Dissociation of within- and between-session extinction of conditioned fear.

Recent findings obtained in patients with phobias or trauma-related anxiety disorders raise doubts concerning the interrelation between acute fear relief during an exposure-based therapeutic session and beneficial treatment progress. In a mouse model explicit for exposure therapy, we challenge the view that within-session fear reduction is the turning point for relearning of a stimulus-threat association. Even though within-session extinction of auditory-cued fear memory was identical for prolonged and spaced tone presentations, only the latter caused between-session extinction. Furthermore, spaced tone presentations led to between-session extinction even in the complete absence of within-session extinction, as observed for remote fear memories and in case of abolished cannabinoid receptor type 1 signaling. Induction of between-session extinction was accompanied by an increase in the number of c-Fos-positive neurons within the basolateral amygdala, the cingulate cortex, and the dentate gyrus, independent of the level of within-session extinction. Together, our findings demonstrate that within-session extinction is neither sufficient nor essential for between-session extinction, thus calling for a reconsideration of current concepts underlying exposure-based therapies.