Cited by 455Neuropeptides and Animal PhysiologyNeurotransmitter Receptor Influence on BehaviorStress Responses and Cortisol

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Genetic variation in human NPY expression affects stress response and emotion

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Zhou, Zhifeng, Zhu, Guanshan, Hariri, Ahmad R., Enoch, Mary-Anne, Scott, David, Sinha, Rajita, Virkkunen, Matti, Mash, Deborah C., Lipsky, Robert H., Hu, Xian-Zhang, Hodgkinson, Colin A., Xu, Ke, Buzas, Beata, Yuan, Qiaoping, Shen, Pei-Hong, Ferrell, Robert E., Manuck, Stephen B., Brown, Sarah M., Hauger, Richard L., Stohler, Christian S., Zubieta, Jon-Kar, Goldman, David·2008·Nature

DOI 10.1038/nature06858PMC PMC2715959

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Abstract

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

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Authors: Zhou, Z., Zhu, G., Hariri, A. R., Enoch, M.-A., Scott, D., Sinha, R., Virkkunen, M., Mash, D. C., Lipsky, R. H., Hu, X.-Z., Hodgkinson, C. A., Xu, K., Buzas, B., Yuan, Q., Shen, P.-H., Ferrell, R. E., Manuck, S. B., Brown, S. M., Hauger, R. L., Stohler, C. S., Zubieta, J.-K., & Goldman, D.
Affiliations: National Institutes of Health (US)
University of Pittsburgh (US)
University of Michigan (US)
Yale University (US)
University of Helsinki (FI)
University of Miami (US)
University of California San Diego (US)
University of Maryland, Baltimore (US)
Corresponding author: Goldman, David
ORCID: Zhou, Zhifeng
Hariri, Ahmad R.
Scott, David
Sinha, Rajita
Mash, Deborah C.
Lipsky, Robert H.
Hu, Xian-Zhang
Hodgkinson, Colin A.
Xu, Ke
Yuan, Qiaoping
Shen, Pei-Hong
Manuck, Stephen B.
Brown, Sarah M.
Hauger, Richard L.
Stohler, Christian S.
Goldman, David
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2008-04
Volume: 452
Issue: 7190
Pages: 997-1001
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature06858
PMC: PMC2715959
OpenAlex: W1981364522
Cited by: 455
References: 36
Citations by year: 2026: 12 · 2025: 19 · 2024: 9 · 2023: 11 · 2022: 12 · 2021: 22 · 2020: 13 · 2019: 17 · 2018: 24 · 2017: 17 · 2016: 28 · 2015: 29 · 2014: 35 · 2013: 34 · 2012: 39
FWCI: 19.03
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Deep Blue (University of Michigan) (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Alliance for Research on Schizophrenia and Depression
National Institutes of Health (Z99‐AA999999)
National Institute on Alcohol Abuse and Alcoholism (Z01AA000301, R01AA013892, R01-AA-13892)
National Heart, Lung, and Blood Institute (R01HL065137, P01HL040962)
National Institute of Mental Health (R01MH074697, K01MH072837)
National Institute on Drug Abuse (K02 DA17232, P50DA016556, K02DA017232, R01DA016423, PL1DA024859, P50-DA16556)
National Institute of Dental and Craniofacial Research (R01DE015396, R01 DE 15396)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: neuropeptide Y, genetic variation, haplotypes, stress response, psychological resilience, trait anxiety, amygdala activation, endogenous opioid system, limbic system, individual differences
MeSH terms: Alleles, Anxiety, Anxiety Disorders, Brain, Emotions, Facial Expression, Finland, Gene Expression Regulation, Haplotypes, Humans, Lymphocytes, Magnetic Resonance Imaging, Male, Neuropeptide Y, Pain, RNA, Messenger, Stress, Physiological, United States, Genetic Variation, Opioid Peptides, Polymorphism, Single Nucleotide, White People

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Genetic variation in human NPY expression affects stress response and emotion

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