Du Jun, Diao Huapeng, Xu Yaling, Li Xia, Yuan Chao, Nie Lili, Zhang Hui, Li Jiani, Wang Yizheng
The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China.
National Clinical Research Center for Aging and Medicine, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Cell Rep. 2025 Jun 24;44(6):115824. doi: 10.1016/j.celrep.2025.115824. Epub 2025 Jun 11.
Stressors can induce anxiety and depression by altering dopaminergic neuronal activity in the ventral tegmental area (VTA). However, the precise modulation of dopaminergic neurons in response to stressors remains largely unclear. Here, we report that stress-responsive VTA astrocytes attenuate the inhibition of dopaminergic neurons and mitigate the progression of anxiety- and depression-like behaviors in adult mice. Stressors specifically elicit VTA astrocytic Ca elevation. Optogenetic VTA astrocyte activation disinhibits dopaminergic neurons via presynaptic adenosine A1 receptors on GABAergic interneurons, producing anxiolytic and antidepressant effects. Disruption of Ca signaling by downregulating astrocytic type 2 inositol 1,4,5-trisphosphate receptors (IPR2s) enhances inhibition of dopaminergic neurons. Mice with VTA astrocytic IPR2 knockdown or impaired release of astrocytic gliotransmitters exhibit anxiety-like phenotypes and increased vulnerability to chronic stresses that induce depression-like behaviors. Together, our results indicate a population of stress-responsive astrocytes in the VTA and highlight their roles in limiting the development of anxiety- and depression-like behaviors.
应激源可通过改变腹侧被盖区（VTA）中多巴胺能神经元的活性来诱发焦虑和抑郁。然而，多巴胺能神经元对应激源的确切调节作用在很大程度上仍不清楚。在此，我们报告应激反应性VTA星形胶质细胞可减弱对多巴胺能神经元的抑制，并减轻成年小鼠焦虑样和抑郁样行为的进展。应激源特异性地引发VTA星形胶质细胞的钙升高。光遗传学激活VTA星形胶质细胞可通过GABA能中间神经元上的突触前腺苷A1受体解除对多巴胺能神经元的抑制，产生抗焦虑和抗抑郁作用。通过下调星形胶质细胞2型肌醇1,4,5-三磷酸受体（IPR2）破坏钙信号，可增强对多巴胺能神经元的抑制。VTA星形胶质细胞IPR2基因敲低或星形胶质细胞神经递质释放受损的小鼠表现出焦虑样表型，并且对诱导抑郁样行为的慢性应激的易感性增加。总之，我们的结果表明VTA中存在一群应激反应性星形胶质细胞，并突出了它们在限制焦虑样和抑郁样行为发展中的作用。
