title: Involvement of CRFR1in the Basolateral Amygdala in the Immediate Fear Extinction Deficit.
abstract: Several animal and clinical studies have highlighted the ineffectiveness of fear extinction sessions delivered shortly after trauma exposure. This phenomenon, termed the immediate extinction deficit, refers to situations in which extinction programs applied shortly after fear conditioning may result in the reduction of fear behaviors (in rodents, frequently measured as freezing responses to the conditioned cue) during extinction training, but failure to consolidate this reduction in the long term. The molecular mechanisms driving this immediate extinction resistance remain unclear. Here we present evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala (BLA) in male Wistar rats. Intra-BLA microinfusion of the CRFR1antagonist NBI30775 enhances extinction recall, whereas administration of the CRF agonist CRF6-33before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser845and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal after treatment with the CRFR1antagonist indicates their dependence on CRFR1actions. These findings can have important implications for the improvement of therapeutic approaches to trauma, as well as furthering our understanding of the neurobiological mechanisms underlying fear-related disorders.
authors.affiliation: Brain Mind Institute , École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Fiona
authors.identifier: 0000-0001-6559-5736
authors.initials: F
authors.lastname: Hollis
authors.affiliation: Brain Mind Institute , École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Sevelinges
authors.affiliation: Brain Mind Institute , École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Jocelyn
authors.identifier: 0000-0003-3637-7654
authors.initials: J
authors.lastname: Grosse
authors.affiliation: Brain Mind Institute , École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Olivia
authors.initials: O
authors.lastname: Zanoletti
authors.affiliation: Brain Mind Institute , École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Carmen
authors.identifier: 0000-0001-7713-8321
authors.initials: C
authors.lastname: Sandi
mesh_terms: D000818:Animals; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: D019703:Calcineurin; D002491:Central Nervous System Agents; D003346:Corticotropin-Releasing Hormone; D011743:Pyrimidines; D018091:Receptors, AMPA; D018019:Receptors, Corticotropin-Releasing Hormone; C412383:R 121919
keywords: basolateral amygdala; corticotropin-releasing factor; fear conditioning; immediate-extinction deficit