Learning to predict threat is essential, but equally important—yet often overlooked—is learning about the absence of threat. Here, by recording neural activity in two nucleus accumbens (NAc) glutamatergic afferents during aversive and neutral cues, we reveal sex-biased encoding of threat cue discrimination. In male mice, NAc afferents from the ventral hippocampus are preferentially activated by threat cues. In female mice, these ventral hippocampus–NAc projections are activated by both threat and nonthreat cues, whereas NAc afferents from medial prefrontal cortex are more strongly recruited by footshock and reliably discriminate threat from nonthreat. Chemogenetic pathway-specific inhibition identifies a double dissociation between ventral hippocampus–NAc and medial prefrontal cortex–NAc projections in cue-mediated suppression of reward-motivated behavior in male and female mice, despite similar synaptic connectivity. We suggest that these sex biases may reflect sex differences in behavioral strategies that may have relevance for understanding sex differences in risk of psychiatric disorders.

学会预测威胁是必不可少的，但同样重要但经常被忽视的是了解没有威胁。在这里，通过在厌恶和中性线索期间记录两个伏隔核 （NAc） 谷氨酸能传入神经的神经活动，我们揭示了威胁线索鉴别的性别偏向编码。在雄性小鼠中，来自腹侧海马体的 NAc 传入神经优先被威胁线索激活。在雌性小鼠中，这些腹侧海马-NAc 投射被威胁和非威胁线索激活，而来自内侧前额叶皮层的 NAc 传入神经更强烈地被足震募集，并可靠地区分威胁和非威胁。化学遗传学途径特异性抑制确定了腹侧海马-NAc 和内侧前额叶皮层-NAc 投射在线索介导的雄性和雌性小鼠对奖励动机行为的抑制中，尽管突触连接相似。我们认为这些性别偏倚可能反映了行为策略中的性别差异，这可能与理解精神疾病风险的性别差异有关。