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:

Going and stopping: dichotomies in behavioral control by the prefrontal cortex

Nature Neuroscience volume 19, pages 656–664 (2016)Cite this article

Subjects

Abstract

The rodent dorsal medial prefrontal cortex (PFC), specifically the prelimbic cortex (PL), regulates the expression of conditioned fear and behaviors interpreted as reward seeking. Meanwhile, the ventral medial PFC, namely the infralimbic cortex (IL), is essential to extinction conditioning in both appetitive and aversive domains. Here we review evidence that supports, or refutes, this “PL-go/IL-stop” dichotomy. We focus on the extinction of conditioned fear and the extinction and reinstatement of cocaine- or heroin-reinforced responding following abstinence. We then synthesize evidence that the PL is essential for developing goal-directed response strategies, while the IL supports habit behavior. Finally, we propose that some functions of the orbital PFC parallel those of the medial PFC in the regulation of response selection. Integration of these discoveries may provide points of intervention for inhibiting untethered drug seeking in drug use disorders, extinction failures in post-traumatic stress disorder, or co-morbidities between the two.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Subregions of the rodent prefrontal cortex.
Figure 2: Connections and functions of the PL and IL.
Figure 3: Acute cocaine dysregulates PL-dependent action selection.

Similar content being viewed by others

References

  1. Peters, J., Kalivas, P.W. & Quirk, G.J. Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn. Mem. 16, 279–288 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Heidbreder, C.A. & Groenewegen, H.J. The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci. Biobehav. Rev. 27, 555–579 (2003).

    Article  PubMed  Google Scholar 

  3. Barker, J.M., Taylor, J.R. & Chandler, L.J. A unifying model of the role of the infralimbic cortex in extinction and habits. Learn. Mem. 21, 441–448 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Herry, C. & Johansen, J.P. Encoding of fear learning and memory in distributed neuronal circuits. Nat. Neurosci. 17, 1644–1654 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Fitzgerald, P.J., Seemann, J.R. & Maren, S. Can fear extinction be enhanced? A review of pharmacological and behavioral findings. Brain Res. Bull. 105, 46–60 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Moorman, D.E., James, M.H., McGlinchey, E.M. & Aston-Jones, G. Differential roles of medial prefrontal subregions in the regulation of drug seeking. Brain Res. 1628 Pt A: 130–146 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Hart, G., Leung, B.K. & Balleine, B.W. Dorsal and ventral streams: the distinct role of striatal subregions in the acquisition and performance of goal-directed actions. Neurobiol. Learn. Mem. 108, 104–118 (2014).

    Article  PubMed  Google Scholar 

  8. Todd, T.P., Vurbic, D. & Bouton, M.E. Behavioral and neurobiological mechanisms of extinction in Pavlovian and instrumental learning. Neurobiol. Learn. Mem. 108, 52–64 (2014).

    Article  PubMed  Google Scholar 

  9. Maren, S. & Holmes, A. Stress and fear extinction. Neuropsychopharmacology 41, 58–79 (2016).

    Article  PubMed  Google Scholar 

  10. Ongür, D. & Price, J.L. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb. Cortex 10, 206–219 (2000).

    Article  PubMed  Google Scholar 

  11. Corbit, L.H. & Balleine, B.W. The role of prelimbic cortex in instrumental conditioning. Behav. Brain Res. 146, 145–157 (2003).

    Article  PubMed  Google Scholar 

  12. Gourley, S.L., Lee, A.S., Howell, J.L., Pittenger, C. & Taylor, J.R. Dissociable regulation of instrumental action within mouse prefrontal cortex. Eur. J. Neurosci. 32, 1726–1734 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jay, T.M. & Witter, M.P. Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J. Comp. Neurol. 313, 574–586 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. McDonald, A.J. Organization of amygdaloid projections to the prefrontal cortex and associated striatum in the rat. Neuroscience 44, 1–14 (1991).

    Article  CAS  PubMed  Google Scholar 

  15. Gabbott, P.L., Warner, T.A. & Busby, S.J. Amygdala input monosynaptically innervates parvalbumin immunoreactive local circuit neurons in rat medial prefrontal cortex. Neuroscience 139, 1039–1048 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Sesack, S.R., Deutch, A.Y., Roth, R.H. & Bunney, B.S. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J. Comp. Neurol. 290, 213–242 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Mcdonald, A.J., Mascagni, F. & Guo, L. Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience 71, 55–75 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. LeDoux, J.E. Coming to terms with fear. Proc. Natl. Acad. Sci. USA 111, 2871–2878 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Blum, S., Hebert, A.E. & Dash, P.K. A role for the prefrontal cortex in recall of recent and remote memories. Neuroreport 17, 341–344 (2006).

    Article  PubMed  Google Scholar 

  20. Corcoran, K.A. & Quirk, G.J. Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. J. Neurosci. 27, 840–844 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Laurent, V. & Westbrook, R.F. Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction. Learn. Mem. 16, 520–529 (2009).

    Article  PubMed  Google Scholar 

  22. Sierra-Mercado, D. Jr., Corcoran, K.A., Lebrón-Milad, K. & Quirk, G.J. Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. Eur. J. Neurosci. 24, 1751–1758 (2006).

    Article  PubMed  Google Scholar 

  23. Sierra-Mercado, D., Padilla-Coreano, N. & Quirk, G.J. Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 36, 529–538 (2011).

    Article  PubMed  Google Scholar 

  24. Sangha, S., Robinson, P.D., Greba, Q., Davies, D.A. & Howland, J.G. Alterations in reward, fear and safety cue discrimination after inactivation of the rat prelimbic and infralimbic cortices. Neuropsychopharmacology 39, 2405–2413 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Courtin, J. et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505, 92–96 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Do-Monte, F.H., Quiñones-Laracuente, K. & Quirk, G.J. A temporal shift in the circuits mediating retrieval of fear memory. Nature 519, 460–463 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rescorla, R.A. & Heth, C.D. Reinstatement of fear to an extinguished conditioned stimulus. J. Exp. Psychol. Anim. Behav. Process. 1, 88–96 (1975).

    Article  CAS  PubMed  Google Scholar 

  28. Morgan, M.A., Romanski, L.M. & LeDoux, J.E. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci. Lett. 163, 109–113 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Quirk, G.J., Russo, G.K., Barron, J.L. & Lebron, K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J. Neurosci. 20, 6225–6231 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Burgos-Robles, A., Vidal-Gonzalez, I., Santini, E. & Quirk, G.J. Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 53, 871–880 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Do-Monte, F.H., Manzano-Nieves, G., Quiñones-Laracuente, K., Ramos-Medina, L. & Quirk, G.J. Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J. Neurosci. 35, 3607–3615 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vidal-Gonzalez, I., Vidal-Gonzalez, B., Rauch, S.L. & Quirk, G.J. Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn. Mem. 13, 728–733 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Milad, M.R., Vidal-Gonzalez, I. & Quirk, G.J. Electrical stimulation of medial prefrontal cortex reduces conditioned fear in a temporally specific manner. Behav. Neurosci. 118, 389–394 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Santini, E., Ge, H., Ren, K., Peña de Ortiz, S. & Quirk, G.J. Consolidation of fear extinction requires protein synthesis in the medial prefrontal cortex. J. Neurosci. 24, 5704–5710 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mueller, D., Porter, J.T. & Quirk, G.J. Noradrenergic signaling in infralimbic cortex increases cell excitability and strengthens memory for fear extinction. J. Neurosci. 28, 369–375 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Quirk, G.J. & Mueller, D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72 (2008).

    Article  PubMed  Google Scholar 

  37. Bravo-Rivera, C., Roman-Ortiz, C., Brignoni-Perez, E., Sotres-Bayon, F. & Quirk, G.J. Neural structures mediating expression and extinction of platform-mediated avoidance. J. Neurosci. 34, 9736–9742 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Moscarello, J.M. & LeDoux, J.E. Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions. J. Neurosci. 33, 3815–3823 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Joel, D., Tarrasch, R., Feldon, J. & Weiner, I. Effects of electrolytic lesions of the medial prefrontal cortex or its subfields on 4-arm baited, 8-arm radial maze, two-way active avoidance and conditioned fear tasks in the rat. Brain Res. 765, 37–50 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Li, X., Zeric, T., Kambhampati, S., Bossert, J.M. & Shaham, Y. The central amygdala nucleus is critical for incubation of methamphetamine craving. Neuropsychopharmacology 40, 1297–1306 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Capriles, N., Rodaros, D., Sorge, R.E. & Stewart, J. A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl.) 168, 66–74 (2003).

    Article  CAS  Google Scholar 

  42. McFarland, K., Davidge, S.B., Lapish, C.C. & Kalivas, P.W. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J. Neurosci. 24, 1551–1560 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. See, R.E. Dopamine D1 receptor antagonism in the prelimbic cortex blocks the reinstatement of heroin-seeking in an animal model of relapse. Int. J. Neuropsychopharmacol. 12, 431–436 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. McFarland, K. & Kalivas, P.W. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 21, 8655–8663 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vassoler, F.M. et al. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation. J. Neurosci. 33, 14446–14454 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stefanik, M.T. et al. Optogenetic inhibition of cocaine seeking in rats. Addict. Biol. 18, 50–53 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Shen, H.W., Gipson, C.D., Huits, M. & Kalivas, P.W. Prelimbic cortex and ventral tegmental area modulate synaptic plasticity differentially in nucleus accumbens during cocaine-reinstated drug seeking. Neuropsychopharmacology 39, 1169–1177 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. McLaughlin, J. & See, R.E. Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl.) 168, 57–65 (2003).

    Article  CAS  Google Scholar 

  49. Di Pietro, N.C., Black, Y.D. & Kantak, K.M. Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats. Eur. J. Neurosci. 24, 3285–3298 (2006).

    Article  PubMed  Google Scholar 

  50. Mashhoon, Y., Wells, A.M. & Kantak, K.M. Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior. Pharmacol. Biochem. Behav. 96, 347–353 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gipson, C.D. et al. Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77, 867–872 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Koya, E. et al. Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology 56 (suppl. 1), 177–185 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Park, W.K. et al. Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J. Neurosci. 22, 2916–2925 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. West, E.A., Saddoris, M.P., Kerfoot, E.C. & Carelli, R.M. Prelimbic and infralimbic cortical regions differentially encode cocaine-associated stimuli and cocaine-seeking before and following abstinence. Eur. J. Neurosci. 39, 1891–1902 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Ramirez, D.R. et al. Dorsal hippocampal regulation of memory reconsolidation processes that facilitate drug context-induced cocaine-seeking behavior in rats. Eur. J. Neurosci. 30, 901–912 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Sorg, B.A., Todd, R.P., Slaker, M. & Churchill, L. Anisomycin in the medial prefrontal cortex reduces reconsolidation of cocaine-associated memories in the rat self-administration model. Neuropharmacology 92, 25–33 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. McFarland, K., Lapish, C.C. & Kalivas, P.W. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 23, 3531–3537 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kalivas, P.W. The glutamate homeostasis hypothesis of addiction. Nat. Rev. Neurosci. 10, 561–572 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Stefanik, M.T., Kupchik, Y.M. & Kalivas, P.W. Optogenetic inhibition of cortical afferents in the nucleus accumbens simultaneously prevents cue-induced transient synaptic potentiation and cocaine-seeking behavior. Brain Struct. Funct. http://dx.doi.org/10.1007/s00429-015-0997-8 (2015).

  60. Stefanik, M.T. & Kalivas, P.W. Optogenetic dissection of basolateral amygdala projections during cue-induced reinstatement of cocaine seeking. Front. Behav. Neurosci. 7, 213 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sotres-Bayon, F., Sierra-Mercado, D., Pardilla-Delgado, E. & Quirk, G.J. Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76, 804–812 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Martín-García, E. et al. Frequency of cocaine self-administration influences drug seeking in the rat: optogenetic evidence for a role of the prelimbic cortex. Neuropsychopharmacology 39, 2317–2330 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Van den Oever, M.C. et al. Ventromedial prefrontal cortex pyramidal cells have a temporal dynamic role in recall and extinction of cocaine-associated memory. J. Neurosci. 33, 18225–18233 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. LaLumiere, R.T., Niehoff, K.E. & Kalivas, P.W. The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learn. Mem. 17, 168–175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Torregrossa, M.M., Sanchez, H. & Taylor, J.R. D-cycloserine reduces the context specificity of pavlovian extinction of cocaine cues through actions in the nucleus accumbens. J. Neurosci. 30, 10526–10533 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Szalay, J.J., Jordan, C.J. & Kantak, K.M. Neural regulation of the time course for cocaine-cue extinction consolidation in rats. Eur. J. Neurosci. 37, 269–277 (2013).

    Article  PubMed  Google Scholar 

  67. Peters, J., LaLumiere, R.T. & Kalivas, P.W. Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J. Neurosci. 28, 6046–6053 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Milad, M.R. & Quirk, G.J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Fuchs, R.A. et al. The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats. Neuropsychopharmacology 30, 296–309 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. LaLumiere, R.T., Smith, K.C. & Kalivas, P.W. Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell. Eur. J. Neurosci. 35, 614–622 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Peters, J., Vallone, J., Laurendi, K. & Kalivas, P.W. Opposing roles for the ventral prefrontal cortex and the basolateral amygdala on the spontaneous recovery of cocaine-seeking in rats. Psychopharmacology (Berl.) 197, 319–326 (2008).

    Article  CAS  Google Scholar 

  72. Choi, D.C., Gourley, S.L. & Ressler, K.J. Prelimbic BDNF and TrkB signaling regulates consolidation of both appetitive and aversive emotional learning. Transl. Psychiatry 2, e205 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gourley, S.L., Howell, J.L., Rios, M., DiLeone, R.J. & Taylor, J.R. Prelimbic cortex bdnf knock-down reduces instrumental responding in extinction. Learn. Mem. 16, 756–760 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ma, Y.Y. et al. Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83, 1453–1467 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bossert, J.M. et al. Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Nat. Neurosci. 14, 420–422 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bossert, J.M. et al. Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J. Neurosci. 32, 4982–4991 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rogers, J.L., Ghee, S. & See, R.E. The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151, 579–588 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Alvarez-Jaimes, L., Polis, I. & Parsons, L.H. Attenuation of cue-induced heroin-seeking behavior by cannabinoid CB1 antagonist infusions into the nucleus accumbens core and prefrontal cortex, but not basolateral amygdala. Neuropsychopharmacology 33, 2483–2493 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Van den Oever, M.C. et al. Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking. Nat. Neurosci. 11, 1053–1058 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Ovari, J. & Leri, F. Inactivation of the ventromedial prefrontal cortex mimics re-emergence of heroin seeking caused by heroin reconditioning. Neurosci. Lett. 444, 52–55 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Rocha, A. & Kalivas, P.W. Role of the prefrontal cortex and nucleus accumbens in reinstating methamphetamine seeking. Eur. J. Neurosci. 31, 903–909 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Lubbers, B.R. et al. Prefrontal gamma-aminobutyric acid type A receptor insertion controls cue-induced relapse to nicotine seeking. Biol. Psychiatry 76, 750–758 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Pfarr, S. et al. Losing control: excessive alcohol seeking after selective inactivation of cue-responsive neurons in the infralimbic cortex. J. Neurosci. 35, 10750–10761 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Willcocks, A.L. & McNally, G.P. The role of medial prefrontal cortex in extinction and reinstatement of alcohol-seeking in rats. Eur. J. Neurosci. 37, 259–268 (2013).

    Article  PubMed  Google Scholar 

  85. Dickinson, A. Contemporary Animal Learning Theory (Cambridge Univ. Press, 1980).

  86. Robinson, T.E. & Berridge, K.C. Addiction. Annu. Rev. Psychol. 54, 25–53 (2003).

    Article  PubMed  Google Scholar 

  87. Jentsch, J.D. & Taylor, J.R. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology (Berl.) 146, 373–390 (1999).

    Article  CAS  Google Scholar 

  88. Everitt, B.J. & Robbins, T.W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8, 1481–1489 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Torregrossa, M.M., Corlett, P.R. & Taylor, J.R. Aberrant learning and memory in addiction. Neurobiol. Learn. Mem. 96, 609–623 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lucantonio, F., Caprioli, D. & Schoenbaum, G. Transition from 'model-based' to 'model-free' behavioral control in addiction: Involvement of the orbitofrontal cortex and dorsolateral striatum. Neuropharmacology 76 Pt B: 407–415 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Balleine, B.W. & O'Doherty, J.P. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology 35, 48–69 (2010).

    Article  PubMed  Google Scholar 

  92. Balleine, B.W. & Dickinson, A. Goal-directed instrumental action: contingency and incentive learning and their cortical substrates. Neuropharmacology 37, 407–419 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Killcross, S. & Coutureau, E. Coordination of actions and habits in the medial prefrontal cortex of rats. Cereb. Cortex 13, 400–408 (2003).

    Article  PubMed  Google Scholar 

  94. Dutech, A., Coutureau, E. & Marchand, A.R. A reinforcement learning approach to instrumental contingency degradation in rats. J. Physiol. Paris 105, 36–44 (2011).

    PubMed  Google Scholar 

  95. Ostlund, S.B. & Balleine, B.W. Lesions of medial prefrontal cortex disrupt the acquisition but not the expression of goal-directed learning. J. Neurosci. 25, 7763–7770 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tran-Tu-Yen, D.A., Marchand, A.R., Pape, J.R., Di Scala, G. & Coutureau, E. Transient role of the rat prelimbic cortex in goal-directed behaviour. Eur. J. Neurosci. 30, 464–471 (2009).

    Article  PubMed  Google Scholar 

  97. Swanson, A.M., Allen, A.G., Shapiro, L.P. & Gourley, S.L. GABAAα1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection. Neuropsychopharmacology 40, 1027–1036 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Butkovich, L.M. et al. Adolescent-onset GABAA α1 silencing regulates reward-related decision making. Eur. J. Neurosci. 42, 2114–2121 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Weissenborn, R., Robbins, T.W. & Everitt, B.J. Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats. Psychopharmacology (Berl.) 134, 242–257 (1997).

    Article  CAS  Google Scholar 

  100. Olmstead, M.C., Lafond, M.V., Everitt, B.J. & Dickinson, A. Cocaine seeking by rats is a goal-directed action. Behav. Neurosci. 115, 394–402 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Zapata, A., Minney, V.L. & Shippenberg, T.S. Shift from goal-directed to habitual cocaine seeking after prolonged experience in rats. J. Neurosci. 30, 15457–15463 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Limpens, J.H., Damsteegt, R., Broekhoven, M.H., Voorn, P. & Vanderschuren, L.J. Pharmacological inactivation of the prelimbic cortex emulates compulsive reward seeking in rats. Brain Res. 1628 Pt A: 210–218 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Mihindou, C., Guillem, K., Navailles, S., Vouillac, C. & Ahmed, S.H. Discriminative inhibitory control of cocaine seeking involves the prelimbic prefrontal cortex. Biol. Psychiatry 73, 271–279 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Chen, B.T. et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496, 359–362 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Pelloux, Y., Murray, J.E. & Everitt, B.J. Differential roles of the prefrontal cortical subregions and basolateral amygdala in compulsive cocaine seeking and relapse after voluntary abstinence in rats. Eur. J. Neurosci. 38, 3018–3026 (2013).

    PubMed  PubMed Central  Google Scholar 

  106. Fuchs, R.A., Evans, K.A., Parker, M.P. & See, R.E. Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats. J. Neurosci. 24, 6600–6610 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Coutureau, E. & Killcross, S. Inactivation of the infralimbic prefrontal cortex reinstates goal-directed responding in overtrained rats. Behav. Brain Res. 146, 167–174 (2003).

    Article  PubMed  Google Scholar 

  108. Smith, K.S., Virkud, A., Deisseroth, K. & Graybiel, A.M. Reversible online control of habitual behavior by optogenetic perturbation of medial prefrontal cortex. Proc. Natl. Acad. Sci. USA 109, 18932–18937 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Smith, K.S. & Graybiel, A.M. A dual operator view of habitual behavior reflecting cortical and striatal dynamics. Neuron 79, 361–374 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Morecraft, R.J., Geula, C. & Mesulam, M.M. Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey. J. Comp. Neurol. 323, 341–358 (1992).

    Article  CAS  PubMed  Google Scholar 

  111. Carmichael, S.T. & Price, J.L. Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys. J. Comp. Neurol. 371, 179–207 (1996).

    Article  CAS  PubMed  Google Scholar 

  112. Schilman, E.A., Uylings, H.B., Galis-de Graaf, Y., Joel, D. & Groenewegen, H.J. The orbital cortex in rats topographically projects to central parts of the caudate-putamen complex. Neurosci. Lett. 432, 40–45 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Wallis, J.D. Cross-species studies of orbitofrontal cortex and value-based decision-making. Nat. Neurosci. 15, 13–19 (2012).

    Article  CAS  Google Scholar 

  114. Gremel, C.M. & Costa, R.M. Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions. Nat. Commun. 4, 2264 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Mailly, P., Aliane, V., Groenewegen, H.J., Haber, S.N. & Deniau, J.-M. The rat prefrontostriatal system analyzed in 3D: evidence for multiple interacting functional units. J. Neurosci. 33, 5718–5727 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rudebeck, P.H. & Murray, E.A. The orbitofrontal oracle: cortical mechanisms for the prediction and evaluation of specific behavioral outcomes. Neuron 84, 1143–1156 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Luk, C.-H. & Wallis, J.D. Choice coding in frontal cortex during stimulus-guided or action-guided decision-making. J. Neurosci. 33, 1864–1871 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zimmermann, K.S., Yamin, J.A., Rainnie, D.G., Kessler, K.J. & Gourley, S.L. Connections of the mouse orbitofrontal cortex and regulation of goal-directed action selection by brain-derived neurotrophic factor. Biol. Psychiatry http://dx.doi.org/10.1016/j.biopsych.2015.10.026 (2016).

  119. Gourley, S.L. et al. The orbitofrontal cortex regulates outcome-based decision-making via the lateral striatum. Eur. J. Neurosci. 38, 2382–2388 (2013).

    Article  PubMed  Google Scholar 

  120. Gross, C. et al. Selective role of the catalytic PI3K subunit p110β in impaired higher order cognition in fragile X syndrome. Cell Rep. 11, 681–688 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gourley, S.L., Swanson, A.M. & Koleske, A.J. Corticosteroid-induced neural remodeling predicts behavioral vulnerability and resilience. J. Neurosci. 33, 3107–3112 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Dias-Ferreira, E. et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science 325, 621–625 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Thomases, D.R., Cass, D.K., Meyer, J.D., Caballero, A. & Tseng, K.Y. Early adolescent MK-801 exposure impairs the maturation of ventral hippocampal control of basolateral amygdala drive in the adult prefrontal cortex. J. Neurosci. 34, 9059–9066 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Burke, A.R. & Miczek, K.A. Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF, and HPA axis. Psychopharmacology (Berl.) 231, 1557–1580 (2014).

    Article  CAS  Google Scholar 

  126. Rosen, G. et al. The mouse brain library @ www.mbl.org International Mouse Genome Conference 14, 166 (2000).

    Google Scholar 

  127. Gourley, S.L., Olevska, A., Gordon, J. & Taylor, J.R. Cytoskeletal determinants of stimulus-response habits. J. Neurosci. 33, 11811–11816 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Vetere, G. et al. Extinction partially reverts structural changes associated with remote fear memory. Learn. Mem. 18, 554–557 (2011).

    Article  PubMed  Google Scholar 

  129. Izquierdo, A., Wellman, C.L. & Holmes, A. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J. Neurosci. 26, 5733–5738 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Sgobio, C. et al. Abnormal medial prefrontal cortex connectivity and defective fear extinction in the presymptomatic G93A SOD1 mouse model of ALS. Genes Brain Behav. 7, 427–434 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Gourley, S.L., Kedves, A.T., Olausson, P. & Taylor, J.R. A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology 34, 707–716 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Milstein, J.A. et al. Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function. PLoS One 8, e57308 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Iafrati, J. et al. Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway. Mol. Psychiatry 19, 417–426 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Kolb, B. & Muhammad, A. Harnessing the power of neuroplasticity for intervention. Front. Hum. Neurosci. 8, 377 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  135. DePoy, L.M. & Gourley, S.L. Synaptic cytoskeletal plasticity in the prefrontal cortex following psychostimulant exposure. Traffic 16, 919–940 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Muñoz-Cuevas, F.J., Athilingam, J., Piscopo, D. & Wilbrecht, L. Cocaine-induced structural plasticity in frontal cortex correlates with conditioned place preference. Nat. Neurosci. 16, 1367–1369 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Schmitzer-Torbert, N. et al. Post-training cocaine administration facilitates habit learning and requires the infralimbic cortex and dorsolateral striatum. Neurobiol. Learn. Mem. 118, 105–112 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Yin, H.H., Ostlund, S.B. & Balleine, B.W. Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks. Eur. J. Neurosci. 28, 1437–1448 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Yin, H.H. et al. Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill. Nat. Neurosci. 12, 333–341 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Jedynak, J.P., Uslaner, J.M., Esteban, J.A. & Robinson, T.E. Methamphetamine-induced structural plasticity in the dorsal striatum. Eur. J. Neurosci. 25, 847–853 (2007).

    Article  PubMed  Google Scholar 

  141. Schoenbaum, G. & Setlow, B. Cocaine makes actions insensitive to outcomes but not extinction: implications for altered orbitofrontal-amygdalar function. Cereb. Cortex 15, 1162–1169 (2005).

    Article  PubMed  Google Scholar 

  142. Nelson, A. & Killcross, S. Amphetamine exposure enhances habit formation. J. Neurosci. 26, 3805–3812 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Nelson, A.J. & Killcross, S. Accelerated habit formation following amphetamine exposure is reversed by D1, but enhanced by D2, receptor antagonists. Front. Neurosci. 7, 76 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Nordquist, R.E. et al. Augmented reinforcer value and accelerated habit formation after repeated amphetamine treatment. Eur. Neuropsychopharmacol. 17, 532–540 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. LeBlanc, K.H., Maidment, N.T. & Ostlund, S.B. Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats. PLoS One 8, e61355 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hinton, E.A., Wheeler, M.G. & Gourley, S.L. Early-life cocaine interferes with BDNF-mediated behavioral plasticity. Learn. Mem. 21, 253–257 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Corbit, L.H., Chieng, B.C. & Balleine, B.W. Effects of repeated cocaine exposure on habit learning and reversal by N-acetylcysteine. Neuropsychopharmacology 39, 1893–1901 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hitchcott, P.K., Quinn, J.J. & Taylor, J.R. Bidirectional modulation of goal-directed actions by prefrontal cortical dopamine. Cereb. Cortex 17, 2820–2827 (2007).

    Article  PubMed  Google Scholar 

  149. Barker, J.M., Torregrossa, M.M. & Taylor, J.R. Bidirectional modulation of infralimbic dopamine D1 and D2 receptor activity regulates flexible reward seeking. Front. Neurosci. 7, 126 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Mueller, D., Bravo-Rivera, C. & Quirk, G.J. Infralimbic D2 receptors are necessary for fear extinction and extinction-related tone responses. Biol. Psychiatry 68, 1055–1060 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank L. Shapiro, A. Allen, L. DePoy, and E. Pitts for valuable feedback and contributions to Figures 1 and 3. This work was supported by PHS DA011717, DA027844 (JRT), MH101477, DA034808 and DA036737 (S.L.G.), and the Connecticut Department of Mental Health and Addiction Services (J.R.T.). The Yerkes National Primate Research Center is supported by the Office of Research Infrastructure Programs/OD P51OD011132.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Emory University School of Medicine, Emory University, Atlanta, Georgia, USA

    Shannon L Gourley

  2. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Emory University, Atlanta, Georgia, USA

    Shannon L Gourley

  3. Graduate Program in Neuroscience, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA

    Shannon L Gourley

  4. Department of Psychiatry, Yale University School of Medicine, Yale University, New Haven, Connecticut, USA

    Jane R Taylor

  5. Interdepartmental Neuroscience Program, Department of Psychology, Yale University, New Haven, Connecticut, USA

    Jane R Taylor

Authors
  1. Shannon L Gourley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jane R Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.L.G. and J.R.T. together prepared the manuscript.

Corresponding author

Correspondence to Shannon L Gourley.

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

Gourley, S., Taylor, J. Going and stopping: dichotomies in behavioral control by the prefrontal cortex. Nat Neurosci 19, 656–664 (2016). https://doi.org/10.1038/nn.4275

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4275

This article is cited by

Search

Advanced 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