Involvement of CRFR1 in the basolateral amygdala in the immediate fear extinction deficit

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/s) 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 micro-infusion of the CRFR1 antagonist NBI30775 enhances extinction recall, while administering the CRF agonist CRF6-33 before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser845 and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal following treatment with the CRFR1 antagonist indicates their dependency on CRFR1 actions. 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. Significance Statement Trauma-related disorders are costly, highlighting the need to understand the reduction of fear through extinction learning for the development of better therapies. When extinction programs are applied too soon after the traumatic event, numerous studies have found it to be ineffective, though the underlying mechanisms were unclear. Here we confirm that futility of immediate extinction and provide a mechanistic explanation. Using a pharmacological approach, we show evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala in this extinction deficit. We link this involvement with downstream molecular targets of the CRF system that are critical in synaptic plasticity, thus explaining the futility of immediate extinction and providing further insight into fear-related disorders.

Published in:
eNeuro, 3, 5, 1-5
Washington, Soc Neuroscience

Note: The status of this file is: EPFL only

 Record created 2016-11-03, last modified 2018-03-17

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