Abstract
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.
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References
Akbari E, Naghdi N, Motamedi F (2006). Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task. Behav Brain Res 173: 47–52.
Akbari E, Naghdi N, Motamedi F (2007). The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze. Peptides 28: 650–656.
Arendt DH, Hassell J, Li H, Achua JK, Guarnieri DJ, Dileone RJ et al (2014). Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala. Psychoneuroendocrinology 40: 17–26.
Bilkei-Gorzo A, Erk S, Schürmann B, Mauer D, Michel K, Boecker H et al (2012). Dynorphins regulate fear memory: from mice to men. J Neurosci 32: 9335–9343.
Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF et al (2005). Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 102: 19168–19173.
Camp MC, Macpherson KP, Lederle L, Graybeal C, Gaburro S, Debrouse LM et al (2012). Genetic strain differences in learned fear inhibition associated with variation in neuroendocrine, autonomic, and amygdala dendritic phenotypes. Neuropsychopharmacology 37: 1534–1547.
Chen X, Li S, Kirouac GJ (2014). Blocking of corticotrophin releasing factor receptor-1 during footshock attenuates context fear but not the upregulation of prepro-orexin mRNA in rats. Pharmacol Biochem Behav 120: 1–6.
de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE et al (1998). The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95: 322–327.
Dietrich H, Jenck F (2010). Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant. Psychopharmacology (Berl) 212: 145–154.
Fanselow MS (1980). Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15: 177–182.
Flavell CR, Lee JL (2012). Post-training unilateral amygdala lesions selectively impair contextual fear memories. Learn Mem 19: 256–263.
Flores A, Maldonado R, Berrendero F (2014). The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward. Biol Psychiatry 75: 499–507.
Gunduz-Cinar O, MacPherson KP, Cinar R, Gamble-George J, Sugden K, Williams B et al (2013). Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18: 813–823.
Hefner K, Whittle N, Juhasz J, Norcross M, Karlsson RM, Saksida LM et al (2008). Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain. J Neurosci 28: 8074–8085.
Herry C, Mons N (2004). Resistance to extinction is associated with impaired immediate early gene induction in medial prefrontal cortex and amygdala. Eur J Neurosci 20: 781–790.
Herry C, Ciocchi S, Senn V, Demmou L, Müller C, Lüthi A (2008). Switching on and off fear by distinct neuronal circuits. Nature 454: 600–606.
Herry C, Ferraguti F, Singewald N, Letzkus JJ, Ehrlich I, Lüthi A (2010). Neuronal circuits of fear extinction. Eur J Neurosci 31: 599–612.
Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA (2001). Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103: 777–797.
Hollander JA, Lu Q, Cameron MD, Kamenecka TM, Kenny PJ (2008). Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci USA 105: 19480–19485.
Holmes A, Singewald N (2013). Individual differences in recovery from traumatic fear. Trends Neurosci 36: 23–31.
Hsu DT, Kirouac GJ, Zubieta JK, Bhatnagar S (2014). Contributions of the paraventricular thalamic nucleus in the regulation of stress, motivation, and mood. Front Behav Neurosci 8: 73.
Isogawa K, Bush DE, LeDoux JE (2013). Contrasting effects of pretraining, posttraining, and pretesting infusions of corticotropin-releasing factor into the lateral amygdala: attenuation of fear memory formation but facilitation of its expression. Biol Psychiatry 73: 353–359.
Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S et al (2010). A key role for orexin in panic anxiety. Nat Med 16: 111–115.
Johnson PL, Molosh A, Fitz SD, Truitt WA, Shekhar A (2012). Orexin, stress, and anxiety/panic states. Prog Brain Res 198: 133–161.
LeDoux JE (1993). Emotional memory: in search of systems and synapses. Ann N Y Acad Sci 702: 149–157.
Li Y, Li S, Wei C, Wang H, Sui N, Kirouac GJ (2010). Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats. Psychopharmacology 212: 251–265.
Li J, Hu Z, de Lecea L (2014). The hypocretins/orexins: integrators of multiple physiological functions. Br J Pharmacol 171: 332–350.
Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M et al (2001). Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435: 6–25.
Maren S, Phan KL, Liberzon I (2013). The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 14: 417–428.
Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB et al (2009). Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry 66: 1075–1082.
Milad MR, Quirk GJ (2012). Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63: 129–151.
Myers KM, Davis M (2007). Mechanisms of fear extinction. Mol Psychiatry 12: 120–150.
Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M et al (2006). Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 26: 398–405.
Paxinos G, Franklin KBJ (2001) The Mouse Brain in Stereotaxic Coordinates. Academic Press: San Diego, CA, USA.
Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG et al (1998). Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18: 9996–10015.
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y et al (2000). A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6: 991–997.
Plaza-Zabala A, Martín-García E, de Lecea L, Maldonado R, Berrendero F (2010). Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior. J Neurosci 30: 2300–2310.
Plaza-Zabala A, Flores Á, Maldonado R, Berrendero F (2012). Hypocretin/orexin signaling in the hypothalamic paraventricular nucleus is essential for the expression of nicotine withdrawal. Biol Psychiatry 71: 214–223.
Ponz A, Khatami R, Poryazova R, Werth E, Boesiger P, Schwartz S et al (2010). Reduced amygdala activity during aversive conditioning in human narcolepsy. Ann Neurol 67: 394–398.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: 573–585.
Scott MM, Marcus JN, Pettersen A, Birnbaum SG, Mochizuki T, Scammell TE et al (2011). Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res 222: 289–294.
Sears RM, Fink AE, Wigestrand MB, Farb CR, de Lecea L, LeDoux JE (2013). Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc Natl Acad Sci USA 110: 20260–20265.
Sierra-Mercado D, Padilla-Coreano N, Quirk GJ (2011). Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 36: 529–538.
Soya S, Shoji H, Hasegawa E, Hondo M, Miyakawa T, Yanagisawa M et al (2013). Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation. J Neurosci 33: 14549–14557.
Steiner MA, Lecourt H, Jenck F (2012). The brain orexin system and almorexant in fear-conditioned startle reactions in the rat. Psychopharmacology (Berl) 223: 465–475.
Tronson NC, Corcoran KA, Jovasevic V, Radulovic J (2012). Fear conditioning and extinction: emotional states encoded by distinct signaling pathways. Trends Neurosci 35: 145–155.
Uslaner JM, Tye SJ, Eddins DM, Wang X, Fox SV, Savitz AT et al (2013). Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Sci Transl Med 5: 179ra44.
Vertes RP, Hoover WB (2008). Projections of the paraventricular and paratenial nuclei of the dorsal midline thalamus in the rat. J Comp Neurol 508: 212–237.
Whittle N, Hauschild M, Lubec G, Holmes A, Singewald N (2010). Rescue of impaired fear extinction and normalization of cortico-amygdala circuit dysfunction in a genetic mouse model by dietary zinc restriction. J Neurosci 30: 13586–13596.
Winsky-Sommerer R, Yamanaka A, Diano S, Borok E, Roberts AJ, Sakurai T et al (2004). Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci 24: 11439–11448.
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We thank Marta Linares for invaluable technical assistance.
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Flores, Á., Valls-Comamala, V., Costa, G. et al. The Hypocretin/Orexin System Mediates the Extinction of Fear Memories. Neuropsychopharmacol 39, 2732–2741 (2014). https://doi.org/10.1038/npp.2014.146
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DOI: https://doi.org/10.1038/npp.2014.146
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