The Hypocretin/Orexin System Mediates the Extinction of Fear Memories

被引:110
作者
Flores, Africa [1 ]
Valls-Comamala, Victoria [1 ]
Costa, Giulia [2 ]
Saravia, Rocio [1 ]
Maldonado, Rafael [1 ]
Berrendero, Fernando [1 ]
机构
[1] Univ Pompeu Fabra, PRBB, Dept Expt & Hlth Sci, Neuropharmacol Lab, Barcelona 08003, Spain
[2] Univ Cagliari, Dept Biomed Sci, Sect Neuropsychopharmacol, Cagliari, Italy
关键词
CORTICOTROPIN-RELEASING-FACTOR; MORRIS WATER MAZE; BASOLATERAL AMYGDALA; IMPAIRS ACQUISITION; OREXIN RECEPTOR-1; NEURONAL CIRCUITS; SEEKING BEHAVIOR; LOCUS-COERULEUS; RAT-BRAIN; EXPRESSION;
D O I
10.1038/npp.2014.146
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:2732 / 2741
页数:10
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共 50 条
[1]   The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze [J].
Akbari, Esmaeil ;
Naghdi, Nasser ;
Motamedi, Fereshteh .
PEPTIDES, 2007, 28 (03) :650-656
[2]   Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task [J].
Akbari, Esmaeil ;
Naghdi, Nasser ;
Motamedi, Fereshteh .
BEHAVIOURAL BRAIN RESEARCH, 2006, 173 (01) :47-52
[3]   Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala [J].
Arendt, David H. ;
Hassell, James ;
Li, Hao ;
Achua, Justin K. ;
Guarnieri, Douglas J. ;
DiLeone, Ralph J. ;
Ronan, Patrick J. ;
Summers, Cliff H. .
PSYCHONEUROENDOCRINOLOGY, 2014, 40 :17-26
[4]   Dynorphins Regulate Fear Memory: from Mice to Men [J].
Bilkei-Gorzo, Andras ;
Erk, Susanne ;
Schuermann, Britta ;
Mauer, Daniela ;
Michel, Kerstin ;
Boecker, Henning ;
Scheef, Lukas ;
Walter, Henrik ;
Zimmer, Andreas .
JOURNAL OF NEUROSCIENCE, 2012, 32 (27) :9335-9343
[5]   Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior [J].
Boutrel, B ;
Kenny, PJ ;
Specio, SE ;
Martin-Fardon, R ;
Markou, A ;
Koob, GF ;
de Lecea, L .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (52) :19168-19173
[6]   Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes [J].
Camp, Marguerite C. ;
MacPherson, Kathryn P. ;
Lederle, Lauren ;
Graybeal, Carolyn ;
Gaburro, Stefano ;
DeBrouse, Lauren M. ;
Ihne, Jessica L. ;
Bravo, Javier A. ;
O'Connor, Richard M. ;
Ciocchi, Stephane ;
Wellman, Cara L. ;
Luethi, Andreas ;
Cryan, John F. ;
Singewald, Nicolas ;
Holmes, Andrew .
NEUROPSYCHOPHARMACOLOGY, 2012, 37 (06) :1534-1547
[7]   Blocking of corticotrophin releasing factor receptor-1 during footshock attenuates context fear but not the upregulation of prepro-orexin mRNA in rats [J].
Chen, Xiaoyu ;
Li, Sa ;
Kirouac, Gilbert J. .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 2014, 120 :1-6
[8]   The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity [J].
De Lecea, L ;
Kilduff, TS ;
Peyron, C ;
Gao, XB ;
Foye, PE ;
Danielson, PE ;
Fukuhara, C ;
Battenberg, ELF ;
Gautvik, VT ;
Bartlett, FS ;
Frankel, WN ;
van den Pol, AN ;
Bloom, FE ;
Gautvik, KM ;
Sutcliffe, JG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (01) :322-327
[9]   Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant [J].
Dietrich, Hendrik ;
Jenck, Francois .
PSYCHOPHARMACOLOGY, 2010, 212 (02) :145-154
[10]  
FANSELOW MS, 1980, PAVLOVIAN J BIOL SCI, V15, P177