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

Abstract

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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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.

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Acknowledgements

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.

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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. (PDF 8190 kb)

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Tye, K., Stuber, G., de Ridder, B. et al. Rapid strengthening of thalamo-amygdala synapses mediates cue–reward learning. Nature 453, 1253–1257 (2008). https://doi.org/10.1038/nature06963

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