lei Chang, Hai-Yin Wu, Dong-Ya Zhu, Chun-Xia Luo
Journal of Neuroscience 17 March 2021, 41 (11) 2523-2539; DOI: 10.1523/JNEUROSCI.0422-20.2021

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Neuronal Nitric Oxide Synthase in Nucleus Accumbens Specifically Mediates Susceptibility to Social Defeat Stress through Cyclin-Dependent Kinase 5
Chun-Yu Yin, Shu-Ying Huang, Ling Gao, Yu-Hui Lin, Lei Chang, Hai-Yin Wu, Dong-Ya Zhu, Chun-Xia Luo
Journal of Neuroscience 17 March 2021, 41 (11) 2523-2539; DOI: 10.1523/JNEUROSCI.0422-20.2021
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Keywords

  • CDK5
  • depression
  • NAc
  • nNOS
  • social defeat

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