Title:
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The hypocretin/orexin system mediates the extinction of fear memories
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Author:
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Flores de los Heros, África, 1985-; Valls Comamala, Victòria, 1987-; Costa, Giulia; Saravia, Rocío; Maldonado, Rafael, 1961-; Berrendero Díaz, Fernando, 1971-
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Abstract:
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Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias. |
Abstract:
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This work was supported by the Instituto de Salud Carlos III grants, #PI13/00042 and #RD12/0028/0023 (RTA-RETICS), by the Spanish Ministry of Science #SAF2011-29864, the/nCatalan Government (SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies (ICREA Academia program). África Flores is a recipient of a predoctoral fellowship from the Spanish Ministry of Education. |
Subject(s):
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-Extinció psicològica -Por -- Aspectes fisiològics -Pèptids -Memòria -- Aspectes fisiològics |
Rights:
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© Nature Publishing Group. http://dx.doi.org/10.1038/npp.2014.146 |
Document type:
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Article Article - Accepted version |
Published by:
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Nature Publishing Group
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