Increased excitatory amino acid transporter 2 levels in basolateral amygdala astrocytes mediate chronic stress–induced anxiety-like behaviorOA
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 2agonists 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.
Xirong Xu;Shoumin Xuan;Shuai Chen;Dan Liu;Qian Xiao;Jie Tu;
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 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 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 University of Chinese of Academy of Sciences,Beijing,ChinaCAS 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 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,ChinaCAS 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 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 University of Chinese of Academy of Sciences,Beijing,ChinaShenzhen 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 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 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,ChinaShenzhen 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 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 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 University of Chinese of Academy of Sciences,Beijing,China Faculty of Life and Health Sciences,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,Guangdong Province,China
化学
anxietyastrocytesbasolateral amygdalabehaviordihydrokainic acidexcitatory amino acid transporter 2fiber photometryglutamateLDN-212320transporter
《Neural Regeneration Research》 2025 (006)
P.1721-1734 / 14
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);the China Postdoctoral Science Foundation,No.2021M693298 (to QX)。
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