A cell-type-specific circuit of somatostatin neurons in the habenula encodes antidepressant action in male mice.

Major depression is characterized by an array of negative experiences, including hopelessness and anhedonia. We hypothesize that inhibition of negative experiences or aversion may generate antidepressant action. To directly test this hypothesis, we perform multimodal behavioral screenings in male mice and identify somatostatin (SST)-expressing neurons in the region X (HBX) between the lateral and medial habenula as a specific type of antidepressant neuron. SST neuronal activity modulation dynamically regulates antidepressant induction and relief. We also explore the circuit basis for encoding these modulations using single-unit recordings. We find that SST neurons receive inhibitory synaptic inputs directly from cholecystokinin-expressing neurons in the bed nucleus of the stria terminalis and project excitatory axon terminals onto proenkephalin-expressing neurons in the interpeduncular nucleus. This study reveals a cell-type-specific circuit of SST neurons in the HBX that encodes antidepressant action, and the control of the circuit may contribute to improving well-being.