title: NPY Y2 receptors in the central amygdala reduce cued but not contextual fear.
abstract: The amygdala is fundamental for associative fear and extinction learning. Recently, also the central nucleus of the amygdala (CEA) has emerged as a site of plasticity actively controlling efferent connections to downstream effector brain areas. Although synaptic transmission is primarily mediated by glutamate and GABA, neuropeptides critically influence the overall response. While neuropeptide Y (NPY) acting via postsynaptic Y1 receptors exerts an important anxiolytic and fear-reducing action, the role of the predominantly presynaptic Y2 receptors is less defined. To investigate the role of Y2 receptors in the CEA we employed viral-vector mediated over-expression of the Y2 selective agonist NPY3-36 in fear conditioning and extinction experiments. NPY3-36 over-expression in the CEA resulted in reduced fear expression during fear acquisition and recall. Interestingly, this effect was blocked by intraperitoneal injection of a brain-penetrant Y2 receptor antagonist. Furthermore, over-expression of NPY3-36 in the CEA also reduced fear expression during fear extinction of CS-induced but not context-related fear. Again, fear extinction appeared delayed by peripheral injection of a Y2 receptor antagonist JNJ-31020028. Importantly, mice with over-expression of NPY3-36 in the CEA also displayed reduced spontaneous recovery and reinstatement, suggesting that Y2 receptor activation supports a permanent suppression of fear. Local deletion of Y2 receptors in the CEA, on the other hand, increased the expression of CS-induced freezing during fear recall and fear extinction. Thus, NPY inhibits fear learning and promotes cued extinction by reducing fear expression also via activation of presynaptic Y2 receptors on CEA neurons.
authors: Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors: D
authors: D
authors: Verma
authors: Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors: J
authors: J
authors: Wood
authors: Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria; Capes Foundation, Ministry of Education of Brazil, 70040-020 Brasília, DF, Brazil.
authors: G
authors: G
authors: Lach
authors: Institute of Virology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, 12203 Berlin, Germany.
authors: M
authors: M
authors: Mietzsch
authors: Institute of Virology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, 12203 Berlin, Germany.
authors: S
authors: S
authors: Weger
authors: Institute of Virology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, 12203 Berlin, Germany.
authors: R
authors: R
authors: Heilbronn
authors: Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
authors: H
authors: H
authors: Herzog
authors: Janssen Research & Development, LLC, San Diego, CA, USA.
authors: P
authors: P
authors: Bonaventure
authors: Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors: G
authors: G
authors: Sperk
authors: Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria. Electronic address: ramon.tasan@i-med.ac.at.
authors: R O
authors: RO
authors: Tasan
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D066274:Central Amygdaloid Nucleus / Q000187:drug effects / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000008:administration & dosage; D003463:Cues; D000229:Dependovirus / Q000235:genetics; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005822:Genetic Vectors; D008297:Male; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D002491:Central Nervous System Agents; C547250:JNJ-31020028; D009478:Neuropeptide Y; D010446:Peptide Fragments; D010879:Piperazines; D017476:Receptors, Neuropeptide Y; C113547:neuropeptide Y (3-36); C095889:neuropeptide Y2 receptor
keywords: Amygdala; Fear conditioning; Fear extinction; NPY; Viral vectors; Y2 receptor