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Distinct cortical–amygdala projections drive reward value encoding and retrieval


The value of an anticipated rewarding event is a crucial component of the decision to engage in its pursuit. But little is known of the networks responsible for encoding and retrieving this value. By using biosensors and pharmacological manipulations, we found that basolateral amygdala (BLA) glutamatergic activity tracks and mediates encoding and retrieval of the state-dependent incentive value of a palatable food reward. Projection-specific, bidirectional chemogenetic and optogenetic manipulations revealed that the orbitofrontal cortex (OFC) supports the BLA in these processes. Critically, the function of ventrolateral and medial OFC→BLA projections is doubly dissociable. Whereas lateral OFC→BLA projections are necessary and sufficient for encoding of the positive value of a reward, medial OFC→BLA projections are necessary and sufficient for retrieving this value from memory. These data reveal a new circuit for adaptive reward valuation and pursuit and provide insight into the dysfunction in these processes that characterizes myriad psychiatric diseases.

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Fig. 1: BLA glutamate release tracks reward value encoding and retrieval.
Fig. 2: BLA glutamate receptor activity is necessary for reward value encoding and retrieval.
Fig. 3: lOFC→BLA and mOFC→BLA projections are necessary for reward value encoding and retrieval, respectively.
Fig. 4: Optical stimulation of lOFC terminals in BLA concurrently with reward experience is sufficient to drive positive value assignment.
Fig. 5: Optical stimulation of mOFC→BLA projections is sufficient to enhance reward value retrieval.

Data availability

All data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

Custom-written Python-based code is available from the corresponding author upon request.


  1. 1.

    Dickinson, A. & Balleine, B. W. Motivational control over goal-directed action. Anim. Learn. Behav. 22, 1–18 (1994).

    Article  Google Scholar 

  2. 2.

    Wassum, K. M. & Izquierdo, A. The basolateral amygdala in reward learning and addiction. Neurosci. Biobehav. Rev. 57, 271–283 (2015).

    Article  Google Scholar 

  3. 3.

    Wassum, K. M., Ostlund, S. B., Maidment, N. T. & Balleine, B. W. Distinct opioid circuits determine the palatability and the desirability of rewarding events. Proc. Natl Acad. Sci. USA 106, 12512–12517 (2009).

    CAS  Article  Google Scholar 

  4. 4.

    Parkes, S. L. & Balleine, B. W. Incentive memory: evidence the basolateral amygdala encodes and the insular cortex retrieves outcome values to guide choice between goal-directed actions. J. Neurosci. 33, 8753–8763 (2013).

    CAS  Article  Google Scholar 

  5. 5.

    West, E. A. et al. Transient inactivation of basolateral amygdala during selective satiation disrupts reinforcer devaluation in rats. Behav. Neurosci. 126, 563–574 (2012).

    Article  Google Scholar 

  6. 6.

    Pitkänen, A., Savander, M., Nurminen, N. & Ylinen, A. Intrinsic synaptic circuitry of the amygdala. Ann. NY Acad. Sci. 985, 34–49 (2003).

    Article  Google Scholar 

  7. 7.

    Price, J. L. Definition of the orbital cortex in relation to specific connections with limbic and visceral structures and other cortical regions. Ann. NY Acad. Sci. 1121, 54–71 (2007).

    Article  Google Scholar 

  8. 8.

    Wassum, K. M. et al. Transient extracellular glutamate events in the basolateral amygdala track reward-seeking actions. J. Neurosci. 32, 2734–2746 (2012).

    CAS  Article  Google Scholar 

  9. 9.

    Malvaez, M. et al. Basolateral amygdala rapid glutamate release encodes an outcome-specific representation vital for reward-predictive cues to selectively invigorate reward-seeking actions. Sci. Rep. 5, 12511 (2015).

    CAS  Article  Google Scholar 

  10. 10.

    Balleine, B. W., Garner, C., Gonzalez, F. & Dickinson, A. Motivational control of heterogeneous instrumental chains. J. Exp. Psychol. Anim. Behav. Process. 21, 203–217 (1995).

    Article  Google Scholar 

  11. 11.

    Williams, K. Ifenprodil discriminates subtypes of the N-methyl-d-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol. Pharmacol. 44, 851–859 (1993).

    CAS  PubMed  Google Scholar 

  12. 12.

    Sheardown, M. J., Nielsen, E. O., Hansen, A. J., Jacobsen, P. & Honoré, T. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemia. Science 247, 571–574 (1990).

    CAS  Article  Google Scholar 

  13. 13.

    Heilbronner, S. R., Rodriguez-Romaguera, J., Quirk, G. J., Groenewegen, H. J. & Haber, S. N. Circuit-based corticostriatal homologies between rat and primate. Biol. Psychiatry 80, 509–521 (2016).

    Article  Google Scholar 

  14. 14.

    Ostlund, S. B. & Balleine, B. W. The contribution of orbitofrontal cortex to action selection. Ann. NY Acad. Sci. 1121, 174–192 (2007).

    Article  Google Scholar 

  15. 15.

    Murray, E. A. & Izquierdo, A. Orbitofrontal cortex and amygdala contributions to affect and action in primates. Ann. NY Acad. Sci. 1121, 273–296 (2007).

    Article  Google Scholar 

  16. 16.

    Baltz, E. T., Yalcinbas, E. A., Renteria, R. & Gremel, C. M. Orbital frontal cortex updates state-induced value change for decision-making. eLife 7, e35988 (2018).

    Article  Google Scholar 

  17. 17.

    Rudebeck, P. H. & Murray, E. A. Balkanizing the primate orbitofrontal cortex: distinct subregions for comparing and contrasting values. Ann. NY Acad. Sci. 1239, 1–13 (2011).

    Article  Google Scholar 

  18. 18.

    Izquierdo, A. Functional heterogeneity within rat orbitofrontal cortex in reward learning and decision making. J. Neurosci. 37, 10529–10540 (2017).

    CAS  Article  Google Scholar 

  19. 19.

    Lichtenberg, N. T. et al. Basolateral amygdala to orbitofrontal cortex projections enable cue-triggered reward expectations. J. Neurosci. 37, 8374–8384 (2017).

    CAS  Article  Google Scholar 

  20. 20.

    Bauer, E. P., Schafe, G. E. & LeDoux, J. E. NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J. Neurosci. 22, 5239–5249 (2002).

    CAS  Article  Google Scholar 

  21. 21.

    Müller, T., Albrecht, D. & Gebhardt, C. Both NR2A and NR2B subunits of the NMDA receptor are critical for long-term potentiation and long-term depression in the lateral amygdala of horizontal slices of adult mice. Learn. Mem 16, 395–405 (2009).

    Article  Google Scholar 

  22. 22.

    Riedel, G., Platt, B. & Micheau, J. Glutamate receptor function in learning and memory. Behav. Brain Res. 140, 1–47 (2003).

    CAS  Article  Google Scholar 

  23. 23.

    Rodrigues, S. M., Schafe, G. E. & LeDoux, J. E. Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning. J. Neurosci. 21, 6889–6896 (2001).

    CAS  Article  Google Scholar 

  24. 24.

    Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    CAS  Article  Google Scholar 

  25. 25.

    Yu, S. Y., Wu, D. C., Liu, L., Ge, Y. & Wang, Y. T. Role of AMPA receptor trafficking in NMDA receptor-dependent synaptic plasticity in the rat lateral amygdala. J. Neurochem. 106, 889–899 (2008).

    CAS  Article  Google Scholar 

  26. 26.

    Jenison, R. L., Rangel, A., Oya, H., Kawasaki, H. & Howard, M. A. Value encoding in single neurons in the human amygdala during decision making. J. Neurosci. 31, 331–338 (2011).

    CAS  Article  Google Scholar 

  27. 27.

    Hernádi, I., Grabenhorst, F. & Schultz, W. Planning activity for internally generated reward goals in monkey amygdala neurons. Nat. Neurosci. 18, 461–469 (2015).

    Article  Google Scholar 

  28. 28.

    Grabenhorst, F., Hernádi, I. & Schultz, W. Prediction of economic choice by primate amygdala neurons. Proc. Natl Acad. Sci. USA 109, 18950–18955 (2012).

    CAS  Article  Google Scholar 

  29. 29.

    Orsini, C. A. et al. Optogenetic inhibition reveals distinct roles for basolateral amygdala activity at discrete time points during risky decision making. J. Neurosci. 37, 11537–11548 (2017).

    CAS  Article  Google Scholar 

  30. 30.

    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  Google Scholar 

  31. 31.

    Howard, J. D., Gottfried, J. A., Tobler, P. N. & Kahnt, T. Identity-specific coding of future rewards in the human orbitofrontal cortex. Proc. Natl Acad. Sci. USA 112, 5195–5200 (2015).

    CAS  Article  Google Scholar 

  32. 32.

    Howard, J. D. & Kahnt, T. Identity-specific reward representations in orbitofrontal cortex are modulated by selective devaluation. J. Neurosci. 37, 2627–2638 (2017).

    CAS  Article  Google Scholar 

  33. 33.

    Suzuki, S., Cross, L. & O’Doherty, J. P. Elucidating the underlying components of food valuation in the human orbitofrontal cortex. Nat. Neurosci. 20, 1780–1786 (2017).

    CAS  Article  Google Scholar 

  34. 34.

    Saddoris, M. P., Gallagher, M. & Schoenbaum, G. Rapid associative encoding in basolateral amygdala depends on connections with orbitofrontal cortex. Neuron 46, 321–331 (2005).

    CAS  Article  Google Scholar 

  35. 35.

    Zimmermann, K. S., Yamin, J. A., Rainnie, D. G., Ressler, 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 81, 366–377 (2017).

    CAS  Article  Google Scholar 

  36. 36.

    Zimmermann, K. S., Li, C. C., Rainnie, D. G., Ressler, K. J. & Gourley, S. L. Memory retention involves the ventrolateral orbitofrontal cortex: comparison with the basolateral amygdala. Neuropsychopharmacology 43, 674 (2018).

    Article  Google Scholar 

  37. 37.

    Gourley, S. L., Zimmermann, K. S., Allen, A. G. & Taylor, J. R. The medial orbitofrontal cortex regulates sensitivity to outcome value. J. Neurosci. 36, 4600–4613 (2016).

    CAS  Article  Google Scholar 

  38. 38.

    Bradfield, L. A., Dezfouli, A., van Holstein, M., Chieng, B. & Balleine, B. W. Medial orbitofrontal cortex mediates outcome retrieval in partially observable task situations. Neuron 88, 1268–1280 (2015).

    CAS  Article  Google Scholar 

  39. 39.

    Stopper, C. M., Green, E. B. & Floresco, S. B. Selective involvement by the medial orbitofrontal cortex in biasing risky, but not impulsive, choice. Cereb. Cortex 24, 154–162 (2014).

    Article  Google Scholar 

  40. 40.

    Dalton, G. L., Wang, N. Y., Phillips, A. G. & Floresco, S. B. Multifaceted contributions by different regions of the orbitofrontal and medial prefrontal cortex to probabilistic reversal learning. J. Neurosci. 36, 1996–2006 (2016).

    CAS  Article  Google Scholar 

  41. 41.

    Wilson, R. C., Takahashi, Y. K., Schoenbaum, G. & Niv, Y. Orbitofrontal cortex as a cognitive map of task space. Neuron 81, 267–279 (2014).

    CAS  Article  Google Scholar 

  42. 42.

    Noonan, M. P., Chau, B. K. H., Rushworth, M. F. S. & Fellows, L. K. Contrasting effects of medial and lateral orbitofrontal cortex lesions on credit assignment and decision-making in humans. J. Neurosci. 37, 7023–7035 (2017).

    CAS  Article  Google Scholar 

  43. 43.

    Murray, E. A., Moylan, E. J., Saleem, K. S., Basile, B. M. & Turchi, J. Specialized areas for value updating and goal selection in the primate orbitofrontal cortex. eLife 4, e11695 (2015).

    Article  Google Scholar 

  44. 44.

    Rudebeck, P. H. & Rich, E. L. Orbitofrontal cortex. Curr. Biol. 28, R1083–R1088 (2018).

    CAS  Article  Google Scholar 

  45. 45.

    Murray, E. A. & Rudebeck, P. H. Specializations for reward-guided decision-making in the primate ventral prefrontal cortex. Nat. Rev. Neurosci. 19, 404–417 (2018).

    CAS  Article  Google Scholar 

  46. 46.

    Plassmann, H., O’Doherty, J. P. & Rangel, A. Appetitive and aversive goal values are encoded in the medial orbitofrontal cortex at the time of decision making. J. Neurosci. 30, 10799–10808 (2010).

    CAS  Article  Google Scholar 

  47. 47.

    Volkow, N. D. & Fowler, J. S. Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb. Cortex 10, 318–325 (2000).

    CAS  Article  Google Scholar 

  48. 48.

    Sladky, R. et al. Disrupted effective connectivity between the amygdala and orbitofrontal cortex in social anxiety disorder during emotion discrimination revealed by dynamic causal modeling for FMRI. Cereb. Cortex 25, 895–903 (2015).

    Article  Google Scholar 

  49. 49.

    Price, J. L. & Drevets, W. C. Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216 (2010).

    Article  Google Scholar 

  50. 50.

    Liu, H. et al. Differentiating patterns of amygdala–frontal functional connectivity in schizophrenia and bipolar disorder. Schizophr. Bull. 40, 469–477 (2014).

    Article  Google Scholar 

  51. 51.

    Wassum, K. M. et al. Silicon wafer-based platinum microelectrode array biosensor for near real-time measurement of glutamate in vivo. Sensors 8, 5023–5036 (2008).

    CAS  Article  Google Scholar 

  52. 52.

    Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).

    CAS  Article  Google Scholar 

  53. 53.

    Schoenbaum, G., Chiba, A. A. & Gallagher, M. Neural encoding in orbitofrontal cortex and basolateral amygdala during olfactory discrimination learning. J. Neurosci. 19, 1876–1884 (1999).

    CAS  Article  Google Scholar 

  54. 54.

    van Duuren, E. et al. Neural coding of reward magnitude in the orbitofrontal cortex of the rat during a five-odor olfactory discrimination task. Learn. Mem. 14, 446–456 (2007).

    Article  Google Scholar 

  55. 55.

    Feltenstein, M. W. & See, R. E. NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse. Neurobiol. Learn. Mem. 88, 435–444 (2007).

    CAS  Article  Google Scholar 

  56. 56.

    Wassum, K. M., Cely, I. C., Balleine, B. W. & Maidment, N. T. Micro-opioid receptor activation in the basolateral amygdala mediates the learning of increases but not decreases in the incentive value of a food reward. J. Neurosci. 31, 1591–1599 (2011).

    CAS  Article  Google Scholar 

  57. 57.

    Wassum, K. M., Greenfield, V. Y., Linker, K. E., Maidment, N. T. & Ostlund, S. B. Inflated reward value in early opiate withdrawal. Addict. Biol. 21, 221–233 (2016).

    CAS  Article  Google Scholar 

  58. 58.

    Davis, J. D. & Perez, M. C. Food deprivation– and palatability-induced microstructural changes in ingestive behavior. Am. J. Physiol. 264, R97–R103 (1993).

    CAS  PubMed  Google Scholar 

  59. 59.

    Berridge, K. C. Modulation of taste affect by hunger, caloric satiety, and sensory-specific satiety in the rat. Appetite 16, 103–120 (1991).

    CAS  Article  Google Scholar 

  60. 60.

    Malvaez, M. et al. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc. Natl Acad. Sci. USA 110, 2647–2652 (2013).

    CAS  Article  Google Scholar 

  61. 61.

    Malvaez, M., Mhillaj, E., Matheos, D. P., Palmery, M. & Wood, M. A. CBP in the nucleus accumbens regulates cocaine-induced histone acetylation and is critical for cocaine-associated behaviors. J. Neurosci. 31, 16941–16948 (2011).

    CAS  Article  Google Scholar 

  62. 62.

    Malvaez, M., Sanchis-Segura, C., Vo, D., Lattal, K. M. & Wood, M. A. Modulation of chromatin modification facilitates extinction of cocaine-induced conditioned place preference. Biol. Psychiatry 67, 36–43 (2010).

    CAS  Article  Google Scholar 

  63. 63.

    Wassum, K. M., Ostlund, S. B., Balleine, B. W. & Maidment, N. T. Differential dependence of Pavlovian incentive motivation and instrumental incentive learning processes on dopamine signaling. Learn. Mem. 18, 475–483 (2011).

    CAS  Article  Google Scholar 

  64. 64.

    Wassum, K. M., Ostlund, S. B., Loewinger, G. C. & Maidment, N. T. Phasic mesolimbic dopamine release tracks reward seeking during expression of Pavlovian-to-instrumental transfer. Biol. Psychiatry 73, 747–755 (2013).

    CAS  Article  Google Scholar 

  65. 65.

    Kaplan, J. M., Roitman, M. F. & Grill, H. J. Ingestive taste reactivity as licking behavior. Neurosci. Biobehav. Rev. 19, 89–98 (1995).

    CAS  Article  Google Scholar 

  66. 66.

    Levin, J. R., Serlin, R. C. & Seaman, M. A. A controlled powerful multiple-comparison strategy for several situations. Psychol. Bull. 115, 153–159 (1994).

    Article  Google Scholar 

  67. 67.

    Tabachnick, B. G., Fidell, L. S. & Osterlind, S. J. Using Multivariate Statistics 4th edn (Allyn and Bacon, 2001).

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This research was supported by NIH grants DA035443, MH106972, and NS087494 to K.M.W. and NIH grants DA038942 and DA024635 to M.M. We acknowledge helpful feedback from N. Lichtenberg and A. Izquierdo on these data and this manuscript.

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M.M. and K.M.W. designed the research and analyzed and interpreted the data. M.M. conducted the research with assistance from C.S., M.D.M., and V.Y.G. M.M. and K.M.W. wrote the manuscript.

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Correspondence to Kate M. Wassum.

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Malvaez, M., Shieh, C., Murphy, M.D. et al. Distinct cortical–amygdala projections drive reward value encoding and retrieval. Nat Neurosci 22, 762–769 (2019).

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