Distinct state anxiety after predictable and unpredictable fear training in mice

• Predictable and unpredictable CS-US timing induced phasic and sustained fear in mice.
• State anxiety was assessed during phasic and sustained fear using the elevated plus-maze test.
• Expression of phasic fear was associated with anxiolytic behavior,sustained component of fear was associated with enduringstate anxiety.

Sustained fear paradigms in rodents have been developed to monitor states of anxious apprehension and to model situations in patients suffering from long-lasting anxiety disorders. A recent report describes a fear conditioning paradigm, allowing distinction between phasic and sustained states of conditioned fear in non-restrained mice. However, so far no prospective studies have yet been conducted to elucidate whether induction of phasic or sustained fear can affect states of anxiety. Here, we used CS (conditioned stimulus) and US (unconditioned stimulus) pairing with predictable and unpredictable timing to induce phasic and sustained fear in mice. State anxiety during various fear response components was assessed using the elevated plus-maze test. Training with unpredictable CS-US timing resulted in CS-evoked sustained components of fear (freezing), while predictable CS-US timing resulted in rapid decline. Data suggested the influence of training procedure on state anxiety which is dependent on progression of conditioned fear during fear memory retrieval. Animals trained with unpredictable CS-US timing showed an unchanged high anxiety state throughout behavioral observation. In contrast, mice trained with predictable CS-US timing showed anxiolytic-like behavior 3 min after CS onset, which was accompanied by a fast decline of the fear conditioned response (freezing). Further systematic studies are needed to validate the phasic/sustained fear model in rodents as translational model for anxiety disorders in humans.