The experience of strong traumata leads to the formation of enduring fear memories that may degenerate into post-traumatic stress disorder. One of the most successful treatments for this condition consists of extinction training during which the repeated exposure to trauma-inducing stimuli in a safe environment results in an attenuation of the fearful component of trauma-related memories. While numerous studies have investigated the neural substrates of recent (e.g., 1-day-old) fear memory attenuation, much less is known about the neural networks mediating the attenuation of remote (e.g., 30-day-old) fear memories. Since extinction training becomes less effective when applied long after the original encoding of the traumatic memory, this represents an important gap in memory research.

Here, we aimed to generate a comprehensive map of brain activation upon effective remote fear memory attenuation in the mouse.

We developed an efficient extinction training paradigm for 1-month-old contextual fear memory attenuation and performed cFos immunohistochemistry and network connectivity analyses on a set of cortical, amygdalar, thalamic, and hippocampal regions.

Remote fear memory attenuation induced cFos in the prelimbic cortex, the basolateral amygdala, the nucleus reuniens of the thalamus, and the ventral fields of the hippocampal CA1 and CA3. All these structures were equally recruited by remote fear memory recall, but not by the recall of a familiar neutral context.

These results suggest that progressive fear attenuation mediated by repetitive exposure is accompanied by sustained neuronal activation and not reverted to a pre-conditioning brain state. These findings contribute to the identification of brain areas as targets for therapeutic approaches against traumatic memories.