Neural substrates of fear conditioning, extinction, and spontaneous recovery in passive avoidance learning: a c-fos study in rats.

Extinguishing fear conditioning and preventing the return of fear are the goal in the treatment of anxiety disorders. However, the neural substrates that mediate fear conditioning, extinction, and spontaneous recovery (i.e., the return of fear) remain uncertain. We utilized the aversive passive avoidance learning paradigm and Fos-like immunoreactivity to elucidate this issue. Exception for naïve rats that did not receive any treatment served as the control group, the other rats were subjected to three sessions of context/footshock (0.5 mA, 2s) pairings followed by 12 extinction sessions (context-no footshock). After the last extinction test, these rats were assigned to one of three groups reflecting the number of resting days before the test session (context-no footshock): Day 8, Day 9, and Day 10 groups. Only the Day 10 group exhibited spontaneous recovery during the test session. Fos-like immunoreactivity associated with fear conditioning was seen in the amygdala and cingulate cortex area 1 (Cg1). The extinction of fear was seen to be related to Cg1, cingulate cortex area 2 (Cg2), piriform cortex (Pir), and entorhinal cortex (Ect). Spontaneous recovery was seen to be related to amygdala, Pir, and Ect. The present findings indicate that the brain substrates of fear acquisition, extinction and spontaneous recovery have different ensembles of brain activations. These differences suggest that different brain targets may be considered for fear extinction and for avoiding the return of fear in anxiety disorders.