Toward a Mechanistic Understanding of How Variability in Neurobiology Shapes Individual Differences in Behavior

  • Ryan BogdanEmail author
  • Justin M. Carré
  • Ahmad R. Hariri
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 12)


Research has begun to identify how variability in brain function contributes to individual differences in complex behavioral traits. Examining variability in molecular signaling pathways with emerging and established methodologies such as pharmacologic fMRI, multimodal PET/fMRI, and hormonal assays are beginning to provide a mechanistic understanding of how individual differences in brain function arise. Against this background, functional genetic polymorphisms are being utilized to understand the origins of variability in signaling pathways as well as to efficiently model how such emergent variability impacts behaviorally relevant brain function and health outcomes. This chapter provides an overview of a research strategy that integrates these complimentary levels of analysis; existing empirical data is used to illustrate the effectiveness of this approach in illuminating the mechanistic neurobiology of individual differences in complex behavioral traits. This chapter also discusses how such efforts can contribute to the identification of predictive risk markers that interact with unique environmental factors to precipitate psychopathology.


Neurogenetics Amygdala Striatum Threat Reward Aggression Stress 



This manuscript is largely based on an earlier publication in the Annual Review of Neuroscience (Hariri 2009).


  1. Abercrombie HC, Giese-Davis J, Sephton S, Epel ES, Turner-Cobb JM, Spiegel D (2004) Flattened cortisol rhythms in metastic breast cancer patients. Psychoneuroendocrinology 29:1082–1092PubMedCrossRefGoogle Scholar
  2. Adkins-Regan E (2005) Hormones and animal social behavior. Princeton University Press, PrincetonGoogle Scholar
  3. Alessi SM, Petry NM (2003) Pathological gambling severity is associated with impulsivity in a delay discounting procedure. Behav Process 64:345–354CrossRefGoogle Scholar
  4. Amat J, Matus-Amat P, Watkins LR, Maier SF (1998) Escapable and inescapable stress differentially alter extracellular levels of 5-HT in the basolateral amygdala of the rat. Brain Res 812:113–120PubMedCrossRefGoogle Scholar
  5. Amat J, Tamblyn JP, Paul ED, Bland ST, Amat P et al (2004) Microinjection of urocortin 2 into the dorsal raphe nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala. Neuroscience 129:509–519PubMedCrossRefGoogle Scholar
  6. Arai K, Nakagomi Y, Iketani M, Shimura Y, Amemiya S, Ohyama K, Shibasaki T (2003) Functional polymorphisms in the mineralocorticoid receptor and amirolide-sensitive sodium channel genes in a patient with sporadic pseudohypoaldosteronism. Hum Genet 112:91–97PubMedCrossRefGoogle Scholar
  7. Bannon MJ, Michelhaugh SK, Wang J, Sacchetti P (2001) The human dopamine transporter gene: gene organization, transcriptional regulation, and potential involvement in neuropsychiatric disorders. Eur Neuropsychopharmacol 11:449–455PubMedCrossRefGoogle Scholar
  8. Baron RA, Richardson D (1994) Human aggression. Plenum, New YorkGoogle Scholar
  9. Bartholome B, Spies CM, Gaber T, Schuchmann S, Kunkel D et al (2004) Membrane glucocorticoid receptors (mGCR) are expressed in normal human peripheral blood mononuclea cells and up-regulated after in vitro stimulation and in patients with rheumatoid arthritis. FASEB J 18:70–80PubMedCrossRefGoogle Scholar
  10. Basavarajappa BS, Yalamanchili R, Cravatt BF, Cooper TB, Hungund BL (2006) Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knockout mice. Neuropharmacology 50:834–844PubMedCrossRefGoogle Scholar
  11. Beaver JD, Lawrence AD, Passamonti L, Calder AJ (2008) Appetitive motivation predicts the neural response to facial signals of aggression. J Neurosci 28:2719–2725PubMedCrossRefGoogle Scholar
  12. Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R (2009) Vulnerability genes or plasticity genes? Mol Psychiatry 14:746–754PubMedCrossRefGoogle Scholar
  13. Berridge KC, Robinson TE (2003) Parsing reward. Trends Neurosci 26:507–513PubMedCrossRefGoogle Scholar
  14. Bickel WK, Odum AL, Madden GJ (1999) Impulsivity and cigarette smoking: delay discounting in current, never, and ex-smokers. Psychopharmacology (Berl) 146:447–454CrossRefGoogle Scholar
  15. Bigos KL, Pollock BG, Aizenstein H, Fisher PM, Bies RR, Hariri AR (2008) Acute 5-HT reuptake blockade potentiates human amygdala reactivity. Neuropsychopharmacology 33:3221–3225PubMedCrossRefGoogle Scholar
  16. Binder (2009) The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology, 34(Suppl 1), S186–195Google Scholar
  17. Binder EB, Nemeroff CB (2010) The CRF system, stress, depression and anxiety-insights from human genetic studies. Mol Psychiatry 15:574–588PubMedCrossRefGoogle Scholar
  18. Bishop SJ, Duncan J, Lawrence AD (2004) State anxiety modulation of the amygdala response to unattended threat-related stimuli. J Neurosci 24:10364–10368PubMedCrossRefGoogle Scholar
  19. Blair RJ (2010) Neuroimaging of psychopathy and antisocial behavior: a targeted review. Curr Psychiatry Rep 12:76–82PubMedCrossRefGoogle Scholar
  20. Blednov YA, Cravatt BF, Boehm SL 2nd, Walker D, Harris RA (2007) Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacology 32:1570–1582PubMedCrossRefGoogle Scholar
  21. Bogdan R, Perlis RH, Fagerness J, Pizzagalli DA (2010) The impact of mineralocorticoid receptor iso/val genotype (rs5522) and stress on reward learning. Genes Brain Behav 9:658–667PubMedGoogle Scholar
  22. Bogdan R, Williamson DE, Hariri AR (in press) Mineralocorticoid receptor iso/val genotype (rs5522) moderates the association between priori childhood emotional neglect and amygdala reactivity. Am J PsychiatryGoogle Scholar
  23. Brady LS, Whitfield HJ, Fox RJ, Gold PW, Herkenham M (1991) Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. J Clin Invest 87:831–837PubMedCrossRefGoogle Scholar
  24. Brown GW, Harris TO (1978) Social origins of depression: a study of psychiatric disorder in women. Tavistock, LondonGoogle Scholar
  25. Buchanan TW, Driscoll D, Mowrer SM, Sollers JJ, Thayer JF et al (2010) Medial prefrontal cortex damage affects physiological and psychological stress responses differently in men and women. Psychoneuroendocrinology 35:56–66PubMedCrossRefGoogle Scholar
  26. Burghardt NS, Sullivan GM, McEwen BS, Gorman JM, LeDoux JE (2004) The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine. Biol Psychiatry 55:1171–1178PubMedCrossRefGoogle Scholar
  27. Burghardt NS, Bush DEA, McEwen BS, LeDoux JE (2007) Acute SSRIs increase conditioned fear expression: blockade with a 5-HT2C receptor antagonist. Biol Psychiatry 62:1111–1118PubMedCrossRefGoogle Scholar
  28. Burns HD, Van Laere K, Sanabria-Bohorquez S, Hamill TG, Bormans G et al (2007) [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci U S A 104:9800–9805PubMedCrossRefGoogle Scholar
  29. Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394:277–281PubMedCrossRefGoogle Scholar
  30. Cardinal RN, Winstanley CA, Robbins TW, Everitt BJ (2004) Limbic corticostriatal systems and delayed reinforcement. Ann N Y Acad Sci 1021:33–50PubMedCrossRefGoogle Scholar
  31. Carré JM, Fisher PM, Manuck SB, Hariri AR (in press-a) Interaction between trait anxiety and trait anger predict predict amygdala reactivity to angry faces in men but not women. Soc Cogn Affect NeurosciGoogle Scholar
  32. Carré JM, McCormick CM (2008) Aggressive behaviour and change in salivary testosterone concentrations predict willingness to engage in a competitive task. Horm Beh 54:403–409CrossRefGoogle Scholar
  33. Carré JM, Murphy KR, Hariri AR (in press-b) What lies beneath the face of aggression. Soc Cogn Affect NeurosciGoogle Scholar
  34. Carré JM, Putnam SK, McCormick CM (2009) Testosterone responses to competition predict future aggressive behaviour at a cost to reward in men. Psychoneuroendocrinology 343:561–570CrossRefGoogle Scholar
  35. Carré JM, Gilchrist JG, Morrissey MD, McCormick CM (2010) Motivational and situations factors and the relationship between testosterone dynamics and human aggression during competition. Biol Psychol 84:346–353PubMedCrossRefGoogle Scholar
  36. Caspi A, Moffitt TE (2006) Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci 7:583–590PubMedCrossRefGoogle Scholar
  37. Chakrabarti B, Kent L, Suckling J, Bullmore E, Baron-Cohen S (2006) Variations in the human cannabinoid receptor (CNR1) gene modulate striatal responses to happy faces. Eur J Neurosci 23:1944–1948PubMedCrossRefGoogle Scholar
  38. Chamberlain NL, Driver ED, Miesfeld RL (1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal dsomain affect transactivation function. Nucleic Acids Res 22:3181–3186PubMedCrossRefGoogle Scholar
  39. Chan SC, Raine A, Lee TM (2010) Attentional bias toward negative affective stimuli and reactive aggression in male batterers. Psychiatry Res 176:246–249PubMedCrossRefGoogle Scholar
  40. Cheon KA, Ryu YH, Kim JW, Cho DY (2005) The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate. Eur Neuropsychopharmacol 15:95–101PubMedCrossRefGoogle Scholar
  41. Chiang KP, Gerber AL, Sipe JC, Cravatt BF (2004) Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet 13:2113–2119PubMedCrossRefGoogle Scholar
  42. Choong CS, Wilson EM (1998) Trinucleotide repeats in the human androgen receptor: a molecular basis for disease. J Mol Endocrinol 21:235–257PubMedCrossRefGoogle Scholar
  43. Coccaro EF, McCloskey MS, Fitzgerald DA, Phan KL (2007) Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression. Biol Psychiatry 62:168–178PubMedCrossRefGoogle Scholar
  44. Cohen S, Janicki-Deverts D, Miller GE (2007) Psychological stress and disease. JAMA 298:1685–1687PubMedCrossRefGoogle Scholar
  45. Cooney RE, Atlas LY, Joormann J, Eugene F, Gotlib IH (2006) Amygdala activation in the processing of neutral faces in social anxiety disorder: is neutral really neutral? Psychiatry Res 148:55–59PubMedCrossRefGoogle Scholar
  46. Cowen PJ, Power AC, Ware CJ, Anderson IM (1994) 5-HT1A receptor sensitivity in major depression.A neuroendocrine study with buspirone. Br J Psychiatry 164:372–379PubMedCrossRefGoogle Scholar
  47. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87PubMedCrossRefGoogle Scholar
  48. Czesak M, Lemonde S, Peterson EA, Rogaeva A, Albert PR (2006) Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism. J Neurosci 26:1864–1871PubMedCrossRefGoogle Scholar
  49. David SP, Murthy NV, Rabiner EA, Munafo MR, Johnstone EC et al (2005) A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 25:2586–2590PubMedCrossRefGoogle Scholar
  50. Davidson RJ, Putnam KM, Larson CL (2000) Dysfunction in the neural circuitry of emotion regulation—a possible prelude to violence. Science 289:591–594PubMedCrossRefGoogle Scholar
  51. de Wit H, Richards JB (2004) Dual determinants of drug use in humans: reward and impulsivity. Nebr Symp Motiv 50:19–55PubMedGoogle Scholar
  52. de Kloet ER, Joëls M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475PubMedCrossRefGoogle Scholar
  53. De Wit H, Flory JD, Acheson A, McLoskey M, Manuck SB (2007) IQ and nonplanning impulsivity are independently associated with delay discounting in middle-aged adults. Pers Indiv Differ 42:111–121CrossRefGoogle Scholar
  54. Depue RA, Luciana M, Arbisi P, Collins P, Leon A (1994) Dopamine and the structure of personality: relation of agonist-induced dopamine activity to positive emotionality. J Pers Soc Psychol 67:485–498PubMedCrossRefGoogle Scholar
  55. DeRijk RH, Wüst S, Meijer OC, Zennaro MC, Federenko IS, Hellhammer DH, Giacchetti G, Vreugdenhil E, Zitman FG, de Kloet ER (2006) A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. J Clin Endocrinol Metab 91:5083–5089PubMedCrossRefGoogle Scholar
  56. DeRijk RH, van Leeuwen N, Klok MD, Zitman FG (2008) Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health. Eur J Pharmacol 585:492–501PubMedCrossRefGoogle Scholar
  57. Derntl B, Windischberger C, Robinson S, Kryspin-Exner I, Gur RC, Moser E, Habel U (2009) Amygdala activity to fear and anger in healthy young males is associated with testosterone. Psychoneuroendocrinology 34:687–693PubMedCrossRefGoogle Scholar
  58. Desarnaud F, Cadas H, Piomelli D (1995) Anandamide amidohydrolase activity in rat brain microsomes. J Biol Chem 270:6030–6035PubMedCrossRefGoogle Scholar
  59. Dickerson SS, Kemeny ME (2004) Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 130:355–391PubMedCrossRefGoogle Scholar
  60. Dickie EW, Armony JL (2008) Amygdala responses to unattended fearful faces: Interaction between sex and trait anxiety. Psychiatry Res 162:51–57PubMedCrossRefGoogle Scholar
  61. Dodge KA, Coie JD (1987) Social-information processing factors in reactive and proactive aggression in children’s peer groups. J Pers Soc Psychol 53:1146–1158PubMedCrossRefGoogle Scholar
  62. Etkin A, Klemenhagen KC, Dudman JT, Rogan MT, Hen R et al (2004) Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces. Neuron 44:1043–1055PubMedCrossRefGoogle Scholar
  63. Evans KC, Wright CI, Wedig MM, Gold AL, Pollack MH, Rauch SL (2008) A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder. Depress Anxiety 25:496–505PubMedCrossRefGoogle Scholar
  64. Fakra E, Hyde LW, Gorka A, Fisher PM, Munoz KE et al (2009) Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety. Arch Gen Psychiatry 66:33–40PubMedCrossRefGoogle Scholar
  65. Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B et al (2007) A whole-genome association study of major determinants for host control of HIV-1. Science 317:944–947PubMedCrossRefGoogle Scholar
  66. Fisher PM, Meltzer CC, Ziolko SK, Price JC, Hariri AR (2006) Capacity for 5-HT1A-mediated autoregulation predicts amygdala reactivity. Nat Neurosci 9:1362–1363PubMedCrossRefGoogle Scholar
  67. Flanagan JM, Gerber AL, Cadet JL, Beutler E, Sipe JC (2006) The fatty acid amide hydrolase 385 A/A (P129T) variant: haplotype analysis of an ancient missense mutation and validation of risk for drug addiction. Hum Genet 120:581–588PubMedCrossRefGoogle Scholar
  68. Forbes EE, Brown SM, Kimak M, Ferrell RE, Manuck SB, Hariri AR (2009) Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity. Mol Psychiatry 14:60–70PubMedCrossRefGoogle Scholar
  69. Forster GL, Feng N, Watt MJ, Korzan WJ, Mouw NJ et al (2006) Corticotropin-releasing factor in the dorsal raphe elicits temporally distinct serotonergic responses in the limbic system in relation to fear behavior. Neuroscience 141:1047–1055PubMedCrossRefGoogle Scholar
  70. Fox HC, Wilker EH, Kreek MJ, Sinha R (2006) Reliability of salivary cortisol assessments in cocaine dependent individuals. J Psychopharmacol 20:650–655PubMedCrossRefGoogle Scholar
  71. Gass P, Reichardt HM, Strekalova T, Henn F, Tronche F (2001) Mice with targetted mutations of glucocorticoid and mineralocorticoid receptors: models for depression and anxiety? Physiol Behav 73:811–825Google Scholar
  72. Gibbons JL, McHugh PR (1962) Plasma cortisol in depressive illness. J Psychiat Res 1:162–171PubMedCrossRefGoogle Scholar
  73. Gibson G, Goldstein DB (2007) Human genetics: the hidden text of genome-wide associations. Curr Biol 17:R929–R932PubMedCrossRefGoogle Scholar
  74. Glahn DC, Lovallo WR, Fox PT (2007) Reduced amygdala activation in young adults at high risk of alcoholism: studies from the Oklahoma family health patterns project. Biol Psychiatry 61:1306–1309PubMedCrossRefGoogle Scholar
  75. Green L, Myerson J (2004) A discounting framework for choice with delayed and probabilistic rewards. Psychol Bull 130:769–792PubMedCrossRefGoogle Scholar
  76. Haas BW, Omura K, Constable RT, Canli T (2007) Emotional conflict and neuroticism: personality-dependent activation in the amygdala and subgenual anterior cingulate. Behav Neurosci 121:249–256PubMedCrossRefGoogle Scholar
  77. Hansenne M, Pitchot W, Pinto E, Reggers J, Scantamburlo G et al (2002) 5-HT1A dysfunction in borderline personality disorder. Psychol Med 32:935–941PubMedCrossRefGoogle Scholar
  78. Hariri AR (2009) The neurobiology of individual differences in complex behavioral traits. Ann Rev Neurosci 32:225–247PubMedCrossRefGoogle Scholar
  79. Hariri AR, Holmes A (2006) Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn Sci 10:182–191PubMedCrossRefGoogle Scholar
  80. Hariri AR, Weinberger DR (2003) Imaging genomics. Br Med Bull 65:259–270PubMedCrossRefGoogle Scholar
  81. Hariri AR, Mattay VS, Tessitore A, Fera F, Smith WG, Weinberger DR (2002a) Dextroamphetamine modulates the response of the human amygdala. Neuropsychopharmacology 27:1036–1040PubMedCrossRefGoogle Scholar
  82. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F et al (2002b) Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400–403PubMedCrossRefGoogle Scholar
  83. Hariri AR, Brown SM, Williamson DE, Flory JD, de Wit H, Manuck SB (2006a) Preference for immediate over delayed rewards is associated with magnitude of ventral striatal activity. J Neurosci 26:13213–13217PubMedCrossRefGoogle Scholar
  84. Hariri AR, Drabant EM, Weinberger DR (2006b) Imaging genetics: perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing. Biol Psychiatry 59:888–897PubMedCrossRefGoogle Scholar
  85. Hariri AR, Gorka A, Hyde LW, Kimak M, Halder I et al (2009) Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function. Biol Psychiatry 66:9–16PubMedCrossRefGoogle Scholar
  86. Harmon-Jones E (2003) Anger and the behavioural approach system. Pers Ind Diff 35:995–1005CrossRefGoogle Scholar
  87. Heinz A, Goldman D, Jones DW, Palmour R, Hommer D et al (2000) Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 22:133–139PubMedCrossRefGoogle Scholar
  88. Hermans E, Ramsey M, van Honk J (2008) Exogenous testosterone enhances responsiveness to social threat in the neural circuitry of social aggression in humans. Biol Psychiatry 63:263–270PubMedCrossRefGoogle Scholar
  89. Hyde LW, Gorka A, Manuck SB, Hariri AR (2011) Perceived social support moderates the link between threat-related amygdala reactivity and trait anxiety. Neuropsychologia 49:651–656PubMedCrossRefGoogle Scholar
  90. Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598PubMedCrossRefGoogle Scholar
  91. Jahn AL, Fox AS, Abercrombie HC, Shelton SE, Oakes TR et al (2010) Subgenual prefrontal cortex activity predicts individual differences in hypothalamic-pituitary-adrenal activity across different contexts. Biol Psychiatry 67:175–181PubMedCrossRefGoogle Scholar
  92. Joëls M, Karst H, DeRijk R, de Kloet ER (2008) The coming out of the brain mineralocorticoid receptor. Trends Neurosci 31:1–7PubMedCrossRefGoogle Scholar
  93. Johnstone T, Somerville LH, Alexander AL, Oakes TR, Davidson RJ et al (2005) Stability of amygdala BOLD response to fearful faces over multiple scan sessions. Neuroimage 25:1112–1123PubMedCrossRefGoogle Scholar
  94. Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413PubMedCrossRefGoogle Scholar
  95. Karst H, Berger S, Turiault M, Tronche F, Schütz G, Joëls M (2006) Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci U S A 102:19204–19207CrossRefGoogle Scholar
  96. Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A et al (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81PubMedCrossRefGoogle Scholar
  97. Kelley AE (2004) Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44:161–179PubMedCrossRefGoogle Scholar
  98. Kern S, Oakes TR, Stone CK, McAuliff EM, Kirschbaum C, Davidson RJ (2008) Glucose metabolic changes in the prefrontal cortex are associated with HPA axis response to a psychosocial stressor. Psychoneuroendocrinology 33:517–529PubMedCrossRefGoogle Scholar
  99. Killgore WD, Yurgelun-Todd DA (2005) Social anxiety predicts amygdala activation in adolescents viewing fearful faces. Neuroreport 16:1671–1675PubMedCrossRefGoogle Scholar
  100. Kirby KN, Petry NM, Bickel WK (1999) Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls. J Exp Psychol Gen 128:78–87PubMedCrossRefGoogle Scholar
  101. Knutson B, Rick S, Wimmer GE, Prelec D, Loewenstein G (2007) Neural predictors of purchases. Neuron 53:147–156PubMedCrossRefGoogle Scholar
  102. Kolber BJ, Muglia LJ (2009) Defining brain region-specific glucocorticoid action during stress by conditional gene disruption in mice. Brain Res 1293:85–90PubMedCrossRefGoogle Scholar
  103. Kudielka BM, Hellhammer DH, Wüst S (2009) Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge. Psychoneuroendocrinology 34:2–18PubMedCrossRefGoogle Scholar
  104. Kuningas M, de Rijk RH, Westendorp RG, Jolle J, Slagboom PE, van Heemst D (2007) Mental performance in old age dependent on cortisol and genetic variance in the mineralocorticoid and glucocorticoid receptors. Neuropsychopharmacology 32:1295–1301PubMedCrossRefGoogle Scholar
  105. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184PubMedCrossRefGoogle Scholar
  106. Lee BT, Ham BJ (2008) Serotonergic genes and amygdala activity in response to negative affective facial stimuli in Korean women. Genes Brain Behav 7:899–905Google Scholar
  107. Lee TM, Chan SC, Raine A (2008) Strong limbic and weak frontal activation to aggressive stimuli in spouse abusers. Mol Psychiatry 13:655–656PubMedCrossRefGoogle Scholar
  108. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD et al (2003) Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23:8788–8799PubMedGoogle Scholar
  109. Lesch KP, Gutknecht L (2004) Focus on The 5-HT1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogenetics. Int J Neuropsychopharmacol 7:381–385PubMedCrossRefGoogle Scholar
  110. Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI et al (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40:584–591PubMedCrossRefGoogle Scholar
  111. Link E, Parish S, Armitage J, Bowman L, Heath S et al (2008) SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 359:789–799PubMedCrossRefGoogle Scholar
  112. LoVerme J, Gaetani S, Fu J, Oveisi F, Burton K, Piomelli D (2005) Regulation of food intake by oleoylethanolamide. Cell Mol Life Sci 62:708–716CrossRefGoogle Scholar
  113. Madden GJ, Petry NM, Badger GJ, Bickel WK (1997) Impulsive and self-control choices in opioid-dependent patients and non-drug-using control participants: drug and monetary rewards. Exp Clin Psychopharmacol 5:256–262PubMedCrossRefGoogle Scholar
  114. Maier SF, Watkins LR (2005) Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev 29:829–841PubMedCrossRefGoogle Scholar
  115. Maldonado R, Valverde O, Berrendero F (2006) Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 29:225–232PubMedCrossRefGoogle Scholar
  116. Manuck SB (2010) The reaction norm in gene x environment interaction. Mol Psychiatry 14:746–754Google Scholar
  117. Manuck SB, Flory JD, McCaffery JM, Matthews KA, Mann JJ, Muldoon MF (1998) Aggression, impulsivity, and central nervous system serotonergic responsivity in a nonpatient sample. Neuropsychopharmacology 19:287–299PubMedGoogle Scholar
  118. Manuck SB, Flory JD, Muldoon MF, Ferrell RE (2003) A neurobiology of intertemporal choice. In: Loewenstein G, Read D, Baumeister RF (eds) Time and decision: economic and psychological perspectives on intertemporal choice. Sage, New York, pp 139–172Google Scholar
  119. Manuck SB, Brown SM, Forbes EE, Hariri AR (2007) Temporal stability of individual differences in amygdala reactivity. Am J Psychiatry 164:1613–1614PubMedCrossRefGoogle Scholar
  120. Manuck SB, Marsland AL, Flory JD, Gorka A, Ferrell RE, Hariri AR (2010) Salivary testosterone and a trinucleotide (CAG) length polymorphism in the androgen receptor gene predict amygdala reactivity in men. Psychoneuroendocrinology 35:94–104PubMedCrossRefGoogle Scholar
  121. Marques AH, Silverman MN, Sternberg EM (2009) Glucocorticoid dysregulationss and their clinical correlated: from receptors to therapeutics. Ann N Y Acad Sci 1179:1–18PubMedCrossRefGoogle Scholar
  122. Márquez C, Nadal R, Armario A (2005) Responsiveness of the hypothalamic-pituitary-adrenal axis to different novel environments is a consistent individual trait in adult male outbred rats. Psychoneuroendocrinology 30:179–188PubMedCrossRefGoogle Scholar
  123. Martinez D, Gelernter J, Abi-Dargham A, van Dyck CH, Kegeles L et al (2001) The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans. Neuropsychopharmacology 24:553–560PubMedCrossRefGoogle Scholar
  124. Mauchnik J, Schmahl C (2010) The latest neuroimaging findings in borderline personality disorder. Curr Psychiatry Rep 12:46–55PubMedCrossRefGoogle Scholar
  125. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J et al (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9:356–369PubMedCrossRefGoogle Scholar
  126. McEwen BS, Gianaros PJ (2010) Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Ann N Y Acad Sci 1186:190–222PubMedCrossRefGoogle Scholar
  127. McGowan PO, Sasaki A, D’Alessio AC, Gymov S, Labonté B et al (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348PubMedCrossRefGoogle Scholar
  128. Mehta PH, Beer J (2010) Neural mechanisms of the testosterone-aggression relation: the role of the orbito-frontal cortex. J Cog Neuro 22:2357–2368CrossRefGoogle Scholar
  129. Meng ID, Manning BH, Martin WJ, Fields HL (1998) An analgesia circuit activated by cannabinoids. Nature 395:381–383PubMedCrossRefGoogle Scholar
  130. Menon M, Jensen J, Vitcu I, Graff-Guerrero A, Crawley A et al (2007) Temporal difference modeling of the blood-oxygen level dependent response during aversive conditioning in humans: effects of dopaminergic modulation. Biol Psychiatry 62:765–772PubMedCrossRefGoogle Scholar
  131. Meyer-Lindenberg A, Buckholtz JW, Kolachana B, Hariri AR, Pezawas L et al (2006) Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc Natl Acad Sci U S A 103:6269–6274PubMedCrossRefGoogle Scholar
  132. Michelhaugh SK, Fiskerstrand C, Lovejoy E, Bannon MJ, Quinn JP (2001) The dopamine transporter gene (SLC6A3) variable number of tandem repeats domain enhances transcription in dopamine neurons. J Neurochem 79:1033–1038PubMedCrossRefGoogle Scholar
  133. Mill J, Asherson P, Browes C, D’Souza U, Craig I (2002) Expression of the dopamine transporter gene is regulated by the 3′ UTR VNTR: evidence from brain and lymphocytes using quantitative RT-PCR. Am J Med Genet 114:975–979PubMedCrossRefGoogle Scholar
  134. Mill J, Asherson P, Craig I, D’Souza UM (2005) Transient expression analysis of allelic variants of a VNTR in the dopamine transporter gene (DAT1). BMC Genet 6:3PubMedCrossRefGoogle Scholar
  135. Mitra R, Ferguson D, Sapolsky RM (2009) Mineralocorticoid receptor overexpression in basolateral amygdala reduces corticosterone secretion and anxiety. Biol Psychiatry 66:686–690PubMedCrossRefGoogle Scholar
  136. Monroe SM (2008) Modern approaches to conceptualizing and measuring human life stress. Annu Rev Clin Psychol 4:33–52PubMedCrossRefGoogle Scholar
  137. Moreira FA, Kaiser N, Monory K, Lutz B (2008) Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors. Neuropharmacology 54:141–150PubMedCrossRefGoogle Scholar
  138. Most SB, Chun MM, Johnson MR, Kiehl KA (2006) Attentional modulation of the amygdala varies with personality. Neuroimage 31:934–944PubMedCrossRefGoogle Scholar
  139. Müller M, Holsboer F, Keck ME (2002) Genetic modification of corticosteroid receptor signaling: novel insights into pathophysiology and treatment strategies of human affective disorders. Neuropeptides 36:117–131PubMedCrossRefGoogle Scholar
  140. Munafo MR, Brown SM, Hariri AR (2008) Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry 63:852–857PubMedCrossRefGoogle Scholar
  141. Nelson RJ, Trainor BC (2007) Neural mechanisms of aggression. Nat Rev Neurosci 8:536–546PubMedCrossRefGoogle Scholar
  142. New AS, Hazlett EA, Buchsbaum MS, Goodman M, Mitelman SA, Newmark R et al (2007) Amygdala-prefrontal disconnection in borderline personality disorder. Neuropsychopharmacology 32:1629–1640PubMedCrossRefGoogle Scholar
  143. Newman S (1999) The medial extended amygdala in male reproductive behavior. A node in the mammalian social behavior network. Ann N Y Acad Sci 877:242–257PubMedCrossRefGoogle Scholar
  144. O’Doherty JP (2004) Reward representations and reward-related learning in the human brain: insights from neuroimaging. Curr Opin Neurobiol 14:769–776PubMedCrossRefGoogle Scholar
  145. Onaivi ES, Leonard CM, Ishiguro H, Zhang PW, Lin Z et al (2002) Endocannabinoids and cannabinoid receptor genetics. Prog Neurobiol 66:307–344PubMedCrossRefGoogle Scholar
  146. Parsey RV, Oquendo MA, Ogden RT, Olvet DM, Simpson N et al (2006) Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry 59:106–111PubMedCrossRefGoogle Scholar
  147. Passamonti L, Rowe JB, Ewbank M, Hampshire A, Keane J, Calder AJ (2008) Connectivity from the ventral anterior cingulate to the amygdala is modulated by appetitive motivation in response to facial signals of aggression. Neuroimage 43:562–570PubMedCrossRefGoogle Scholar
  148. Patel S, Cravatt BF, Hillard CJ (2005) Synergistic interactions between cannabinoids and environmental stress in the activation of the central amygdala. Neuropsychopharmacology 30:497–507PubMedCrossRefGoogle Scholar
  149. Phan KL, Fitzgerald DA, Nathan PJ, Tancer ME (2006) Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia. Biol Psychiatry 59:424–429PubMedCrossRefGoogle Scholar
  150. Phan KL, Angstadt M, Golden J, Onyewuenyi I, Popovska A, de Wit H (2008) Cannabinoid modulation of amygdala reactivity to social signals of threat in humans. J Neurosci 28:2313–2319PubMedCrossRefGoogle Scholar
  151. Phillips ML, Drevets WC, Rauch SL, Lane R (2003) Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 54:515–528PubMedCrossRefGoogle Scholar
  152. Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884PubMedCrossRefGoogle Scholar
  153. Piomelli D, Beltramo M, Glasnapp S, Lin SY, Goutopoulos A et al (1999) Structural determinants for recognition and translocation by the anandamide transporter. Proc Natl Acad Sci U S A 96:5802–5807PubMedCrossRefGoogle Scholar
  154. Pruessner JC, Dedovic K, Pressner M, Lord C, Buss C et al (2010) Stress regulation in the central nervous system: evidence from structural and functional neuroimaging studies in human populations. Psychoneuroendocrinology 35:179–191PubMedCrossRefGoogle Scholar
  155. Raine A, Buchsbaum M, LaCasse L (1997) Brain abnormalities in murderers indicated by positron emission tomography. Biol Psychiatry 42:495–508PubMedCrossRefGoogle Scholar
  156. Rajender S, Pandu G, Sharma JD, Gandhi KP, Singh L, Thangaraj K (2008) Reduced CAG repeats length in androgen receptor gene is associated with violent criminal behavior. Int J Legal Med 122:367–372PubMedCrossRefGoogle Scholar
  157. Ray RD, Ochsner KN, Cooper JC, Robertson ER, Gabrieli JD, Gross JJ (2005) Individual differences in trait rumination and the neural systems supporting cognitive reappraisal. Cogn Affect Behav Neurosci 5:156–168PubMedCrossRefGoogle Scholar
  158. Reul JM, Gesing A, Droste S, Stec IS, Weber A et al (2000) The brain mineralocorticoid receptor: greedy for ligand, mysterious in function. Euro J Pharmacol 405:235–249CrossRefGoogle Scholar
  159. Rhodes RA, Murthy NV, Dresner MA, Selvaraj S, Stavrakakis N et al (2007) Human 5-HT transporter availability predicts amygdala reactivity in vivo. J Neurosci 27:9233–9237PubMedCrossRefGoogle Scholar
  160. Robson P (2005) Human studies of cannabinoids and medicinal cannabis. Handb Exp Pharmacol 168:719–756PubMedCrossRefGoogle Scholar
  161. Rodrigues SM, LeDoux JE, Sapolsky RM (2009) The influence of stress hormones on fear circuitry. Annu Rev Neurosci 32:289–313PubMedCrossRefGoogle Scholar
  162. Roney JR, Simmons ZL, Lukaszewski AW (2009) Androgen receptor gene sequence and basal cortisol concentrations predict men’s hormonal responses to potential mates. Proc Soc Biol 277:57–63CrossRefGoogle Scholar
  163. Rozeboom AM, Akil H, Seasholtz AF (2007) Mineralocorticoid receptor overexpression in forebrain decreases anxiety-like behavior and alters the stress response in mice. Proc Natl Acad of Sci U S A 104:4688–4693CrossRefGoogle Scholar
  164. Sadikot AF, Parent A (1990) The monoaminergic innervation of the amygdala in the squirrel monkey: an immunohistochemical study. Neuroscience 36:431–447PubMedCrossRefGoogle Scholar
  165. Scherma M, Medalie J, Fratta W, Vadivel SK, Makriyannis A et al (2008) The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition. Neuropharmacology 54:129–140PubMedCrossRefGoogle Scholar
  166. Sesack SR, Hawrylak VA, Guido MA, Levey AI (1998) Cellular and subcellular localization of the dopamine transporter in rat cortex. Adv Pharmacol 42:171–174PubMedCrossRefGoogle Scholar
  167. Sharp T, Boothman L, Raley J, Queree P (2007) Important messages in the ‘post’: recent discoveries in 5-HT neurone feedback control. Trends Pharmacol Sci 28:629–636PubMedCrossRefGoogle Scholar
  168. Siessmeier T, Kienast T, Wrase J, Larsen JL, Braus DF et al (2006) Net influx of plasma 6-[18F]fluoro-l-DOPA (FDOPA) to the ventral striatum correlates with prefrontal processing of affective stimuli. Eur J Neurosci 24:305–313PubMedCrossRefGoogle Scholar
  169. Siever LJ (2008) Neurobiology of aggression and violence. Am J Psychiatry 165:429–442PubMedCrossRefGoogle Scholar
  170. Simon NG (2002) Hormonal processes in the development and expression of aggressive behavior. In: Pfaff DW et al (eds) Hormones, brain and behavior. Academic Press, San DiegoGoogle Scholar
  171. Simpson CA, Vuchinich RE (2000) Reliability of a measure of temporal discounting. Psychol Rec 50:3–16Google Scholar
  172. Sipe JC, Chiang K, Gerber AL, Beutler E, Cravatt BF (2002) A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci U S A 99:8394–8399PubMedCrossRefGoogle Scholar
  173. Solinas M, Tanda G, Justinova Z, Wertheim CE, Yasar S et al (2007) The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport. J Pharmacol Exp Ther 321:370–380PubMedCrossRefGoogle Scholar
  174. Somerville LH, Kim H, Johnstone T, Alexander AL, Whalen PJ (2004) Human amygdala responses during presentation of happy and neutral faces: correlations with state anxiety. Biol Psychiatry 55:897–903PubMedCrossRefGoogle Scholar
  175. Sorice-Gomez E, Matias I, Rueda-Orozco PE, Cisneros M, Petrosino S et al (2007) Pharmacological enhancement of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increases c-Fos expression in the hypothalamus. Br J Pharmacol 151:1109–1116CrossRefGoogle Scholar
  176. Stein MB, Goldin PR, Sareen J, Zorrilla LT, Brown GG (2002) Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry 59:1027–1034PubMedCrossRefGoogle Scholar
  177. Stein MB, Simmons AN, Feinstein JS, Paulus MP (2007) Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry 164:318–327PubMedCrossRefGoogle Scholar
  178. Tarullo AR, Gunnar MR (2006) Child maltreatment and the developing HPA axis. Hormones Behav 50:632–639CrossRefGoogle Scholar
  179. Tessitore A, Hariri AR, Fera F, Smith WG, Chase TN et al (2002) Dopamine modulates the response of the human amygdala: a study in Parkinson’s disease. J Neurosci 22:9099–9103PubMedGoogle Scholar
  180. Thode K, Walss-Bass C, Hariri AR, Olvera R, Munoz K, et al Functional evidence implicating the role of the corticotropin-releasing hormone receptor 1 in the development of stress-related disorders. Am J Psychiatry (unpublished observation)Google Scholar
  181. Tyndale RF, Payne JI, Gerber AL, Sipe JC (2007) The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: studies of drug use and dependence in Caucasians. Am J Med Genet B Neuropsychiatr Genet 144:660–666Google Scholar
  182. Ulrich-Lai YM, Herman JP (2009) Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10:397–409PubMedCrossRefGoogle Scholar
  183. Urry HL, van Reekum CM, Johnstone T, Kalin NH, Thurow ME et al (2006) Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict diurnal pattern of cortisol secretion among older adults. J Neurosci 26:4415–4425PubMedCrossRefGoogle Scholar
  184. van Dyck CH, Malison RT, Jacobsen LK, Seibyl JP, Staley JK et al (2005) Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. J Nucl Med 46:745–751PubMedGoogle Scholar
  185. Van Leeuwen N, Kumsta R, Entringer S, de Kloet ER, Zitman FG, DeRijk RH, Wust S (2010) Functional mineralocorticoid receptor (MR) gene variation influences the cortisol awakening response after dexamethasone. Psychoneuroendocrinology 35:339–349PubMedCrossRefGoogle Scholar
  186. Van Ness SH, Owens MJ, Kilts CD (2005) The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet 6:55CrossRefGoogle Scholar
  187. van Praag HM, de Kloet R, van Os J (2004) Stress the brain and depression. Cambridge University Press, New YorkCrossRefGoogle Scholar
  188. van Wingen GA, Zylick SA, Pieters S, Mattern C, Verkes RJ, Buitelaar JK, Fernandez G (2008) Testosterone increases amygdala reactivity in middle-aged women to a young adulthood level. Neuropsychopharmacology 34:539–547PubMedCrossRefGoogle Scholar
  189. van Wingen GA, Mattern C, Verkes RJ, Buitelaar J, Fernandez G (2010) Testosterone reduces amygdala-orbitalfrontal cortex coupling. Psychoneuroendocrinology 35:105–113PubMedCrossRefGoogle Scholar
  190. Vermeersch H, T’Sjoen G, Kaufman JM, Vincke J, Van Houtte M (2010) Testosterone, androgen receptor gene CAG repeat length, mood and behaviour in adolescent males. Eur J Endocrinol 163:319–328PubMedCrossRefGoogle Scholar
  191. Viding E, Williamson DE, Hariri AR (2006) Developmental imaging genetics: challenges and promises for translational research. Dev Psychopathol 18:877–892PubMedCrossRefGoogle Scholar
  192. Viveros MP, Marco EM, File SE (2005) Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 81:331–342PubMedCrossRefGoogle Scholar
  193. Volkow ND, Fowler JS, Wang GJ (1999) Imaging studies on the role of dopamine in cocaine reinforcement and addiction in humans. J Psychopharmacol 13:337–345PubMedCrossRefGoogle Scholar
  194. Wei XY, Yang JY, Dong YX, Wu CF (2007) Anxiolytic-like effects of oleamide in group-housed and socially isolated mice. Prog Neuropsychopharmacolo Biol Psychiatry 31:1189–1195CrossRefGoogle Scholar
  195. Whalen PJ, Shin LM, Somerville LH, McLean AA, Kim H (2002) Functional neuroimaging studies of the amygdala in depression. Semin Clin Neuropsychiatry 7:234–242PubMedCrossRefGoogle Scholar
  196. Williamson DE, Birmaher B, Ryan ND, Shiffrin TP, Lusky JA et al (2003) The stressful life events schedule for children and adolescents: development and validation. Psychiatry Res 119:225–241PubMedCrossRefGoogle Scholar
  197. Yehuda R (2002) Post-traumatic stress disorder. N Engl J Med 346:108–114PubMedCrossRefGoogle Scholar
  198. Zitzmann M, Nieschlag E (2003) The CAG repeat polymorphism within the androgen receptor gene and maleness. Int J Androl 26:76–83PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Ryan Bogdan
    • 1
    Email author
  • Justin M. Carré
    • 1
    • 2
  • Ahmad R. Hariri
    • 1
  1. 1.Laboratory of NeuroGenetics, Department of Psychology & NeuroscienceInstitute for Genome Sciences & Policy, Duke UniversityDurhamUSA
  2. 2.Laboratory of Social NeuroendocrinologyDepartment of Psychology, Wayne State UniversityDetroitUSA

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