Astrocytic modulation of GABA transmission in the VTA limits progression of anxiety- and depression-like behaviors in adult mice

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 Ca²⁺ elevation. Optogenetic VTA astrocyte activation disinhibits dopaminergic neurons via presynaptic adenosine A1 receptors on GABAergic interneurons, producing anxiolytic and antidepressant effects. Disruption of Ca²⁺ signaling by downregulating astrocytic type 2 inositol 1,4,5-trisphosphate receptors (IP₃R2s) enhances inhibition of dopaminergic neurons. Mice with VTA astrocytic IP₃R2 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.