Neuropeptide Y (NPY) produces anxiolytic effects in rodent models, and naturally occurring low NPY expression in humans has been associated with negative emotional phenotypes. Studies in rodent models have also demonstrated that NPY elicits reward behaviors through its action in the nucleus accumbens (NAc), but the impact of NPY on the human NAc is largely unexplored. We recruited 222 healthy young adults of either sex and genetically selected 53 of these subjects at the extremes of NPY expression (Low-NPY and High-NPY) to participate in functional magnetic resonance imaging. Responses of the NAc and surrounding ventral striatum were quantified during a monetary incentive delay task in which stimuli varied by salience (high versus low) and valence (win versus loss). We found that bilateral NAc responses to high-salience versus low-salience stimuli were greater for Low-NPY subjects relative to High-NPY subjects, regardless of stimulus valence. To our knowledge, these results provide the first evidence in humans linking NPY with salience sensitivity of the NAc, raising the possibility that individual differences in NPY expression moderate the risk for disorders of mesoaccumbal function such as addictions and mood disorders. Additionally, we found that head motion was greater among High-NPY subjects, consistent with previous reports linking NPY with hyperactivity. Future studies in animal models are warranted to elucidate the neural mechanisms through which NPY influences NAc function and related behaviors.

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We thank Yarden Ginsburg and staff at the Michigan Clinical Research Unit for help with clinical assessment and phlebotomy; Bob Lyons and the UM DNA Sequencing Core for sequencing; Tom Chenevert, Suzan Lowe, and Sara Easler in the UM Department of Radiology for assistance with fMRI acquisition; Shana Black, Joe Heffernan, and Daniel Kessler for fMRI processing tools; and Brian Knutson for helpful discussions. This study was supported by NIMH (K23 MH092648), NCRR (UL1 RR024986), NCATS (2UL1 TR000433). Dr. Mickey reports no biomedical financial interests related to this work over the last 3 years or in the foreseeable future. In 2016, he served as a paid consultant to Alkermes, Inc., on an unrelated topic.

Author information


  1. University of Utah, Salt Lake City, UT, 84108, USA

    • Katherine G. Warthen
    • , Keith G. Jones
    • , Jon-Kar Zubieta
    • , Robert C. Welsh
    •  & Brian J. Mickey
  2. University of Michigan, Ann Arbor, MI, 48109, USA

    • Benjamin Sanford
    • , Kendal Walker
    • , Mike Angstadt
    • , Chandra Sripada
    • , Jon-Kar Zubieta
    • , Margit Burmeister
    •  & Brian J. Mickey
  3. NIAAA, Rockville, MD, 20852, USA

    • David Goldman


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Correspondence to Brian J. Mickey.

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