title: Fear but not fright: re-evaluating traumatic experience attenuates anxiety-like behaviors after fear conditioning.
abstract: Fear allows organisms to cope with dangerous situations and remembering these situations has an adaptive role preserving individuals from injury and death. However, recalling traumatic memories can induce re-experiencing the trauma, thus resulting in a maladaptive fear. A failure to properly regulate fear responses has been associated with anxiety disorders, like Posttraumatic Stress Disorder (PTSD). Thus, re-establishing the capability to regulate fear has an important role for its adaptive and clinical relevance. Strategies aimed at erasing fear memories have been proposed, although there are limits about their efficiency in treating anxiety disorders. To re-establish fear regulation, here we propose a new approach, based on the re-evaluation of the aversive value of traumatic experience. Mice were submitted to a contextual-fear-conditioning paradigm in which a neutral context was paired with an intense electric footshock. Three weeks after acquisition, conditioned mice were treated with a less intense footshock (pain threshold). The effectiveness of this procedure in reducing fear expression was assessed in terms of behavioral outcomes related to PTSD (e.g., hyper-reactivity to a neutral tone, anxiety levels in a plus maze task, social avoidance, and learning deficits in a spatial water maze) and of amygdala activity by evaluating c-fos expression. Furthermore, a possible role of lateral orbitofrontal cortex (lOFC) in mediating the behavioral effects induced by the re-evaluation procedure was investigated. We observed that this treatment: (i) significantly mitigates the abnormal behavioral outcomes induced by trauma; (ii) persistently attenuates fear expression without erasing contextual memory; (iii) prevents fear reinstatement; (iv) reduces amygdala activity; and (v) requires an intact lOFC to be effective. These results suggest that an effective strategy to treat pathological anxiety should address cognitive re-evaluation of the traumatic experience mediated by lOFC.
authors.affiliation: Cell Biology and Neurobiology Institute (IBCN), CNR/IRCCS Fondazione Santa Lucia Rome, Italy ; Department of Human Sciences, Libera Università Maria SS. Assunta Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Costanzi
authors.affiliation: Cell Biology and Neurobiology Institute (IBCN), CNR/IRCCS Fondazione Santa Lucia Rome, Italy ; Department of Psychology, Sapienza University Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Saraulli
authors.affiliation: Cell Biology and Neurobiology Institute (IBCN), CNR/IRCCS Fondazione Santa Lucia Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cannas
authors.affiliation: Cell Biology and Neurobiology Institute (IBCN), CNR/IRCCS Fondazione Santa Lucia Rome, Italy ; Department of Human Sciences, Libera Università Maria SS. Assunta Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Alessandro
authors.affiliation: Confocal Microscopy Unit, EBRI-European Brain Research Institute Rome, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Florenzano
authors.affiliation: Department of Psychology, Sapienza University Rome, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Rossi-Arnaud
authors.affiliation: Cell Biology and Neurobiology Institute (IBCN), CNR/IRCCS Fondazione Santa Lucia Rome, Italy ; Department of Psychology and "Daniel Bovet" Center, Sapienza University Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cestari
keywords: amygdala; contextual fear conditioning; fear reinstatement; fear sensitization; lateral orbitofrontal cortex; spontaneous recovery