Neuron-astrocyte coupling in lateral habenula mediates depressive-like behaviors

The lateral habenula (LHb) neurons and astrocytes have been strongly implicated in depression etiology, but it was not clear how the two dynamically interact during depression onset. Here, using multi-brain-region calcium photometry recording in freely moving mice, we discover that stress induces a most rapid astrocytic calcium rise and a bimodal neuronal response in the LHb. LHb astrocytic calcium requires the α_1A-adrenergic receptor and depends on a recurrent neural network between the LHb and locus coeruleus (LC). Through the gliotransmitter glutamate and ATP/adenosine, LHb astrocytes mediate the second-wave LHb neuronal activation and norepinephrine (NE) release. Activation or inhibition of LHb astrocytic calcium signaling facilitates or prevents stress-induced depressive-like behaviors, respectively. These results identify a stress-induced positive feedback loop in the LHb-LC axis, with astrocytes being a critical signaling relay. The identification of this prominent neuron-glia interaction may shed light on stress management and depression prevention.