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NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA

Song Nan, Gao Yan, Lu Shanshan, Yang Shenglian, Yuan Chao, Sun Wenyu
doi: https://doi.org/10.1101/2021.12.01.470503
Song Nan
1Center of Cognition and Brain Science, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
2Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
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  • For correspondence: songnan@ibms.pumc.edu.cn
Gao Yan
1Center of Cognition and Brain Science, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
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Lu Shanshan
1Center of Cognition and Brain Science, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
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Yang Shenglian
1Center of Cognition and Brain Science, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
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Yuan Chao
1Center of Cognition and Brain Science, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
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Sun Wenyu
2Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
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Abstract

Major depressive disorder (MDD) is characterized by diverse debilitating symptoms that include loss of motivation and anhedonia. If multiple medications, psychotherapy, and electroconvulsive therapy fail in some patients with MDD, their condition is then termed treatment – resistant depression (TRD). MDD can be associated with abnormalities in the reward–system–dopaminergic mesolimbic pathway, in which the nucleus accumbens (NAc) and ventral tegmental area (VTA) play major roles. Deep brain stimulation (DBS) applied to the NAc alleviates the depressive symptoms of MDD. However, the mechanism underlying the effects of this DBS has remained elusive. In this study, using the chronic unpredictable mild stress (CUMS) mouse model, we investigated the behavioral and neurobiological effects of NAc – DBS on the multidimensional depression – like phenotypes induced by CUMS by integrating behavioral, in vivo microdialysis coupled with high-performance liquid chromatography – electrochemical detector (HPLC – ECD), calcium imaging, pharmacological, and genetic manipulation methods in freely moving mice. We found that long–term and repeated, but not single, NAc–DBS induced robust antidepressant responses in CUMS mice. Moreover, even a single trial NAc–DBS led to the elevation of the γ–aminobutyric acid (GABA) neurotransmitter, accompanied by the increase in dopamine (DA) neuron activity in the VTA. Both the inhibition of the GABAA receptor activity and knockdown of the GABAA–α1 gene in VTA–GABA neurons blocked the antidepressant effect of NAc–DBS in CUMS mice. Our results showed that NAc– DBS could disinhibit VTA–DA neurons by regulating the level of GABA and the activity of VTA–GABA in the VTA and could finally correct the depression–like behaviors in the CUMS mouse model.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 02, 2021.
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NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA
Song Nan, Gao Yan, Lu Shanshan, Yang Shenglian, Yuan Chao, Sun Wenyu
bioRxiv 2021.12.01.470503; doi: https://doi.org/10.1101/2021.12.01.470503
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NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA
Song Nan, Gao Yan, Lu Shanshan, Yang Shenglian, Yuan Chao, Sun Wenyu
bioRxiv 2021.12.01.470503; doi: https://doi.org/10.1101/2021.12.01.470503

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