title: Selective breeding for high anxiety introduces a synonymous SNP that increases neuropeptide S receptor activity.
abstract: Neuropeptide S (NPS) has generated substantial interest due to its anxiolytic and fear-attenuating effects in rodents, while a corresponding receptor polymorphism associated with increased NPS receptor (NPSR1) surface expression and efficacy has been implicated in an increased risk of panic disorder in humans. To gain insight into this paradox, we examined the NPS system in rats and mice bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior, and, thereafter, determined the effect of central NPS administration on anxiety- and fear-related behavior. The HAB phenotype was accompanied by lower basal NPS receptor (Npsr1) expression, which we could confirm via in vitro dual luciferase promoter assays. Assessment of shorter Npsr1 promoter constructs containing a sequence mutation that introduces a glucocorticoid receptor transcription factor binding site, confirmed via oligonucleotide pull-down assays, revealed increased HAB promoter activity-an effect that was prevented by dexamethasone. Analogous to the human NPSR1 risk isoform, functional analysis of a synonymous single nucleotide polymorphism in the coding region of HAB rodents revealed that it caused a higher cAMP response to NPS stimulation. Assessment of the behavioral consequence of these differences revealed that intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as well as the impaired cued-fear extinction in HAB rats and the enhanced fear expression in HAB mice, respectively. These results suggest that alterations in the NPS system, conserved across rodents and humans, contribute to innate anxiety and fear, and that HAB rodents are particularly suited to resolve the apparent discrepancy between the preclinical and clinical findings to date.
authors: Department of Behavioral and Molecular Neurobiology, and.
authors: David A
authors: http://orcid.org/0000-0001-8753-5005
authors: DA
authors: Slattery
authors: Department of Behavioral and Molecular Neurobiology, and Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors: Roshan R
authors: RR
authors: Naik
authors: Department of Behavioral and Molecular Neurobiology, and.
authors: Thomas
authors: T
authors: Grund
authors: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors: Yi-Chun
authors: YC
authors: Yen
authors: Department of Pharmacology and Toxicology, University of Innsbruck, 6020 Innsbruck, Austria.
authors: Simone B
authors: SB
authors: Sartori
authors: Department of Behavioral and Molecular Neurobiology, and.
authors: Andrea
authors: A
authors: Füchsl
authors: Department of Behavioral and Molecular Neurobiology, and.
authors: Beate C
authors: BC
authors: Finger
authors: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, DK-8000 Aarhus, Denmark.
authors: Betina
authors: http://orcid.org/0000-0001-6939-5088
authors: B
authors: Elfving
authors: Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
authors: Uwe
authors: U
authors: Nordemann
authors: Department of Chemistry and Pharmaceutical Sciences and Laboratorio per le Tecnologie delle Terapie Avanzate, University of Ferrara, 44100 Ferrara, Italy.
authors: Remo
authors: R
authors: Guerrini
authors: Department of Medical Sciences, Section of Pharmacology, National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors: Girolamo
authors: http://orcid.org/0000-0001-5436-959X
authors: G
authors: Calo
authors: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, DK-8000 Aarhus, Denmark, Pharmaceutical Centre of Excellence, School of Pharmacy, North West University, Potchefstroom, 2520, South Africa.
authors: Gregers
authors: G
authors: Wegener
authors: Clinical Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden, and.
authors: Aleksander A
authors: AA
authors: Mathé
authors: Department of Pharmacology and Toxicology, University of Innsbruck, 6020 Innsbruck, Austria.
authors: Nicolas
authors: N
authors: Singewald
authors: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors: Ludwig
authors: L
authors: Czibere
authors: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors: Rainer
authors: R
authors: Landgraf
authors: Department of Behavioral and Molecular Neurobiology, and inga.neumann@biologie.uni-regensburg.de.
authors: Inga D
authors: ID
authors: Neumann
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D001947:Breeding / Q000379:methods; D005239:Fear / Q000502:physiology / Q000523:psychology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: C515062:NPSR1 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: anxiety; basolateral amygdala; fear; paraventricular nucleus; promoter fragmentation