Fear-related disorders (for example, phobias and anxiety) cause a substantial public health problem. To date, studies of the neural basis of fear have mostly focused on the amygdala. Here we identify a molecularly defined amygdala-independent tetra-synaptic pathway for olfaction-evoked innate fear and anxiety in male mice. This pathway starts with inputs from the olfactory bulb mitral and tufted cells to pyramidal neurons in the dorsal peduncular cortex that in turn connect to cholecystokinin-expressing (Cck⁺) neurons in the superior part of lateral parabrachial nucleus, which project to tachykinin 1-expressing (Tac1⁺) neurons in the parasubthalamic nucleus. Notably, the identified pathway is specifically involved in odor-driven innate fear. Selective activation of this pathway induces innate fear, while its inhibition suppresses odor-driven innate fear. In addition, the pathway is both necessary and sufficient for stress-induced anxiety-like behaviors. These findings reveal a forebrain-to-hindbrain neural substrate for sensory-triggered fear and anxiety that bypasses the amygdala.

与恐惧相关的疾病（例如恐惧症和焦虑症）会导致严重的公共健康问题。迄今为止，对恐惧的神经基础的研究主要集中在杏仁核上。在这里，我们确定了一种分子定义的不依赖杏仁核的四突触通路，用于雄性小鼠嗅觉诱发的先天恐惧和焦虑。该通路起始于嗅球二尖瓣和簇状细胞的输入，输入到背脚皮质中的锥体神经元，这些神经元又连接到臂旁核外侧核上部表达胆囊收缩素 ( Cck ⁺ ) 的神经元，该神经元投射到表达速激肽 1 的神经元。副丘脑核中的( Tac1 ⁺ ) 神经元。值得注意的是，所确定的途径特别涉及气味驱动的先天恐惧。该通路的选择性激活会引起先天恐惧，而其抑制则抑制气味驱动的先天恐惧。此外，该途径对于压力引起的焦虑样行为既是必要的也是充分的。这些发现揭示了绕过杏仁核的感觉触发恐惧和焦虑的前脑到后脑神经基质。