Reward-Predictive Cues Enhance Excitatory Synaptic Strength onto Midbrain Dopamine Neurons
Garret D. Stuber1,
Bram de Ridder1,
M. Scott Bowers1,
Ruud N. Joosten2,
Matthijs G. Feenstra2, and
1 Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, CA 94608, USA.
2 Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands.
3 Wheeler Center for the Neurobiology of Drug Addiction, University of California, San Francisco, San Francisco, CA 94143, USA.
Fig. 1.. Phasic DA release in the NAc to reward-predictive stimuli develops during learning. (A to C) Single-trial example traces of DA release during different stages of conditioning. Red horizontal bar indicates CS duration, which was followed by sucrose delivery (at 10 s). Black vertical ticks indicate nosepokes into the sucrose receptacle. Insets show background-subtracted cyclic voltammograms taken from the DA peak to the pellet delivery in (A) and from the DA peak to CS onset in (B) and (C). (D) The development of DA release in response to the CS in a single rat across four conditioning sessions each consisting of 32 trials. CS onset occurred at t = 0. (E) Nosepokes made during the CS period correlated with amount of [DA]cue/[DA]reward across 13 behavioral sessions in n = 8 rats tested. (F) Bar graph of data in (E) showing that rats with the greatest conditioned-approach behavior to the CS showed significantly higher [DA]cue/[DA]reward.
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Fig. 2.. Excitatory synaptic strength is transiently increased after the acquisition of a cue-reward association. (A) Schematic of the CS+ and CS– behavioral paradigms. (B) Conditioned-approach behavior (CS nosepokes, 10 s prior) increased over five sessions in the CS+ group but not in the CS– group. (C) Example traces of AMPAR- and NMDAR-mediated currents taken from CS+ and CS– rats after (1 hour) conditioning sessions 1, 3, or 5. (D) Average data showing that the AMPAR/NMDAR was transiently elevated only in CS+ rats immediately after conditioning session 3. (E) Analysis of CS+ data from sessions 3 through 5 showing that rats that showed a >30% increase in cue-directed nosepokes over the previous conditioning session displayed a significant increase in the AMPAR/NMDAR versus rats that did not show an increase in performance.
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Fig. 3.. NMDAR antagonism blocks LTP and cue-reward learning. (A and B) Example and average data showing that LTP was induced in cells taken from CS– rats after session 3. (C and D) Example and average data showing that LTP could not be induced in cells taken from CS+ rats. (E and F) An example experiment and average data showing that NMDAR antagonism blocked the induction of LTP in cells taken from naïve rats. (G) Behavioral data showing NMDAR antagonism in the VTA blocked the acquisition of the cue-reward association. (H) Behavioral data showing that NMDAR antagonism had no effect on conditioned-approach behavior after learning had occurred.
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