Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

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

  2. 2.

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

  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).

  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).

  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).

  6. 6.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  14. 14.

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

  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).

  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).

  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).

  18. 18.

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

  19. 19.

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

  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).

  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).

  22. 22.

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

  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).

  24. 24.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  44. 44.

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

  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).

  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).

  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).

  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).

  49. 49.

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

  50. 50.

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

  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).

  52. 52.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  65. 65.

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

  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).

  67. 67.

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

Download references

Acknowledgements

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.

Author information

Affiliations

  1. Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA

    • Melissa Malvaez
    • , Christine Shieh
    • , Michael D. Murphy
    • , Venuz Y. Greenfield
    •  & Kate M. Wassum
  2. Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA

    • Kate M. Wassum

Authors

  1. Search for Melissa Malvaez in:

  2. Search for Christine Shieh in:

  3. Search for Michael D. Murphy in:

  4. Search for Venuz Y. Greenfield in:

  5. Search for Kate M. Wassum in:

Contributions

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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Kate M. Wassum.

Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41593-019-0374-7