中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (6): 1721-1734.doi: 10.4103/NRR.NRR-D-23-01411

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

基底外侧杏仁核星形胶质细胞中兴奋性氨基酸转运体2水平上调可介导慢性应激诱导的焦虑样行为

  

  • 出版日期:2025-06-15 发布日期:2024-11-12

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

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:2025-06-15 Published:2024-11-12
  • Contact: Jie Tu, PhD, jie.tu@siat.ac.cn; Qian Xiao, PhD, qian.xiao@siat.ac.cn
  • Supported by:
    This study was supported 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); and the China Postdoctoral Science Foundation, No. 2021M693298 (to QX).

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摘要：

最近，实验证据对星形胶质细胞仅作为大脑内支持细胞的传统认知提出了挑战，这揭示了星形胶质细胞可积极参与调节大脑功能和编码与情绪相关的行为。具体而言，位于基底外侧杏仁核中的星形胶质细胞与调节慢性应激诱导的焦虑样行为有关，然而，基底外侧杏仁核中星形胶质细胞确切分子调节机制尚不清楚。此次实验发现，在由不可预测的慢性应激诱导的焦虑样小鼠模型中，可见基底外侧杏仁核中兴奋性氨基酸转运体2表达上调。值得注意的是，在基底外侧杏仁核星形胶质细胞内特异性敲低兴奋性氨基酸转运体2可减轻应激小鼠的焦虑样行为。有趣的是，通过颅内给予兴奋性氨基酸转运体2激动剂或过表达兴奋性氨基酸转运体2，可诱发小鼠焦虑样行为。进一步单核RNA测序结果也证实，慢性应激诱导基底外侧杏仁核星形胶质细胞中兴奋性氨基酸转运体2上调。此外在体钙信号记录可见，慢性应激小鼠基底外侧杏仁核脑区中的兴奋性神经元的钙活动比正常小鼠显著升高；而特异性敲低基底外侧杏仁核星形胶质细胞兴奋性氨基酸转运体2表达后，其钙活动并无明显升高，且焦虑样行为明显缓解。此外，在基底外侧杏仁核中施用兴奋性氨基酸转运体2抑制剂可显著降低应激小鼠的焦虑水平。上述表明，基底外侧杏仁核星形细胞兴奋性氨基酸转运体2可通过影响局部谷氨酸能神经元的活性参与调节慢性应激诱导的焦虑样行为，且靶向基底外侧杏仁核中的兴奋性氨基酸转运体2成为治疗焦虑的一种潜在策略。

https://orcid.org/0000-0002-1432-5784 (Jie Tu); https://orcid.org/0000-0002-3665-9590 (Qian Xiao)

关键词: 焦虑, 兴奋性氨基酸转运体2, 星形胶质细胞, 基底外侧杏仁核, 谷氨酸, 行为, LDN-212320, 转运体, 二氢红藻氨酸, 纤维光度法

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 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 basolateral amygdala 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, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2 agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice. After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders. 

Key words: anxiety, astrocytes, basolateral amygdala, behavior, dihydrokainic acid, excitatory amino acid transporter 2, fiber photometry, glutamate, LDN-212320, transporter