Sex-biased neural encoding of threat discrimination in nucleus accumbens afferents drives suppression of reward behavior

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. Muir et al. explore threat discrimination in male and female mice and find that, despite similar behavioral acquisition, there are surprising sex differences in the neural encoding that drives suppression of reward seeking under threat.