中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (on line): 1-14.

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Increased excitatory amino acid transporter 2 levels in basolateral amygdala astrocytes mediate chronic stressinduced anxiety-like behavior

  

  • 出版日期:2024-01-01 发布日期:2024-03-23

Xirong Xu1, 2, 3, 4, Shoumin Xuan2, 3, Shuai Chen2, 3, 4, Dan Liu2, 3, Qian Xiao1, 2, 3, *, Jie Tu1, 2, 3, 4, 5, *
  

  1. 1 Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China; 2 CAS Key Laboratory of Brain Connectome and Manipulation, Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China; 3 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China; 4 University of Chinese of Academy of Sciences, Beijing, China; 5 Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China
  • Online:2024-01-01 Published:2024-03-23
  • Contact: Jie Tu, PhD, jie.tu@siat.ac.cn; Qian Xiao, PhD, qian.xiao@siat.ac.cn.
  • Supported by:
    This study was funded by the National Natural Science Foundation of China, Nos. 32371070 (to JT), 31761163005 (to JT), 32100824 (to QX), the Shenzhen Science and Technology Program, Nos. RCBS20210609104606024 (to QX), JCY20210324101813035 (to DL), the Guangdong Provincial Key S&T Program, No. 2018B030336001 (to JT), the Key Basic Research Program of Shenzhen Science and Technology Innovation Commission, Nos. JCYJ20200109115405930 (to JT), JCYJ20220818101615033 (to DL), JCYJ20210324115811031 (to QX), JCYJ20200109150717745 (to QX), Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases, No. ZDSYS20220304163558001 (to JT), Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, No. 2023B1212060055 (to JT), the China Postdoctoral Science Foundation, No. 2021M693298 (to QX).

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摘要：

Abstract: The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions. Specifically, astrocytes in the basolateral amygdala (BLA) have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which BLA astrocytes regulate chronic stress-induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress (UCMS), the expression of excitatory amino acid transporter 2 (EAAT2) was upregulated in the BLA. Interestingly, our findings indicate that the targeted knockdown of EAAT2 specifically within the BLA astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of EAAT2 in the BLA, whether achieved through intracranial administration of EAAT2 agonists or through injection of EAAT2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our singlenucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of EAAT2 specifically in astrocytes in the BLA. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the BLA of mice subjected to chronic stress was higher compared with normal mice. After knocking down the expression of EAAT2 in the BLA, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an EAAT2 inhibitor in the BLA yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that BLA astrocytic EAAT2 plays a role in in the regulation of UCMS-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting EAAT2 in the BLA holds therapeutic promise for addressing anxiety disorders.

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