Increasing Resilience to Traumatic Stress: Understanding the Protective Role of Well-Being

  • J. Tory Toole
  • Mark A. RiceJr
  • Jordan Cargill
  • Travis J. A. Craddock
  • Barry Nierenberg
  • Nancy G. Klimas
  • Mary Ann Fletcher
  • Mariana Morris
  • Joel Zysman
  • Gordon BroderickEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1781)


The brain maintains homeostasis in part through a network of feedback and feed-forward mechanisms, where neurochemicals and immune markers act as mediators. Using a previously constructed model of biobehavioral feedback, we found that in addition to healthy equilibrium another stable regulatory program supported chronic depression and anxiety. Exploring mechanisms that might underlie the contributions of subjective well-being to improved therapeutic outcomes in depression, we iteratively screened 288 candidate feedback patterns linking well-being to molecular signaling networks for those that maintained the original homeostatic regimes. Simulating stressful trigger events on each candidate network while maintaining high levels of subjective well-being isolated a specific feedback network where well-being was promoted by dopamine and acetylcholine, and itself promoted norepinephrine while inhibiting cortisol expression. This biobehavioral feedback mechanism was especially effective in reproducing well-being’s clinically documented ability to promote resilience and protect against onset of depression and anxiety.

Key words

Computational modeling Reverse engineering Homeostatic regulation Depression Well-being Positive psychology 



Funding was provided by US Department of Defense Congressionally Directed Medical Research Program (CDMRP) awards ( GW093042, GW140142 (Broderick—PI), and GW120045 (Morris—PI). This research was conducted in collaboration with the high-performance computing team at the University of Miami Center for Computational Science (CCS) (

Disclaimer: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense.


  1. 1.
    Ryff CD, Keyes CLM (1995) The structure of psychological well-being revisited. J Pers Soc Psychol 69(4):719CrossRefGoogle Scholar
  2. 2.
    Wood AM, Joseph S (2010) The absence of positive psychological (eudemonic) well-being as a risk factor for depression: a ten year cohort study. J Affect Disord 122(3):213–217CrossRefGoogle Scholar
  3. 3.
    Ryff CD, Singer BH, Love GD (2004) Positive health: connecting well-being with biology. Philos Trans R Soc Lond B Biol Sci 359(1449):1383CrossRefGoogle Scholar
  4. 4.
    Fava GA (2016) Well-being therapy. In: The Wiley handbook of positive clinical psychology. Wiley, Hoboken, p 395CrossRefGoogle Scholar
  5. 5.
    Wurtman RJ, Pohorecky LA, Baliga BS (1972) Adrenocortical control of the biosynthesis of epinephrine and proteins in the adrenal medulla. Pharmacol Rev 24(2):411–426PubMedGoogle Scholar
  6. 6.
    Janssen SA, Arntz A, Bouts S (1998) Anxiety and pain: epinephrine-induced hyperalgesia and attentional influences. Pain 76(3):309–316CrossRefGoogle Scholar
  7. 7.
    Piazza PV, Rougé-Pont F, Deroche V, Maccari S, Simon H, Le Moal M (1996) Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission. Proc Natl Acad Sci 93(16):8716–8720CrossRefGoogle Scholar
  8. 8.
    Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z (2009) Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci 106(33):14075–14079CrossRefGoogle Scholar
  9. 9.
    Tafet GE, Toister-Achituv M, Shinitzky M (2001) Enhancement of serotonin uptake by cortisol: a possible link between stress and depression. Cogn Affect Behav Neurosci 1(1):96–104CrossRefGoogle Scholar
  10. 10.
    Bergstrom DA, Walters JR (1984) Dopamine attenuates the effects of GABA on single unit activity in the globus pallidus. Brain Res 310(1):23–33CrossRefGoogle Scholar
  11. 11.
    Daw ND, Kakade S, Dayan P (2002) Opponent interactions between serotonin and dopamine. Neural Netw 15(4):603–616CrossRefGoogle Scholar
  12. 12.
    Gillard ER, Dang DQ, Stanley BG (1993) Evidence that neuropeptide Y and dopamine in the perifornical hypothalamus interact antagonistically in the control of food intake. Brain Res 628(1):128–136CrossRefGoogle Scholar
  13. 13.
    El Mansari M, Guiard BP, Chernoloz O, Ghanbari R, Katz N, Blier P (2010) Relevance of norepinephrine–dopamine interactions in the treatment of major depressive disorder. CNS Neurosci Ther 16(3):e1–e17CrossRefGoogle Scholar
  14. 14.
    Calabresi P, Picconi B, Parnetti L, Di Filippo M (2006) A convergent model for cognitive dysfunctions in Parkinson’s disease: the critical dopamine–acetylcholine synaptic balance. Lancet Neurol 5(11):974–983CrossRefGoogle Scholar
  15. 15.
    Biello SM, Golombek DA, Harrington ME (1997) Neuropeptide Y and glutamate block each other’s phase shifts in the suprachiasmatic nucleus in vitro. Neuroscience 77(4):1049–1057CrossRefGoogle Scholar
  16. 16.
    Serfozo P, Bartfai T, Vizi ES (1986) Presynaptic effects of neuropeptide Y on [3 H] noradrenaline and [3 H] acetylcholine release. Regul Pept 16(2):117–123CrossRefGoogle Scholar
  17. 17.
    Dryden S, McCarthy HD, Malabu UH, Ware M, Williams G (1993) Increased neuropeptide Y concentrations in specific hypothalamic nuclei of the rat following treatment with methysergide: evidence that NPY may mediate serotonin’s effects on food intake. Peptides 14(4):791–796CrossRefGoogle Scholar
  18. 18.
    Herman JP, Renda A, Bodie B (2003) Norepinephrine–gamma-aminobutyric acid (GABA) interaction in limbic stress circuits: effects of reboxetine on GABAergic neurons. Biol Psychiatry 53(2):166–174CrossRefGoogle Scholar
  19. 19.
    Wahlestedt CLAES, Hakanson ROLF, Vaz CA, Zukowska-Grojec ZOFIA (1990) Norepinephrine and neuropeptide Y: vasoconstrictor cooperation in vivo and in vitro. Am J Phys Regul Integr Comp Phys 258(3):R736–R742Google Scholar
  20. 20.
    Bremner JD, Krystal JH, Southwick SM, Charney DS (1996) Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 23(1):39–51CrossRefGoogle Scholar
  21. 21.
    Southwick SM, Bremner JD, Rasmusson A, Morgan CA, Arnsten A, Charney DS (1999) Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry 46(9):1192–1204CrossRefGoogle Scholar
  22. 22.
    Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27(5):699–711CrossRefGoogle Scholar
  23. 23.
    Zhang K, Grady CJ, Tsapakis EM, Andersen SL, Tarazi FI, Baldessarini RJ (2004) Regulation of working memory by dopamine D4 receptor in rats. Neuropsychopharmacology 29(9):1648CrossRefGoogle Scholar
  24. 24.
    Delgado PL, Moreno FA (1999) Role of norepinephrine in depression. J Clin Psychiatry 61:5–12Google Scholar
  25. 25.
    Casey DE, Gerlach J, Christensson E (1980) Behavioral aspects of GABA-dopamine interrelationships in the monkey. Brain Res Bull 5:269–273CrossRefGoogle Scholar
  26. 26.
    Moises HC, Woodward DJ (1980) Potentiation of GABA inhibitory action in cerebellum by locus coeruleus stimulation. Brain Res 182(2):327–344CrossRefGoogle Scholar
  27. 27.
    Bankson MG, Yamamoto BK (2004) Serotonin–GABA interactions modulate MDMA-induced mesolimbic dopamine release. J Neurochem 91(4):852–859CrossRefGoogle Scholar
  28. 28.
    Edden RA, Crocetti D, Zhu H, Gilbert DL, Mostofsky SH (2012) Reduced GABA concentration in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 69(7):750–753CrossRefGoogle Scholar
  29. 29.
    Russell VA, Wiggins TM (2000) Increased glutamate-stimulated norepinephrine release from prefrontal cortex slices of spontaneously hypertensive rats. Metab Brain Dis 15(4):297–304CrossRefGoogle Scholar
  30. 30.
    Mathew SJ, Coplan JD, Smith EL, Schoepp DD, Rosenblum LA, Gorman JM (2001) Glutamate—hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders. CNS Spectr 6(07):555–564CrossRefGoogle Scholar
  31. 31.
    Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 41(1):237–260CrossRefGoogle Scholar
  32. 32.
    Aultman JM, Moghaddam B (2001) Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task. Psychopharmacology 153(3):353–364CrossRefGoogle Scholar
  33. 33.
    Carrey NJ, MacMaster FP, Gaudet L, Schmidt MH (2007) Striatal creatine and glutamate/glutamine in attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 17(1):11–17CrossRefGoogle Scholar
  34. 34.
    Paul IA, Skolnick P (2003) Glutamate and depression. Ann N Y Acad Sci 1003(1):250–272CrossRefGoogle Scholar
  35. 35.
    Van Praag HM, Kahn RS, Asnis GM, Wetzler S, Brown SL, Bleich A, Korn ML (1987) Denosologization of biological psychiatry or the specificity of 5-HT disturbances in psychiatric disorders. J Affect Disord 13(1):1–8CrossRefGoogle Scholar
  36. 36.
    Aghajanian GK, Marek GJ (1999) Serotonin–glutamate interactions: a new target for antipsychotic drugs. Neuropsychopharmacology 21:S122–S133CrossRefGoogle Scholar
  37. 37.
    MacDermot J, Higashida H, Wilson SP, Matsuzawa H, Minna J, Nirenberg M (1979) Adenylate cyclase and acetylcholine release regulated by separate serotonin receptors of somatic cell hybrids. Proc Natl Acad Sci 76(3):1135–1139CrossRefGoogle Scholar
  38. 38.
    Keely SL, Lincoln TM, Corbin JD (1978) Interaction of acetylcholine and epinephrine on heart cyclic AMP-dependent protein kinase. Am J Phys Heart Circ Phys 234(4):H432–H438Google Scholar
  39. 39.
    Dixon JS, Jen PY, Gosling JA (2000) The distribution of vesicular acetylcholine transporter in the human male genitourinary organs and its co-localization with neuropeptide Y and nitric oxide synthase. Neurourol Urodyn 19(2):185–194CrossRefGoogle Scholar
  40. 40.
    Walker SW, Strachan MWJ, Lightly ERT, Williams BC, Bird IM (1990) Acetylcholine stimulates cortisol secretion through the M3 muscarinic receptor linked to a polyphosphoinositide-specific phospholipase C in bovine adrenal fasciculata/reticularis cells. Mol Cell Endocrinol 72(3):227–238CrossRefGoogle Scholar
  41. 41.
    Kalsner S, Quillan M (1988) Presynaptic interactions between acetylcholine and adrenergic antagonists on norepinephrine release. J Pharmacol Exp Ther 244(3):879–891PubMedGoogle Scholar
  42. 42.
    Leboulenger F, Benyamina M, Delarue C, Netchitailo P, Saint-Pierre S, Vaudry H (1988) Neuronal and paracrine regulation of adrenal steroidogenesis: interactions between acetylcholine, serotonin and vasoactive intestinal peptide (VIP) on corticosteroid production by frog interrenal tissue. Brain Res 453(1):103–109CrossRefGoogle Scholar
  43. 43.
    Guiard BP, El Mansari M, Merali Z, Blier P (2008) Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. Int J Neuropsychopharmacol 11(5):625–639CrossRefGoogle Scholar
  44. 44.
    Korsgaard S, Gerlach J, Christensson E (1985) Behavioral aspects of serotonin-dopamine interaction in the monkey. Eur J Pharmacol 118(3):245–252CrossRefGoogle Scholar
  45. 45.
    O’hara R, Schröder CM, Mahadevan R, Schatzberg AF, Lindley S, Fox S et al (2007) Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol. Mol Psychiatry 12(6):544–555CrossRefGoogle Scholar
  46. 46.
    Connor KM, Davidson JR (1998) The role of serotonin in posttraumatic stress disorder: neurobiology and pharmacotherapy. CNS Spectr 3(S2):42–51CrossRefGoogle Scholar
  47. 47.
    Charney DS, Woods SW, Goodman WK, Heninger GR (1987) Serotonin function in anxiety. Psychopharmacology 92(1):14–24CrossRefGoogle Scholar
  48. 48.
    Owens MJ, Nemeroff CB (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40(2):288–295PubMedGoogle Scholar
  49. 49.
    Roelands B, Meeusen R (2010) Alterations in central fatigue by pharmacological manipulations of neurotransmitters in normal and high ambient temperature. Sports Med 40(3):229–246CrossRefGoogle Scholar
  50. 50.
    Czermak C, Staley JK, Kasserman S, Bois F, Young T, Henry S, Tamagnan GD, Seibyl JP, Krystal JH, Neumeister A (2008) β2 Nicotinic acetylcholine receptor availability in post-traumatic stress disorder. Int J Neuropsychopharmacol 11(3):419–424CrossRefGoogle Scholar
  51. 51.
    Botly LC, De Rosa E (2008) A cross-species investigation of acetylcholine, attention, and feature binding. Psychol Sci 19(11):1185–1193CrossRefGoogle Scholar
  52. 52.
    Daniel JM, Dohanich GP (2001) Acetylcholine mediates the estrogen-induced increase in NMDA receptor binding in CA1 of the hippocampus and the associated improvement in working memory. J Neurosci 21(17):6949–6956CrossRefGoogle Scholar
  53. 53.
    Mendoza L, Xenarios I (2006) Theoretical biology and medical Modelling. Theor Biol Med Model 3:13CrossRefGoogle Scholar
  54. 54.
    Thomas R (1991) Regulatory networks seen as asynchronous automata: a logical description. J Theor Biol 153(1):1–23CrossRefGoogle Scholar
  55. 55.
    Craddock TJ, Fritsch P, Rice MA Jr, del Rosario RM, Miller DB, Fletcher MA, Klimas NG, Broderick G (2014) A role for homeostatic drive in the perpetuation of complex chronic illness: gulf war illness and chronic fatigue syndrome. PLoS One 9(1):e84839CrossRefGoogle Scholar
  56. 56.
    Fritsch P, Craddock TJ, del Rosario RM, Rice MA, Smylie A, Folcik VA, de Vries G, Fletcher MA, Klimas NG, Broderick G (2013) Succumbing to the laws of attraction: exploring the sometimes pathogenic versatility of discrete immune logic. Systems Biomedicine 1(3):179–194CrossRefGoogle Scholar
  57. 57.
    Müller N, Schwarz MJ (2007) The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 12:988–1000CrossRefGoogle Scholar
  58. 58.
    Soeteman DI, Miller M, Kim JJ (2012) Modeling the risks and benefits of depression treatment for children and young adults. Value Health 15(5):724–729CrossRefGoogle Scholar
  59. 59.
    Gruwez B, Poirier MF, Dauphin A, Olié JP, Tod M (2007) A kinetic-pharmacodynamic model for clinical trial simulation of antidepressant action: application to clomipramine–lithium interaction. Contemp Clin Trials 28(3):276–287CrossRefGoogle Scholar
  60. 60.
    Holca-Lamarre R, Lücke J, Obermayer K (2017) Models of Acetylcholine and Dopamine Signals Differentially Improve Neural Representations. Front. Comput Neurosci 11:54Google Scholar
  61. 61.
    Cipresso P, Immekus JC (2017) Back to the Future of Quantitative Psychology and Measurement: Psychometrics in the Twenty-First Century. Front Psychol 8:2099Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • J. Tory Toole
    • 1
  • Mark A. RiceJr
    • 1
    • 2
  • Jordan Cargill
    • 1
  • Travis J. A. Craddock
    • 1
    • 3
  • Barry Nierenberg
    • 1
  • Nancy G. Klimas
    • 3
    • 4
  • Mary Ann Fletcher
    • 3
    • 4
  • Mariana Morris
    • 3
    • 4
  • Joel Zysman
    • 6
  • Gordon Broderick
    • 2
    • 5
    Email author
  1. 1.College of Psychology, Nova Southeastern UniversityFt. LauderdaleUSA
  2. 2.Center for Clinical Systems Biology, Rochester General Hospital Research InstituteRochesterUSA
  3. 3.Institute for Neuro-Immune Medicine, Nova Southeastern UniversityFt. LauderdaleUSA
  4. 4.Miami Veterans Affairs Medical CenterMiamiUSA
  5. 5.Department of Biomedical EngineeringRochester Institute of TechnologyRochesterUSA
  6. 6.Center for Computational Science, University of MiamiMiamiUSA

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