Cue-dependent safety and fear learning in a discriminative auditory fear conditioning paradigm in the mouse.

Discrimination between sensory stimuli associated with safety and threat is crucial for behavioral decisions. Discriminative conditioning paradigms with two acoustic conditioned stimuli (one paired with shock [CS+], the other unpaired with shock [CS-]) have been widely used as an experimental model for fear learning. However, no attention has been paid to the effect of the CS- on safety in the paradigms, because the CS- served as a neutral cue or elevated the freezing level due to fear generalization although less effectively than the CS+. By using a noise and a tone as two acoustic CSs in a discriminative auditory fear conditioning (AFC) paradigm, here we demonstrate that mice learn safety for the CS- while showing fear for the CS+ with opposing emotional behaviors. We found that after learning mice exhibited a significant suppression of context-dependent freezing during the CS-, but not during the CS+, indicating learned safety without fear generalization for the CS-. In contrast, the mice showed an enhanced level of freezing during the CS+ even in a novel spatial context, indicating cued fear for the CS+. Moreover, the CS+ also induced rapid defensive behaviors, whereas the CS- disinhibited normal exploratory behaviors. On the other hand, mice showed no significant suppression of contextual fear during the CS- in a paradigm with a pair of tone CSs at different frequencies, although they clearly discriminated the two tones. These results suggest our AFC paradigm with the noise and tone CSs as a useful experimental model for cue-dependent discriminative learning of safety and threat.