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

Nature volume 453, pages 12531257 (26 June 2008) | Download Citation



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.

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  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 4.

    & Neuronal signalling of fear memory. Nature Rev. Neurosci. 5, 844–852 (2004)

  5. 5.

    , & Involvement of the amygdala in stimulus–reward associations: interaction with the ventral striatum. Neuroscience 30, 77–86 (1989)

  6. 6.

    , , & Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci. Biobehav. Rev. 26, 321–352 (2002)

  7. 7.

    & Parallel incentive processing: an integrated view of amygdala function. Trends Neurosci. 29, 272–279 (2006)

  8. 8.

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

  9. 9.

    , , & Neuronal responsiveness to various sensory stimuli, and associative learning in the rat amygdala. Neuroscience 68, 339–361 (1995)

  10. 10.

    & Amygdala neurons differentially encode motivation and reinforcement. J. Neurosci. 27, 3937–3945 (2007)

  11. 11.

    , , & The primate amygdala represents the positive and negative value of visual stimuli during learning. Nature 439, 865–870 (2006)

  12. 12.

    & 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)

  13. 13.

    , & Studies on gustatory responses of amygdaloid neurons in rats. Exp. Brain Res. 56, 12–22 (1984)

  14. 14.

    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)

  15. 15.

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

  16. 16.

    , , & Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001)

  17. 17.

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

  18. 18.

    & Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999)

  19. 19.

    , & Quantal analysis of paired-pulse facilitation in guinea pig hippocampal slices. Neurosci. Lett. 77, 187–192 (1987)

  20. 20.

    , & Spatiotemporal asymmetry of associative synaptic plasticity in fear conditioning pathways. Neuron 52, 883–896 (2006)

  21. 21.

    , , & Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature 426, 841–845 (2003)

  22. 22.

    , & 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)

  23. 23.

    , , & N-methyl-d-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning. Behav. Neurosci. 114, 84–98 (2000)

  24. 24.

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

  25. 25.

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

  26. 26.

    & Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997)

  27. 27.

    , , & Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005)

  28. 28.

    , , , & Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala. Neuron 34, 289–300 (2002)

  29. 29.

    , & Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron 19, 613–624 (1997)

  30. 30.

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

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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


  1. Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, USA

    • Kay M. Tye
    • , Garret D. Stuber
    • , Bram de Ridder
    • , Antonello Bonci
    •  & Patricia H. Janak
  2. Program in Neuroscience,

    • Kay M. Tye
    • , Antonello Bonci
    •  & Patricia H. Janak
  3. Department of Neurology, and,

    • Antonello Bonci
    •  & Patricia H. Janak
  4. Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, California 94143, USA

    • Antonello Bonci
    •  & Patricia H. Janak


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Corresponding author

Correspondence to Patricia H. Janak.

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    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.

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