Functional Association Between the Brain and Physiological Responses Accompanying Negative and Positive Emotions and Its Regulation by Genetic Factors

  • Hideki Ohira
Part of the Primatology Monographs book series (PrimMono)


Negative emotions such as fear and acute stress elicit integrated enhancement of responses in the cardiovascular system, hypothalamo–pituitary–adrenocortical axis, and innate immunity. On the other hand, during experiences of positive emotions, secretion of central and peripheral dopamine and natural killer cell activity are enhanced without increased sympathetic activity. Such physiological responses accompanying emotions are not rigid and stereotyped but can be flexibly regulated by the brain on the basis of cognitive appraisal of the emotional situation. Using a combination of neuroimaging and physiological recording in humans, we have shown that a neural network that includes several portions of the prefrontal cortex and limbic regions plays a key role in the regulation of emotion. Furthermore, there are wide individual differences in the emotional reactivity in both negative and positive emotional domains. Genetic factors such as gene polymorphisms of the serotonin transporter gene and the opioid receptor gene can explain portions of the individual differences of emotional reactivity.


Positron Emission Tomography Natural Killer Cell Emotion Regulation Positive Emotion Natural Killer Cell Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author sincerely thanks the following collaborators for their excellent contributions to the studies contained in this chapter: Dr. Tetsuya Iidaka (Nagoya University), Dr. Michio Nomura (Kyoto University), Dr. Masahiro Matsunaga (Fujita Health University), Dr. Tokiko Isowa (Mie University), Dr. Kenta Kimura (Nagoya University), Ms. Naho Ichikawa (University of Pittsburgh), Mr. Makoto Miyakoshi (National Center for Geriatrics and Gerontology), Dr. Noriaki Kanayama (The University of Tokyo), Mr. Hiroki Murakami (National Center of Neurology and Psychiatry), and Mr. Takahiro Osumi (Nagoya University).


  1. Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci 8:365–371CrossRefPubMedGoogle Scholar
  2. Bargh JA (1997) The automaticity in everyday life. In: Wyer RS Jr (ed) Advances in social cognition, vol 10. Lawrence Erlbaum Association, Mahwah, pp 1–61Google Scholar
  3. Barr CS, Newman TK, Shannon C, Parker C, Dvoskin RL, Becker ML, Schwandt M, Champoux M, Lesch KP, Goldman D, Suomi SJ, Higley JD (2004) Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic–pituitary–adrenal axis response to stress in infant macaques. Biol Psychiatry 55:733–738CrossRefPubMedGoogle Scholar
  4. Bland ST, Hargrave D, Pepin JL, Amat J, Watkins LR, Maier SF (2003) Stressor controllability modulates stress-induced dopamine and serotonin efflux and morphine-induced serotonin efflux in the medial prefrontal cortex. Neuropsychopharmacology 28:1589–1596CrossRefPubMedGoogle Scholar
  5. Blascovich J, Mendes WB, Hunter SB, Salomon K (1999) Social “facilitation” as challenge and threat. J Pers Soc Psychol 77:68–77CrossRefPubMedGoogle Scholar
  6. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, Gong J, Schluger J, Strong JA, Leal SM, Tischfield JA, Kreek M, Yu L (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 95:9608–9613CrossRefPubMedGoogle Scholar
  7. Bosch JA, Berntson GG, Cacioppo JT, Marucha PT (2005) Differential mobilization of functionally distinct natural killer subsets during acute psychologic stress. Psychosom Med 67:366–375CrossRefPubMedGoogle Scholar
  8. Bowers MB Jr, Malison RT, Seibyl JP, Kosten TR (1998) Plasma homovanillic acid and the dopamine transporter during cocaine withdrawal. Biol Psychiatry 43:278–281CrossRefPubMedGoogle Scholar
  9. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389CrossRefPubMedGoogle Scholar
  10. Cavada C, Company T, Tejedor J, Cruz-Rizzolo RJ, Reinoso-Suarez F (2000) The anatomical connections of the macaque monkey orbitofrontal cortex. A review. Cereb Cortex 10:220–242CrossRefPubMedGoogle Scholar
  11. Charmandari E, Tsigos C, Chrousos G (2005) Endocrinology of the stress response. Annu Rev Physiol 67:259–284CrossRefPubMedGoogle Scholar
  12. Chiao JY, Blizinsky KD (2010) Culture-gene coevolution of individualism-collectivism and the serotonin transporter gene. Proc Biol Sci 277:529–537CrossRefPubMedGoogle Scholar
  13. Chou WY, Yang LC, Lu HF, Ko JY, Wang CH, Lin SH, Lee TH, Concejero A, Hsu CJ (2006) Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 50:787–792CrossRefPubMedGoogle Scholar
  14. Cohen S, Doyle WJ, Turner RB, Alper CM, Skoner DP (2003) Emotional style and susceptibility to the common cold. Psychosom Med 65:652–657CrossRefPubMedGoogle Scholar
  15. Collier DA, Stöber G, Li T, Heils A, Catalano M, Di Bella D (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460PubMedGoogle Scholar
  16. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56CrossRefPubMedGoogle Scholar
  17. Dhabhar FS, Miller AH, McEwen BS, Spencer RL (1995) Effects of stress on immune cell distribution: dynamics and hormonal mechanisms. J Immunol 154:5511–5527PubMedGoogle Scholar
  18. Engler H, Dawils L, Hoves S, Kurth S, Stevenson JR, Schauenstein K, Stefanski V (2004) Effects of social stress on blood leukocyte distribution: the role of alpha- and beta-adrenergic mechanisms. J Neuroimmunol 156:153–162CrossRefPubMedGoogle Scholar
  19. Esch T, Stefano GB (2005) Love promotes health. Neuroendocrinol Lett 26:52–55Google Scholar
  20. Fuster JM (1999) Synopsis of function and dysfunction of the frontal lobe. Acta Psychiatr Scand 99:51–57CrossRefGoogle Scholar
  21. Garavan H, Ross TJ, Stein EA (1999) Right hemispheric dominance of inhibitory control: an event-related functional MRI study. Proc Natl Acad Sci USA 96:8301–8306CrossRefPubMedGoogle Scholar
  22. Goldman-Rakic PS (1987) Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In: Plum F (ed) Handbook of physiology, vol 15(1). The nervous system, higher functions of the brain. American Physiological Society, Bethesda, pp 373–417Google Scholar
  23. Gotlib IH, Joormann J, Minor KL, Hallmayer J (2008) HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry 63:847–851CrossRefPubMedGoogle Scholar
  24. Haake P, Krueger TH, Goebel MU, Heberling KM, Hartmann U, Schedlowski M (2004) Effects of sexual arousal on lymphocyte subset circulation and cytokine production in man. NeuroImmunomodulation 11:293–298CrossRefPubMedGoogle Scholar
  25. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400–403CrossRefPubMedGoogle Scholar
  26. Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, Riederer P, Lesch KP (1995) Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm Gen Sect 102:247–254CrossRefPubMedGoogle Scholar
  27. Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624CrossRefPubMedGoogle Scholar
  28. Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S, Grüsser SM, Flor H, Schumann G, Mann K, Büchel C (2005) Amygdala–prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 8:20–21CrossRefPubMedGoogle Scholar
  29. Isowa T, Ohira H, Murashima S (2004) Reactivity of immune, endocrine and cardiovascular parameters to active and passive acute stress. Biol Psychol 65:101–120CrossRefPubMedGoogle Scholar
  30. Isowa T, Ohira H, Murashima S (2006) Immune, endocrine and cardiovascular responses to controllable and uncontrollable acute stress. Biol Psychol 71:202–213CrossRefPubMedGoogle Scholar
  31. Kimura K, Isowa T, Ohira H, Murashima S (2005) Temporal variation of acute stress responses in sympathetic nervous and immune systems. Biol Psychol 70:131–139CrossRefPubMedGoogle Scholar
  32. Kimura K, Ohira H, Isowa T, Matsunaga M, Murashima S (2007) Regulation of lymphocytes redistribution via autonomic nervous activity during stochastic learning. Brain Behav Immun 21:921–934CrossRefPubMedGoogle Scholar
  33. Konishi S, Nakajima K, Uchida I, Kikyo H, Kameyama M, Miyashita Y (1999) Common inhibitory mechanism in human inferior prefrontal cortex revealed by event-related functional MRI. Brain 122:981–991CrossRefPubMedGoogle Scholar
  34. Kringelbach ML, Rolls ET (2004) The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology. Prog Neurobiol 72:341–372CrossRefGoogle Scholar
  35. Lang PJ, Bradley MM, Cuthbert BN (1995) International affective picture system (IAPS). National Institute of Mental Health Center for the Study of Emotion and Attention, BethesdaGoogle Scholar
  36. Lazarus RS, Folkman S (1984) Stress, appraisal, and coping. Springer, New YorkGoogle Scholar
  37. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531CrossRefPubMedGoogle Scholar
  38. Lötsch J, Stuck B, Hummel T (2006) The human l-opioid receptor gene polymorphism 118A  >  G decreases cortical activation in response to specific nociceptive stimulation. Behav Neurosci 120:1218–1224CrossRefPubMedGoogle Scholar
  39. 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 29:829–841CrossRefPubMedGoogle Scholar
  40. Marsland AL, Cohen S, Rabin BS, Manuck SB (2006) Trait positive affect and antibody response to hepatitis B vaccination. Brain Behav Immun 20:261–269CrossRefPubMedGoogle Scholar
  41. Matsunaga M, Isowa T, Kimura K, Miyakoshi M, Kanayama N, Murakami H, Sato S, Konagaya T, Nogimori T, Fukuyama S, Shinoda J, Yamada J, Ohira H (2008) Associations among central nervous, endocrine, and immune activities when positive emotions are elicited by looking at a favorite person. Brain Behav Immun 22:408–417CrossRefPubMedGoogle Scholar
  42. Matsunaga M, Isowa T, Murakami H, Kasugai K, Yoneda M, Kaneko H, Ohira H (2009) Association of polymorphism in the human mu-opioid receptor OPRM1 gene with proinflammatory cytokine levels and health perception. Brain Behav Immun 23:931–935CrossRefPubMedGoogle Scholar
  43. Matsunaga M, Murakami H, Yamakawa K, Isowa T, Kasugai K, Yoneda M, Kaneko H, Fukuyama S, Shinoda J, Yamada J, Ohira H (2010) Genetic variations in the serotonin transporter gene-linked polymorphic region influence attraction for a favorite person and the associated interactions between the central nervous and immune systems. Neurosci Lett 468:211–215CrossRefPubMedGoogle Scholar
  44. McCaffery JM, Bleil M, Pogue-Geile MF, Ferrell RE, Manuck SB (2003) Allelic variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cardiovascular reactivity in young adult male and female twins of European–American descent. Psychosom Med 65:721–728CrossRefPubMedGoogle Scholar
  45. McEwen BS (1998) Stress, adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci 840:33–44CrossRefPubMedGoogle Scholar
  46. McKenna F, McLaughlin PJ, Lewis BJ, Sibbring GC, Cummerson JA, Bowen-Jones D, Moots RJ (2002) Dopamine receptor expression on human T- and B-lymphocytes, monocytes, neutrophils, eosinophils and NK cells: a flow cytometric study. J Neuroimmunol 132:34–40CrossRefPubMedGoogle Scholar
  47. Mills PJ, Berry CC, Dimsdale JE, Ziegler MG, Nelesen RA, Kennedy BP (1995) Lymphocyte subset redistribution in response to acute experimental stress: effects of gender, ethnicity, hypertension, and the sympathetic nervous system. Brain Behav Immun 9:61–69CrossRefPubMedGoogle Scholar
  48. Mizuno T, Aoki M, Shimada Y, Inoue M, Nakaya K, Takahashi T, Itoyama Y, Kanazawa M, Utsumi A, Endo Y, Nomura T, Hiratsuka M, Mizugaki M, Goto J, Hongo M, Fukudo S (2006) Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety. J Psychosom Res 60:91–97CrossRefPubMedGoogle Scholar
  49. Morris JS, Öhman A, Dolan RJ (1998) Conscious and unconscious emotional learning in the human amygdala. Nature 393:467–470CrossRefPubMedGoogle Scholar
  50. Morris JS, Öhman A, Dolan RJ (1999) A subcortical pathway to the right amygdala mediating “unseen” fear. Proc Natl Acad Sci USA 96:1680–1685CrossRefPubMedGoogle Scholar
  51. Murphy ST, Zajonc RB (1993) Affect, cognition, and awareness: affective priming with optimal and suboptimal stimulus exposures. J Pers Soc Psychol 64:723–739CrossRefPubMedGoogle Scholar
  52. Murray EA (2007) The amygdala, reward and emotion. Trends Cogn Sci 11:489–497CrossRefPubMedGoogle Scholar
  53. Nomura M, Ohira H, Haneda K, Iidaka T, Sadato N, Okada T, Yonekura Y (2004) Functional association of the amygdala and ventral prefrontal cortex during cognitive evaluation of facial expressions primed by masked angry faces: an event-related fMRI study. Neuroimage 21:352–363CrossRefPubMedGoogle Scholar
  54. Ohira H, Nomura M, Ichikawa N, Isowa T, Iidaka T, Sato A, Fukuyama S, Nakajima T, Yamada J (2006) Association of neural and physiological responses during voluntary emotion suppression. Neuroimage 29:721–733CrossRefPubMedGoogle Scholar
  55. Ohira H, Isowa T, Nomura M, Ichikawa N, Kimura K, Miyakoshi M, Iidaka T, Fukuyama S, Nakajima T, Yamada J (2008) Imaging brain and immune association accompanying cognitive appraisal of an acute stressor. Neuroimage 39:500–514CrossRefPubMedGoogle Scholar
  56. Ohira H, Fukuyama S, Kimura K, Nomura M, Isowa T, Ichikawa N, Matsunaga M, Shinoda J, Yamada J (2009a) Regulation of natural killer cell redistribution by prefrontal cortex during stochastic learning. Neuroimage 47:897–907CrossRefPubMedGoogle Scholar
  57. Ohira H, Matsunaga M, Isowa T, Nomura M, Ichikawa N, Kimura K, Kanayama N, Murakami H, Osumi T, Konagaya T, Nogimori T, Fukuyama S, Shinoda J, Yamada J (2009b) Polymorphism of the serotonin transporter gene modulates brain and physiological responses to acute stress in Japanese men. Stress 12:533–543Google Scholar
  58. Peters ML, Godaert GL, Ballieux RE, Brosschot JF, Sweep FC, Swinkels LM, van Vliet M, Heijnen CJ (1999) Immune responses to experimental stress: effects of mental effort and uncontrollability. Psychosom Med 61:513–524PubMedGoogle Scholar
  59. Peters ML, Godaert GL, Ballieux RE, Heijnen CJ (2003) Moderation of physiological stress responses by personality traits and daily hassles: less flexibility of immune system responses. Biol Psychol 65:21–48CrossRefPubMedGoogle Scholar
  60. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR (2005) 5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 8:828–834CrossRefPubMedGoogle Scholar
  61. Planalp S, Fitness J, Fehr B (2006) Emotion in theories of close relationships. In: Vangelisti A, Perlman D (eds) The Cambridge handbook of personal relationships. Cambridge University Press, Cambridge, pp 369–384CrossRefGoogle Scholar
  62. Price JL (1999) Prefrontal cortical networks related to visceral function and mood. Ann N Y Acad Sci 877:383–396CrossRefPubMedGoogle Scholar
  63. Price JL (2003) Comparative aspects of amygdala connectivity. Ann N Y Acad Sci 985:50–58CrossRefPubMedGoogle Scholar
  64. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD (1993) Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA 90:2542–2546CrossRefPubMedGoogle Scholar
  65. Ray LA, Hutchison KE (2004) A polymorphism of the l-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol Clin Exp Res 28:1789–1795CrossRefPubMedGoogle Scholar
  66. Stefano GB, Esch T (2005) Love and stress. Neuroendocrinol Lett 26:173–174PubMedGoogle Scholar
  67. Straub RH, Herrmann M, Berkmiller G, Frauenholz T, Lang B, Schölmerich J, Falk W (1997) Neuronal regulation of interleukin 6 secretion in murine spleen: adrenergic and opioidergic control. J Neurochem 68:1633–1639CrossRefPubMedGoogle Scholar
  68. Tjurmina OA, Armando I, Saavedra JM, Goldstein DS, Murphy DL (2002) Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology 143:4520–4526CrossRefPubMedGoogle Scholar
  69. Whalen PJ, Phelps EA (2009) The human amygdala. Guilford Press, New YorkGoogle Scholar
  70. Whalen PJ, Rauch SL, Etoff NL, McInerney SC, Lee MB, Jenike MA (1998) Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. J Neurosci 18:411–418PubMedGoogle Scholar
  71. Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, Kuhn CM, Lewis JG, Schanberg SM, Stafford-Smith M, Suarez EC, Clary GL, Svenson IK, Siegler IC (2001) Central nervous system serotonin function and cardiovascular responses to stress. Psychosom Med 63:300–305PubMedGoogle Scholar
  72. Won SJ, Chuang YC, Huang WT, Liu HS, Lin MT (1995) Suppression of natural killer cell activity in mouse spleen lymphocytes by several dopamine receptor antagonists. Experientia 51:343–348CrossRefPubMedGoogle Scholar

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© Springer 2011

Authors and Affiliations

  1. 1.Department of PsychologyGraduate School of Environmental Studies, Nagoya UniversityNagoyaJapan

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