Ho, Ping-ChenPing-ChenHoHsiao, Fu-YunFu-YunHsiaoChiu, Shi-HongShi-HongChiuLee, Syun-RueiSyun-RueiLeeHAU-JIE YAU2024-03-262024-03-262023-1208926638https://scholars.lib.ntu.edu.tw/handle/123456789/641371Recent 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.endefensive behavior; stress; substantia nigra; ventral tegmental area; zona increta[SDGs]SDG3journal article10.1096/fj.202201989RR379836622-s2.0-85177476854https://api.elsevier.com/content/abstract/scopus_id/85177476854