Emotion Processing, Major Depression, and Functional Genetic Variation of Neuropeptide Y | Depressive Disorders | JAMA Psychiatry | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Dalgleish  T The emotional brain.  Nat Rev Neurosci 2004;5 (7) 583- 589PubMedGoogle ScholarCrossref
Phan  KLWager  TTaylor  SFLiberzon  I Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI.  Neuroimage 2002;16 (2) 331- 348PubMedGoogle ScholarCrossref
Phillips  MLDrevets  WCRauch  SLLane  R Neurobiology of emotion perception, I: the neural basis of normal emotion perception.  Biol Psychiatry 2003;54 (5) 504- 514PubMedGoogle ScholarCrossref
Bouchard  TJ  JrMcGue  M Genetic and environmental influences on human psychological differences.  J Neurobiol 2003;54 (1) 4- 45PubMedGoogle ScholarCrossref
Adrian  TEAllen  JMBloom  SRGhatei  MARossor  MNRoberts  GWCrow  TJTatemoto  KPolak  JM Neuropeptide Y distribution in human brain.  Nature 1983;306 (5943) 584- 586PubMedGoogle ScholarCrossref
Allen  YSAdrian  TEAllen  JMTatemoto  KCrow  TJBloom  SRPolak  JM Neuropeptide Y distribution in the rat brain.  Science 1983;221 (4613) 877- 879PubMedGoogle ScholarCrossref
Tatemoto  KCarlquist  MMutt  V Neuropeptide Y: a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide.  Nature 1982;296 (5858) 659- 660PubMedGoogle ScholarCrossref
Gehlert  DR Introduction to the reviews on neuropeptide Y.  Neuropeptides 2004;38 (4) 135- 140PubMedGoogle ScholarCrossref
Kask  AHarro  Jvon Hörsten  SRedrobe  JPDumont  YQuirion  R The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y.  Neurosci Biobehav Rev 2002;26 (3) 259- 283PubMedGoogle ScholarCrossref
Heilig  M The NPY system in stress, anxiety and depression.  Neuropeptides 2004;38 (4) 213- 224PubMedGoogle ScholarCrossref
Smith  PAMoran  TDAbdulla  FTumber  KKTaylor  BK Spinal mechanisms of NPY analgesia.  Peptides 2007;28 (2) 464- 474PubMedGoogle ScholarCrossref
Brumovsky  PShi  TSLandry  MVillar  MJHökfelt  T Neuropeptide tyrosine and pain.  Trends Pharmacol Sci 2007;28 (2) 93- 102PubMedGoogle ScholarCrossref
Craig  AD A new view of pain as a homeostatic emotion.  Trends Neurosci 2003;26 (6) 303- 307PubMedGoogle ScholarCrossref
Morgan  CA  IIIRasmusson  AMWang  SHoyt  GHauger  RLHazlett  G Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report.  Biol Psychiatry 2002;52 (2) 136- 142PubMedGoogle ScholarCrossref
Morgan  CA  IIIRasmusson  AMWinters  BHauger  RLMorgan  JHazlett  GSouthwick  S Trauma exposure rather than posttraumatic stress disorder is associated with reduced baseline plasma neuropeptide-Y levels.  Biol Psychiatry 2003;54 (10) 1087- 1091PubMedGoogle ScholarCrossref
Morgan  CA  IIIWang  SSouthwick  SMRasmusson  AHazlett  GHauger  RLCharney  DS Plasma neuropeptide-Y concentrations in humans exposed to military survival training.  Biol Psychiatry 2000;47 (10) 902- 909PubMedGoogle ScholarCrossref
Yehuda  RBrand  SYang  RK Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping.  Biol Psychiatry 2006;59 (7) 660- 663PubMedGoogle ScholarCrossref
Berrettini  WHDoran  ARKelsoe  JRoy  APickar  D Cerebrospinal fluid neuropeptide Y in depression and schizophrenia.  Neuropsychopharmacology 1987;1 (1) 81- 83PubMedGoogle ScholarCrossref
Caberlotto  LHurd  YL Reduced neuropeptide Y mRNA expression in the prefrontal cortex of subjects with bipolar disorder.  Neuroreport 1999;10 (8) 1747- 1750PubMedGoogle ScholarCrossref
Czermak  CHauger  RDrevets  WCLuckenbaugh  DAGeraci  MCharney  DSNeumeister  A Plasma NPY concentrations during tryptophan and sham depletion in medication-free patients with remitted depression.  J Affect Disord 2008;110 (3) 277- 281PubMedGoogle ScholarCrossref
Hashimoto  HOnishi  HKoide  SKai  TYamagami  S Plasma neuropeptide Y in patients with major depressive disorder.  Neurosci Lett 1996;216 (1) 57- 60PubMedGoogle ScholarCrossref
Heilig  MZachrisson  OThorsell  AEhnvall  AMottagui-Tabar  SSjögren  MAsberg  MEkman  RWahlestedt  CAgren  H Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism.  J Psychiatr Res 2004;38 (2) 113- 121PubMedGoogle ScholarCrossref
Ordway  GAStockmeier  CAMeltzer  HYOverholser  JCJaconetta  SWiddowson  PS Neuropeptide Y in frontal cortex is not altered in major depression.  J Neurochem 1995;65 (4) 1646- 1650PubMedGoogle ScholarCrossref
Widdowson  PSOrdway  GAHalaris  AE Reduced neuropeptide Y concentrations in suicide brain.  J Neurochem 1992;59 (1) 73- 80PubMedGoogle ScholarCrossref
Widerlöv  ELindström  LHWahlestedt  CEkman  R Neuropeptide Y and peptide YY as possible cerebrospinal fluid markers for major depression and schizophrenia, respectively.  J Psychiatr Res 1988;22 (1) 69- 79PubMedGoogle ScholarCrossref
Zhou  ZZhu  GHariri  AREnoch  MAScott  DSinha  RVirkkunen  MMash  DCLipsky  RHHu  XZHodgkinson  CAXu  KBuzas  BYuan  QShen  PHFerrell  REManuck  SBBrown  SMHauger  RLStohler  CSZubieta  JKGoldman  D Genetic variation in human NPY expression affects stress response and emotion.  Nature 2008;452 (7190) 997- 1001PubMedGoogle ScholarCrossref
Heitzeg  MMNigg  JTYau  WYZubieta  JKZucker  RA Affective circuitry and risk for alcoholism in late adolescence: differences in frontostriatal responses between vulnerable and resilient children of alcoholic parents.  Alcohol Clin Exp Res 2008;32 (3) 414- 426PubMedGoogle ScholarCrossref
Bradley  MMLang  PJ Affective Norms for English Words (ANEW): Instruction Manual and Affective Ratings.  Gainesville Center for Research in Psychophysiology, University of Florida1999;
Ward  BD AlphaSim. http://afni.nimh.nih.govAccessed January, 2010
Domschke  KDannlowski  UHohoff  COhrmann  PBauer  JKugel  HZwanzger  PHeindel  WDeckert  JArolt  VSuslow  TBaune  BT Neuropeptide Y (NPY) gene: impact on emotional processing and treatment response in anxious depression.  Eur Neuropsychopharmacol 2010;20 (5) 301- 309PubMedGoogle ScholarCrossref
Phillips  MLDrevets  WCRauch  SLLane  R Neurobiology of emotion perception, II: implications for major psychiatric disorders.  Biol Psychiatry 2003;54 (5) 515- 528PubMedGoogle ScholarCrossref
Price  JLDrevets  WC Neurocircuitry of mood disorders.  Neuropsychopharmacology 2010;35 (1) 192- 216PubMedGoogle ScholarCrossref
Yoshimura  SOkamoto  YOnoda  KMatsunaga  MUeda  KSuzuki  S Shigetoyamawaki Rostral anterior cingulate cortex activity mediates the relationship between the depressive symptoms and the medial prefrontal cortex activity.  J Affect Disord 2010;122 (1-2) 76- 85PubMedGoogle ScholarCrossref
Elliott  RRubinsztein  JSSahakian  BJDolan  RJ The neural basis of mood-congruent processing biases in depression.  Arch Gen Psychiatry 2002;59 (7) 597- 604PubMedGoogle ScholarCrossref
Hsu  DTLangenecker  SAKennedy  SEZubieta  JKHeitzeg  MM fMRI BOLD responses to negative stimuli in the prefrontal cortex are dependent on levels of recent negative life stress in major depressive disorder.  Psychiatry Res 2010;183 (3) 202- 208PubMedGoogle ScholarCrossref
Zubieta  JKSmith  YRBueller  JAXu  YKilbourn  MRJewett  DMMeyer  CRKoeppe  RAStohler  CS Regional mu opioid receptor regulation of sensory and affective dimensions of pain.  Science 2001;293 (5528) 311- 315PubMedGoogle ScholarCrossref
Zubieta  JKSmith  YRBueller  JAXu  YKilbourn  MRJewett  DMMeyer  CRKoeppe  RAStohler  CS Mu-opioid receptor-mediated antinociceptive responses differ in men and women.  J Neurosci 2002;22 (12) 5100- 5107PubMedGoogle Scholar
Watson  DClark  LA The PANAS-X: Manual for the Positive and Negative Affect Schedule—Expanded Form.  Iowa City University of Iowa1994;
Watson  DClark  LATellegen  A Development and validation of brief measures of positive and negative affect: the PANAS scales.  J Pers Soc Psychol 1988;54 (6) 1063- 1070PubMedGoogle ScholarCrossref
Kennedy  SEKoeppe  RAYoung  EAZubieta  JK Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women.  Arch Gen Psychiatry 2006;63 (11) 1199- 1208PubMedGoogle ScholarCrossref
Mickey  BJDucci  FHodgkinson  CALangenecker  SAGoldman  DZubieta  JK Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo.  J Neurosci 2008;28 (44) 11354- 11359PubMedGoogle ScholarCrossref
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders.  New York Biometric Research Dept, New York Psychiatric Institute1995;
Burmeister  MMcInnis  MGZöllner  S Psychiatric genetics: progress amid controversy.  Nat Rev Genet 2008;9 (7) 527- 540PubMedGoogle ScholarCrossref
Sullivan  PF Spurious genetic associations.  Biol Psychiatry 2007;61 (10) 1121- 1126PubMedGoogle ScholarCrossref
Elliott  RRubinsztein  JSSahakian  BJDolan  RJ Selective attention to emotional stimuli in a verbal go/no-go task: an fMRI study.  Neuroreport 2000;11 (8) 1739- 1744PubMedGoogle ScholarCrossref
Epstein  JPan  HKocsis  JHYang  YButler  TChusid  JHochberg  HMurrough  JStrohmayer  EStern  ESilbersweig  DA Lack of ventral striatal response to positive stimuli in depressed vs normal subjects.  Am J Psychiatry 2006;163 (10) 1784- 1790PubMedGoogle ScholarCrossref
Drevets  WCPrice  JLFurey  ML Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.  Brain Struct Funct 2008;213 (1-2) 93- 118PubMedGoogle ScholarCrossref
Sajdyk  TJShekhar  AGehlert  DR Interactions between NPY and CRF in the amygdala to regulate emotionality.  Neuropeptides 2004;38 (4) 225- 234PubMedGoogle ScholarCrossref
Charney  DS Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress.  Am J Psychiatry 2004;161 (2) 195- 216PubMedGoogle ScholarCrossref
Feder  ANestler  EJCharney  DS Psychobiology and molecular genetics of resilience.  Nat Rev Neurosci 2009;10 (6) 446- 457PubMedGoogle ScholarCrossref
Original Article
February 7, 2011

Emotion Processing, Major Depression, and Functional Genetic Variation of Neuropeptide Y

Author Affiliations

Author Affiliations: Molecular and Behavioral Neuroscience Institute (Drs Mickey, Heitzeg, Hsu, Langenecker, Love, Peciña, Shafir, and Zubieta) and Department of Psychiatry (Drs Mickey, Heitzeg, Hsu, Langenecker, Shafir, and Zubieta), University of Michigan, Ann Arbor; and Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville (Drs Zhou, Hodgkinson, and Goldman and Ms Heinz) and University of Maryland Dental School, Baltimore (Dr Stohler).

Arch Gen Psychiatry. 2011;68(2):158-166. doi:10.1001/archgenpsychiatry.2010.197

Context  Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD).

Objective  To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis.

Design  Cross-sectional, case-control study.

Setting  Academic medical center.

Participants  Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data.

Main Outcome Measures  Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD.

Results  Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results.

Conclusions  These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.