Skip to main content

Thank you for visiting 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.

Rapid strengthening of thalamo-amygdala synapses mediates cue–reward learning


What neural changes underlie individual differences in goal-directed learning? The lateral amygdala (LA) is important for assigning emotional and motivational significance to discrete environmental cues1,2,3,4, including those that signal rewarding events5,6,7,8. Recognizing that a cue predicts a reward enhances an animal’s ability to acquire that reward; however, the cellular and synaptic mechanisms that underlie cue–reward learning are unclear. Here we show that marked changes in both cue-induced neuronal firing and input-specific synaptic strength occur with the successful acquisition of a cue–reward association within a single training session. We performed both in vivo and ex vivo electrophysiological recordings in the LA of rats trained to self-administer sucrose. We observed that reward-learning success increased in proportion to the number of amygdala neurons that responded phasically to a reward-predictive cue. Furthermore, cue–reward learning induced an AMPA (α-amino-3-hydroxy-5-methyl-isoxazole propionic acid)-receptor-mediated increase in the strength of thalamic, but not cortical, synapses in the LA that was apparent immediately after the first training session. The level of learning attained by individual subjects was highly correlated with the degree of synaptic strength enhancement. Importantly, intra-LA NMDA (N-methyl-d-aspartate)-receptor blockade impaired reward-learning performance and attenuated the associated increase in synaptic strength. These findings provide evidence of a connection between LA synaptic plasticity and cue–reward learning, potentially representing a key mechanism underlying goal-directed behaviour.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Reward-related learning success is correlated with rapid increases in cue-related firing.
Figure 2: Degree of AMPAR/NMDAR enhancement predicts cue–reward learning.
Figure 3: Successful cue–reward learning induces an increase in mEPSC amplitude but not in frequency or paired-pulse ratio.
Figure 4: Local NMDAR blockade attenuates reward-related learning and the associated increase in mEPSC amplitude.


  1. LeDoux, J. The emotional brain, fear, and the amygdala. Cell. Mol. Neurobiol. 23, 727–738 (2003)

    Article  PubMed  Google Scholar 

  2. Davis, M. in The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (ed. Aggleton, J. P.) 255–306 (Wiley, Chichester, UK, 1992)

    Google Scholar 

  3. Rosenkranz, J. A. & Grace, A. A. Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning. Nature 417, 282–287 (2002)

    ADS  CAS  Article  PubMed  Google Scholar 

  4. Maren, S. & Quirk, G. J. Neuronal signalling of fear memory. Nature Rev. Neurosci. 5, 844–852 (2004)

    CAS  Article  Google Scholar 

  5. Cador, M., Robbins, T. W. & Everitt, B. J. Involvement of the amygdala in stimulus–reward associations: interaction with the ventral striatum. Neuroscience 30, 77–86 (1989)

    CAS  Article  PubMed  Google Scholar 

  6. Cardinal, R. N., Parkinson, J. A., Hall, J. & Everitt, B. J. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci. Biobehav. Rev. 26, 321–352 (2002)

    Article  PubMed  Google Scholar 

  7. Balleine, B. W. & Killcross, S. Parallel incentive processing: an integrated view of amygdala function. Trends Neurosci. 29, 272–279 (2006)

    CAS  Article  PubMed  Google Scholar 

  8. 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  PubMed  PubMed Central  Google Scholar 

  9. Uwano, T., Nishijo, H., Ono, T. & Tamura, R. Neuronal responsiveness to various sensory stimuli, and associative learning in the rat amygdala. Neuroscience 68, 339–361 (1995)

    CAS  Article  PubMed  Google Scholar 

  10. Tye, K. M. & Janak, P. H. Amygdala neurons differentially encode motivation and reinforcement. J. Neurosci. 27, 3937–3945 (2007)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Paton, J. J., Belova, M. A., Morrison, S. E. & Salzman, C. D. The primate amygdala represents the positive and negative value of visual stimuli during learning. Nature 439, 865–870 (2006)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Doron, N. N. & Ledoux, J. E. Organization of projections to the lateral amygdala from auditory and visual areas of the thalamus in the rat. J. Comp. Neurol. 412, 383–409 (1999)

    CAS  Article  PubMed  Google Scholar 

  13. Azuma, S., Yamamoto, T. & Kawamura, Y. Studies on gustatory responses of amygdaloid neurons in rats. Exp. Brain Res. 56, 12–22 (1984)

    CAS  Article  PubMed  Google Scholar 

  14. Nakashima, M. et al. An anterograde and retrograde tract-tracing study on the projections from the thalamic gustatory area in the rat: distribution of neurons projecting to the insular cortex and amygdaloid complex. Neurosci. Res. 36, 297–309 (2000)

    CAS  Article  PubMed  Google Scholar 

  15. McDonald, A. J. Cortical pathways to the mammalian amygdala. Prog. Neurobiol. 55, 257–332 (1998)

    CAS  Article  PubMed  Google Scholar 

  16. Ungless, M. A., Whistler, J. L., Malenka, R. C. & Bonci, A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  17. Perkel, D. J. & Nicoll, R. A. Evidence for all-or-none regulation of neurotransmitter release: implications for long-term potentiation. J. Physiol. (Lond.) 471, 481–500 (1993)

    CAS  Article  Google Scholar 

  18. Malenka, R. C. & Nicoll, R. A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999)

    CAS  Article  PubMed  Google Scholar 

  19. Hess, G., Kuhnt, U. & Voronin, L. L. Quantal analysis of paired-pulse facilitation in guinea pig hippocampal slices. Neurosci. Lett. 77, 187–192 (1987)

    CAS  Article  PubMed  Google Scholar 

  20. Shin, R. M., Tsvetkov, E. & Bolshakov, V. Y. Spatiotemporal asymmetry of associative synaptic plasticity in fear conditioning pathways. Neuron 52, 883–896 (2006)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Humeau, Y., Shaban, H., Bissiere, S. & Luthi, A. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature 426, 841–845 (2003)

    ADS  CAS  Article  PubMed  Google Scholar 

  22. Burns, L. H., Everitt, B. J. & Robbins, T. W. Intra-amygdala infusion of the N-methyl-d-aspartate receptor antagonist AP5 impairs acquisition but not performance of discriminated approach to an appetitive CS. Behav. Neural Biol. 61, 242–250 (1994)

    CAS  Article  PubMed  Google Scholar 

  23. Baldwin, A. E., Holahan, M. R., Sadeghian, K. & Kelley, A. E. N-methyl-d-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning. Behav. Neurosci. 114, 84–98 (2000)

    CAS  Article  PubMed  Google Scholar 

  24. Rosenkranz, J. A., Moore, H. & Grace, A. A. The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. J. Neurosci. 23, 11054–11064 (2003)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Samson, R. D. & Pare, D. A spatially structured network of inhibitory and excitatory connections directs impulse traffic within the lateral amygdala. Neuroscience 141, 1599–1609 (2006)

    CAS  Article  PubMed  Google Scholar 

  26. McKernan, M. G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro . Nature 390, 607–611 (1997)

    ADS  CAS  Article  PubMed  Google Scholar 

  27. Rumpel, S., LeDoux, J., Zador, A. & Malinow, R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005)

    ADS  CAS  Article  PubMed  Google Scholar 

  28. Tsvetkov, E., Carlezon, W. A., Benes, F. M., Kandel, E. R. & Bolshakov, V. Y. Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala. Neuron 34, 289–300 (2002)

    CAS  Article  PubMed  Google Scholar 

  29. Quirk, G. J., Armony, J. L. & LeDoux, J. E. Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron 19, 613–624 (1997)

    CAS  Article  PubMed  Google Scholar 

  30. McGaugh, J. L. Memory consolidation and the amygdala: a systems perspective. Trends Neurosci. 25, 456–461 (2002)

    CAS  Article  PubMed  Google Scholar 

Download references


We thank H. L. Fields, R. A. Nicoll, A. J. Doupe, B. T. Chen, M. J. Wanat and F. W. Hopf for critical comments; W. W. Schairer, J. J. Cone and L. D. Tye for technical assistance; and T. M. Gill and A. D. Milstein for discussion and technical advice. This study was supported by the State of California for Medical Research on Alcohol and Substance Abuse through the University of California at San Francisco (P.H.J. and A.B.), National Institutes of Health grant RO1DA115096 (A.B.) and a National Science Foundation Graduate Research Fellowship (K.M.T.).

Author Contributions K.M.T. performed the experiments and analyzed the data, with assistance and training in whole-cell recording from G.D.S., who performed pilot mEPSC experiments. B.R. performed cannula surgeries and trained K.M.T. in microinjection techniques. A.B. and P.H.J. provided mentorship and resources. K.M.T., G.D.S., A.B. and P.H.J. contributed to study design, results analysis, interpretation and manuscript writing.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Patricia H. Janak.

Supplementary information

Supplementary Information

This file contains Supplementary Figures and Legends 1-9 and Supplementary Tables 1-3. These Supplementary Figures and Tables collectively contain further analysis of the data presented within the main text, data from additional experiments that further support the main conclusions of the paper, and schematics of electrode and cannulae placements in the amygdala. (PDF 8190 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tye, K., Stuber, G., de Ridder, B. et al. Rapid strengthening of thalamo-amygdala synapses mediates cue–reward learning. Nature 453, 1253–1257 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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