Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Stress effects on the neural substrates of motivated behavior

Abstract

Exposure to stress has profound, but complex, actions on motivated behavior and decision-making. These effects are central to core symptoms of a number of psychiatric disorders that are precipitated or augmented by stress, such as depressive disorders and substance use disorders. Studying the neural substrates of stress's effects on motivation has revealed that stress affects multiple targets on circuits throughout the brain using diverse molecular signaling processes. Moreover, stress does not have unitary effects on motivated behavior, but differences in the intensity, duration, intermittency, controllability and nature of the stressor produce qualitatively and quantitatively different behavioral endpoints. Unsurprisingly, the results of neuroscientific investigations into stress and motivation often open more questions than they resolve. Here we discuss contemporary results pertaining to the neural mechanisms by which stress alters motivation, identify points of contention and highlight integrative areas for continuing research into these multifaceted complexities.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Key studies referenced in this review.

Kim Caesar/Nature Publishing Group

Figure 2: Stress effects on effort-based decision-making.

Kim Caesar/Nature Publishing Group

Similar content being viewed by others

References

  1. McEwen, B.S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105–122 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Rodrigues, S.M., Ledoux, J.E. & Sapolsky, R.M. The influence of stress hormones on fear circuitry. Annu. Rev. Neurosci. 32, 289–313 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Willner, P., Towell, A., Sampson, D., Sophokleous, S. & Muscat, R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl.) 93, 358–364 (1987).

    Article  CAS  Google Scholar 

  4. Willner, P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52, 90–110 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Kudryavtseva, N.N., Bakshtanovskaya, I.V. & Koryakina, L.A. Social model of depression in mice of C57BL/6J strain. Pharmacol. Biochem. Behav. 38, 315–320 (1991).

    Article  CAS  PubMed  Google Scholar 

  6. Golden, S.A., Covington, H.E., Berton, O. & Russo, S.J. A standardized protocol for repeated social defeat stress in mice. Nat. Protoc. 6, 1183–1191 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Insel, T.R. & Landis, S.C. Twenty-five years of progress: the view from NIMH and NINDS. Neuron 80, 561–567 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Anisman, H. & Matheson, K. Stress, depression, and anhedonia: caveats concerning animal models. Neurosci. Biobehav. Rev. 29, 525–546 (2005).

    Article  PubMed  Google Scholar 

  10. Nestler, E.J. & Hyman, S.E. Animal models of neuropsychiatric disorders. Nat. Neurosci. 13, 1161–1169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Berton, O., Hahn, C.-G. & Thase, M.E. Are we getting closer to valid translational models for major depression? Science 338, 75–79 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Monteggia, L.M., Malenka, R.C. & Deisseroth, K. Depression: the best way forward. Nature 515, 200–201 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Deisseroth, K. Circuit dynamics of adaptive and maladaptive behavior. Nature 505, 309–317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huang, Z.J. & Zeng, H. Genetic approaches to neural circuits in the mouse. Annu. Rev. Neurosci. 36, 183–215 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Luo, L., Callaway, E.M. & Svoboda, K. Genetic dissection of neural circuits. Neuron 57, 634–660 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fields, H.L., Hjelmstad, G.O., Margolis, E.B. & Nicola, S.M. Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement. Annu. Rev. Neurosci. 30, 289–316 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Berridge, K.C. From prediction error to incentive salience: mesolimbic computation of reward motivation. Eur. J. Neurosci. 35, 1124–1143 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cohen, J.Y., Haesler, S., Vong, L., Lowell, B.B. & Uchida, N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 482, 85–88 (2012). In this work, the authors recorded the firing patterns of neurons in the VTA during reward and punishment procedures. The neurons were neurochemically identified by optogenetics with cell type–specific expression of channelrhodopsin-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nicola, S.M. The nucleus accumbens as part of a basal ganglia action selection circuit. Psychopharmacology (Berl.) 191, 521–550 (2007).

    Article  CAS  Google Scholar 

  20. du Hoffmann, J. & Nicola, S.M. Dopamine invigorates reward seeking by promoting cue-evoked excitation in the nucleus accumbens. J. Neurosci. 34, 14349–14364 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Flagel, S.B. et al. A selective role for dopamine in stimulus-reward learning. Nature 469, 53–57 (2011). This paper demonstrated that multiple valuation systems have different dependencies on dopamine transmission.

    Article  CAS  PubMed  Google Scholar 

  22. Phillips, P.E.M., Stuber, G.D., Heien, M.L.A.V., Wightman, R.M. & Carelli, R.M. Subsecond dopamine release promotes cocaine seeking. Nature 422, 614–618 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Floresco, S.B., Tse, M.T.L. & Ghods-Sharifi, S. Dopaminergic and glutamatergic regulation of effort- and delay-based decision making. Neuropsychopharmacology 33, 1966–1979 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Nicola, S.M. The flexible approach hypothesis: unification of effort and cue-responding hypotheses for the role of nucleus accumbens dopamine in the activation of reward-seeking behavior. J. Neurosci. 30, 16585–16600 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Salamone, J.D., Correa, M., Farrar, A. & Mingote, S.M. Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacology (Berl.) 191, 461–482 (2007).

    Article  CAS  Google Scholar 

  26. Salamone, J.D., Correa, M., Farrar, A.M., Nunes, E.J. & Pardo, M. Dopamine, behavioral economics, and effort. Front. Behav. Neurosci. 3, 13 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Salamone, J.D. & Correa, M. The mysterious motivational functions of mesolimbic dopamine. Neuron 76, 470–485 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Treadway, M.T. et al. Dopaminergic mechanisms of individual differences in human effort-based decision-making. J. Neurosci. 32, 6170–6176 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ikemoto, S. & Panksepp, J. The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res. Brain Res. Rev. 31, 6–41 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Gunaydin, L.A. et al. Natural neural projection dynamics underlying social behavior. Cell 157, 1535–1551 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Aragona, B.J. et al. Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds. Nat. Neurosci. 9, 133–139 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Robinson, D.L., Heien, M.L.A.V. & Wightman, R.M. Frequency of dopamine concentration transients increases in dorsal and ventral striatum of male rats during introduction of conspecifics. J. Neurosci. 22, 10477–10486 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Willuhn, I. et al. Phasic dopamine release in the nucleus accumbens in response to pro-social 50 kHz ultrasonic vocalizations in rats. J. Neurosci. 34, 10616–10623 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tye, K.M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behavior. Nature 493, 537–541 (2013). This study demonstrated reduced dopamine function following chronic mild stress and showed that restoring dopamine function reversed depression-like behaviors.

    Article  CAS  PubMed  Google Scholar 

  35. Chaudhury, D. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013). This paper showed that phasic activity of VTA dopamine neurons increased the susceptibility for social-defeat stress to induce a depressive-like phenotype in mice.

    Article  CAS  PubMed  Google Scholar 

  36. Friedman, A.K. et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science 344, 313–319 (2014).This paper showed that enhancing VTA dopamine neuron activity in mice susceptible to social-defeat stress reversed depression-like behaviors. This effect was considered to be somewhat paradoxical, as the susceptible mice already exhibited hyperactivity in dopamine neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chang, C.-H. & Grace, A.A. Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats. Biol. Psychiatry 76, 223–230 (2014). This paper demonstrated that chronic mild stress reduces the number of spontaneously firing midbrain dopamine neurons.

    Article  CAS  PubMed  Google Scholar 

  38. Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007). This work identified molecular differences in the VTA-NAc pathway between individual mice that were susceptible or resilient to social-defeat stress and in postmortem tissue from depressed human patients and controls.

    Article  CAS  PubMed  Google Scholar 

  39. Cao, J.-L. et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J. Neurosci. 30, 16453–16458 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wanat, M.J., Hopf, F.W., Stuber, G.D., Phillips, P.E.M. & Bonci, A. Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih. J. Physiol. (Lond.) 586, 2157–2170 (2008). This study identified the cellular mechanism by which CRF increases the basal firing rate of VTA dopamine neurons.

    Article  CAS  Google Scholar 

  41. Cannon, C.M. & Palmiter, R.D. Reward without dopamine. J. Neurosci. 23, 10827–10831 (2003). This work demonstrated that reward preferences can be exhibited in animals that do not have intact dopamine transmission.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pardo, M., López-Cruz, L., Miguel, N.S., Salamone, J.D. & Correa, M. Selection of sucrose concentration depends on the effort required to obtain it: studies using tetrabenazine, D1, D2, and D3 receptor antagonists. Psychopharmacology (Berl.) 232, 2377–2391 (2015).

    Article  CAS  Google Scholar 

  43. Lammel, S., Tye, K.M. & Warden, M.R. Progress in understanding mood disorders: optogenetic dissection of neural circuits. Genes Brain Behav. 13, 38–51 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Valenti, O., Lodge, D.J. & Grace, A.A. Aversive stimuli alter ventral tegmental area dopamine neuron activity via a common action in the ventral hippocampus. J. Neurosci. 31, 4280–4289 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Valenti, O., Gill, K.M. & Grace, A.A. Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure. Eur. J. Neurosci. 35, 1312–1321 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wanat, M.J., Bonci, A. & Phillips, P.E.M. CRF acts in the midbrain to attenuate accumbens dopamine release to rewards but not their predictors. Nat. Neurosci. 16, 383–385 (2013). This paper described afferent-selective regulation of dopamine transmission by CRF in the VTA and demonstrated its role in mediating alterations of motivation following acute restraint stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lammel, S. et al. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57, 760–773 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Lammel, S., Ion, D.I., Roeper, J. & Malenka, R.C. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70, 855–862 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lammel, S. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212–217 (2012). This paper reported that VTA dopamine neurons with distinct projection targets encode reward and aversion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Watabe-Uchida, M., Zhu, L., Ogawa, S.K., Vamanrao, A. & Uchida, N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74, 858–873 (2012). This work provided a comprehensive brain-wide survey of neurons that synapse onto midbrain dopamine neurons.

    Article  CAS  PubMed  Google Scholar 

  51. Matsui, A., Jarvie, B.C., Robinson, B.G., Hentges, S.T. & Williams, J.T. Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance, and expression of withdrawal. Neuron 82, 1346–1356 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lemos, J.C. et al. Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature 490, 402–406 (2012). This paper identified a mechanism by which CRF regulates dopamine that is ablated by repeated swim stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Peciña, S., Schulkin, J. & Berridge, K.C. Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress? BMC Biol. 4, 8 (2006). This work demonstrated that CRF acts in the NAc to enhance the effects of Pavlovian stimuli on instrumental behavior.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lim, M.M. et al. CRF receptors in the nucleus accumbens modulate partner preference in prairie voles. Horm. Behav. 51, 508–515 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bessa, J.M. et al. Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. Transl. Psychiatry 3, e266 (2013). This paper reported that chronic mild stress produced hypertrophy and increased expression of the genes encoding neurotrophins, cell adhesion molecules and synaptic proteins in NAc medium spiny neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Christoffel, D.J. et al. I,B kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J. Neurosci. 31, 314–321 (2011). This study reported that repeated social defeat stress caused alterations in dendritic structure and plasticity in NAc medium spiny neurons, and it identified a molecular signaling pathway involved in these effects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Walsh, J.J. et al. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat. Neurosci. 17, 27–29 (2014). This study investigated the interactions between mesolimbic dopamine, neurotrophic and stress-related factors, and actual stress exposure in mediating stress-induced social withdrawal.

    Article  CAS  PubMed  Google Scholar 

  58. Francis, T.C. et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol. Psychiatry 77, 212–222 (2015). This study examined stress-induced changes in electrophysiological properties of specific populations of NAc medium spiny neurons, as well as the dissociable contributions of each subpopulation to distinct forms of motivated behavior disrupted by social defeat stress.

    Article  PubMed  Google Scholar 

  59. Khibnik, L.A. et al. Stress and cocaine trigger divergent and cell type–specific regulation of synaptic transmission at single spines in nucleus accumbens. Biol. Psychiatry (2015).

  60. Dias, C. et al. β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature 516, 51–55 (2014). This paper characterized the involvement of a molecular signaling pathway in a specific subpopulation of NAc medium spiny neurons contributing to stress-induced effects on select forms of motivated behavior.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lim, B.K., Huang, K.W., Grueter, B.A., Rothwell, P.E. & Malenka, R.C. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487, 183–189 (2012). This paper revealed the mechanisms through which a feeding-related peptide affects stress-induced changes in sucrose preference by altering physiological properties of a specific subpopulation of medium spiny neurons in the NAc.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lutter, M. et al. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat. Neurosci. 11, 752–753 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chuang, J.-C. et al. Ghrelin mediates stress-induced food-reward behavior in mice. J. Clin. Invest. 121, 2684–2692 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wu, Q., Clark, M.S. & Palmiter, R.D. Deciphering a neuronal circuit that mediates appetite. Nature 483, 594–597 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Carter, M.E., Soden, M.E., Zweifel, L.S. & Palmiter, R.D. Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Atasoy, D., Betley, J.N., Su, H.H. & Sternson, S.M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Betley, J.N., Cao, Z.F.H., Ritola, K.D. & Sternson, S.M. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155, 1337–1350 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jennings, J.H., Rizzi, G., Stamatakis, A.M., Ung, R.L. & Stuber, G.D. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341, 1517–1521 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jennings, J.H. et al. Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors. Cell 160, 516–527 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Krashes, M.J. et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507, 238–242 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Shah, B.P. et al. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc. Natl. Acad. Sci. USA 111, 13193–13198 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nieh, E.H. et al. Decoding neural circuits that control compulsive sucrose seeking. Cell 160, 528–541 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hardaway, J.A., Crowley, N.A., Bulik, C.M. & Kash, T.L. Integrated circuits and molecular components for stress and feeding: implications for eating disorders. Genes Brain Behav. 14, 85–97 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Aberman, J.E., Ward, S.J. & Salamone, J.D. Effects of dopamine antagonists and accumbens dopamine depletions on time-constrained progressive-ratio performance. Pharmacol. Biochem. Behav. 61, 341–348 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Hamill, S., Trevitt, J.T., Nowend, K.L., Carlson, B.B. & Salamone, J.D. Nucleus accumbens dopamine depletions and time-constrained progressive ratio performance: effects of different ratio requirements. Pharmacol. Biochem. Behav. 64, 21–27 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Berridge, K.C., Venier, I.L. & Robinson, T.E. Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: implications for arousal and anhedonia hypotheses of dopamine function. Behav. Neurosci. 103, 36–45 (1989). This study demonstrated that the hedonic reactivity to sucrose is preserved following dopamine depletion.

    Article  CAS  PubMed  Google Scholar 

  77. Shafiei, N., Gray, M., Viau, V. & Floresco, S.B. Acute stress induces selective alterations in cost/benefit decision-making. Neuropsychopharmacology 37, 2194–2209 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Valentin, V.V., Dickinson, A. & O'Doherty, J.P. Determining the neural substrates of goal-directed learning in the human brain. J. Neurosci. 27, 4019–4026 (2007). This study adapted tasks traditionally used in rodents for human imaging studies of valuation systems.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dickinson, A. Action and habits: the development of behavioral autonomy. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 67–78 (1985). This paper proposed that goal-directed actions could become habits depending on the nature and extent of training. This is now the predominant view of habit formation.

    Article  Google Scholar 

  80. Balleine, B.W. & Dickinson, A. The role of incentive learning in instrumental outcome revaluation by sensory-specific satiety. Anim. Learn. Behav. 26, 46–59 (1998).

    Article  Google Scholar 

  81. Schwabe, L. & Wolf, O.T. Stress prompts habit behavior in humans. J. Neurosci. 29, 7191–7198 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schwabe, L. & Wolf, O.T. Socially evaluated cold pressor stress after instrumental learning favors habits over goal-directed action. Psychoneuroendocrinology 35, 977–986 (2010).

    Article  PubMed  Google Scholar 

  83. Schwabe, L., Tegenthoff, M., Höffken, O. & Wolf, O.T. Concurrent glucocorticoid and noradrenergic activity shifts instrumental behavior from goal-directed to habitual control. J. Neurosci. 30, 8190–8196 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Schwabe, L., Höffken, O., Tegenthoff, M. & Wolf, O.T. Preventing the stress-induced shift from goal-directed to habit action with a β-adrenergic antagonist. J. Neurosci. 31, 17317–17325 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Schwabe, L., Tegenthoff, M., Höffken, O. & Wolf, O.T. Simultaneous glucocorticoid and noradrenergic activity disrupts the neural basis of goal-directed action in the human brain. J. Neurosci. 32, 10146–10155 (2012). This paper demonstrated that concurrent activation of glucocorticoid and noradrenergic systems promotes habit formation and disrupts neural activity patterns associated with goal-directed decisions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Braun, S. & Hauber, W. Acute stressor effects on goal-directed action in rats. Learn. Mem. 20, 700–709 (2013).

    Article  PubMed  Google Scholar 

  87. Dias-Ferreira, E. et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science 325, 621–625 (2009). This study found that chronic unpredictable stress causes habit formation in rats and concomitant anatomical alterations in corticostriatal circuits associated with goal-directed versus habitual behavior.

    Article  CAS  PubMed  Google Scholar 

  88. Soares, J.M. et al. Stress-induced changes in human decision-making are reversible. Transl. Psychiatry 2, e131 (2012). This study replicated in humans the findings observed in ref. 87, observing stress-associated habitual behavior and changes in corticostriatal structure and functional activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gourley, S.L. et al. Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding. Proc. Natl. Acad. Sci. USA 109, 20714–20719 (2012). This paper showed that exogenous elevation of stress-related signals promotes habitual behavior, whereas medial prefrontal neurotrophins mediate motivation to seek reward.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Otto, A.R., Raio, C.M., Chiang, A., Phelps, E.A. & Daw, N.D. Working-memory capacity protects model-based learning from stress. Proc. Natl. Acad. Sci. USA 110, 20941–20946 (2013). This paper reported that acute cold-pressor stress in humans selectively disrupted model-based valuation processes that underlie cognitive and deliberative decision-making.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Arnsten, A.F.T. Stress signalling pathways that impair prefrontal cortex structure and function. Nat. Rev. Neurosci. 10, 410–422 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Arnsten, A.F.T., Wang, M.J. & Paspalas, C.D. Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76, 223–239 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. McEwen, B.S. & Morrison, J.H. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79, 16–29 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gamo, N.J. et al. Stress impairs prefrontal cortical function via D1 dopamine receptor interactions with hyperpolarization-activated cyclic nucleotide-gated channels. Biol. Psychiatry (2015).

  95. Kim, J.J., Song, E.Y. & Kosten, T.A. Stress effects in the hippocampus: synaptic plasticity and memory. Stress 9, 1–11 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Schwabe, L. & Wolf, O.T. Stress and multiple memory systems: from ′thinking′ to ′doing′. Trends Cogn. Sci. (Regul Ed) 17, 60–68 (2013).

    Article  PubMed  Google Scholar 

  97. Guenzel, F.M., Wolf, O.T. & Schwabe, L. Glucocorticoids boost stimulus-response memory formation in humans. Psychoneuroendocrinology 45, 21–30 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Thai, C.A., Zhang, Y. & Howland, J.G. Effects of acute restraint stress on set-shifting and reversal learning in male rats. Cogn. Affect. Behav. Neurosci. 13, 164–173 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Butts, K.A., Floresco, S.B. & Phillips, A.G. Acute stress impairs set-shifting but not reversal learning. Behav. Brain Res. 252, 222–229 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health grants P50-MH106428 and F31-DA036278.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul E M Phillips.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hollon, N., Burgeno, L. & Phillips, P. Stress effects on the neural substrates of motivated behavior. Nat Neurosci 18, 1405–1412 (2015). https://doi.org/10.1038/nn.4114

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4114

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing