Abstract
RationaleThe 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.ObjectivesHere, we aimed to generate a comprehensive map of brain activation upon effective remote fear memory attenuation in the mouse.MethodsWe 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.ResultsRemote 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.ConclusionThese 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.
Highlights
Traumatic events induce some of the most persistent forms of memory, which contribute to the pathogenesis of a number of stress and anxiety-related disorders including post-traumatic stress disorder (PTSD)
For the initial spaced extinction behavioral analysis, statistical significance was determined by one-way ANOVA; for behavioral analysis of the four groups further used for cFos activation, statistical significance was calculated by two-way ANOVA
Statistical significance of cFos quantifications was determined by one-way ANOVA of cFos density after home cage, context only, recall, and extinction followed by Sidak post-hoc multiple comparison analysis in case of significance
Summary
Traumatic events induce some of the most persistent forms of memory, which contribute to the pathogenesis of a number of stress and anxiety-related disorders including post-traumatic stress disorder (PTSD). Animals are subjected to fear conditioning during which an unconditioned noxious stimulus (US) is paired with a neutral conditioned stimulus (CS). After this association has been formed, the presentation of the CS alone induces high fear responses (memory recall); repeated exposure to the CS mediates a progressive reduction of fear responses (fear extinction). Such paradigms have been widely exploited to investigate the neural circuits at the basis of 1day-old fear memory extinction (for review, see Bouton 2004; Psychopharmacology (2019) 236:369–381
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