A nigroincertal projection mediates aversion and enhances coping responses to potential threat

Abstract

Recent studies have shown that the non‐DA neurons in the ventral tegmental area (VTA) and substantia nigra (SN) not only modulate motivational behaviors but also regulate defensive behaviors. While zona incerta (ZI) is a threat‐responsive substrate and receives innervations from the ventral midbrain, the function of the ventral midbrain‐to‐ZI connection remains poorly defined. Here, we demonstrate that the ZI receives heterogenous innervations from the ventral midbrain. By utilizing a retrograde AAV preferentially labeling non‐DA neurons in the ventral midbrain, we found that ZI‐projecting non‐DA cells in the ventral midbrain are activated by restraint stress. We focused on the SN and found that SN‐to‐ZI GABAergic input is engaged by a predatory odor. Sustained pan‐neuronal SN‐to‐ZI activation results in aversion and enhances defensive behaviors, likely through a disinhibition mechanism to recruit downstream brain regions that regulate defensive behaviors. Collectively, our results reveal a novel role of nigroincertal projection in mediating negative valence and regulating defensive behaviors.