Slattery, David A. and Naik, Roshan R. and Grund, Thomas and Yen, Yi-Chun and Sartori, Simone B. and Fuechsl, Andrea and Finger, Beate C. and Elfving, Betina and Nordemann, Uwe and Guerrini, Remo and Calo, Girolamo and Wegener, Gregers and Mathe, Aleksander A. and Singewald, Nicolas and Czibere, Ludwig and Landgraf, Rainer and Neumann, Inga D. (2015) Selective Breeding for High Anxiety Introduces a Synonymous SNP That Increases Neuropeptide S Receptor Activity. JOURNAL OF NEUROSCIENCE, 35 (11). pp. 4599-4613. ISSN 0270-6474,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DEPRESSION-LIKE BEHAVIOR; TRAIT ANXIETY; MOUSE MODEL; GLUCOCORTICOID-RECEPTOR; EXPRESSING NEURONS; PANIC DISORDER; MESSENGER-RNA; GLYOXALASE-I; RATS; AMYGDALA; anxiety; basolateral amygdala; fear; paraventricular nucleus; promoter fragmentation |
| Subjects: | 500 Science > 590 Zoological sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Zoologie > Tierphysiologie/Neurobiologie (Prof. Dr. Inga Neumann) Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Jul 2019 13:42 |
| Last Modified: | 23 Jul 2019 13:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5777 |
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