Neuron-type-specific signals for reward and punishment in the ventral tegmental area

Abstract

Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction error), but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We 'tagged' dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error.

Figure 1. Odour-outcome association task in mice

a, Licking behaviour from a representative experimental session. Black bars indicate CS and US delivery. Shaded regions around lick traces denote SEM. b, Mean ± SEM licks during the delay between CS and US as a function of days of the experiment across animals.

Figure 2. VTA neurons show three distinct response types

a, Responses of example neurons. b, Responses of all neurons. Yellow: increase from baseline, cyan: decrease from baseline. Each row represents one neuron. The similarity order of the three main clusters is arranged to match the order presented in (a). c, Top, the first three principal components of the auROC curves. Points are coloured based on hierarchical clustering from the dendrogram. Bottom, classification of neurons based on response differences between big-reward and no-reward trials during the delay versus during the CS or US. d, Average firing rates from Types I - III neurons.

Figure 3. Identifying dopaminergic and GABAergic neurons

a, Voltage trace from 10 pulses of 20 Hz light stimulation (cyan bars). Two light-triggered spikes are shown below. b, Response from this neuron to 20 Hz (left) and 50 Hz (right) stimulation. Ticks represent spikes. c, Quantification of light-evoked responses and mapping of response types in DAT-Cre mice. Blue, Type I; red, Type II; grey, Type III neurons. Identified dopaminergic neurons are indicated by filled circles. Abscissa: energy (integral of the squared voltage values, ∫v²dt) of the light-evoked response from each neuron. Ordinate: cross-correlation between the mean spontaneous spike and the light-evoked response. Example neurons are shown to the right (black, spontaneous spikes; cyan, light-evoked voltages). d, Light-evoked responses in Vgat-Cre mice. Conventions are the same as in (c).

Figure 4. Response variability based on CS-US preference, reward omission and air puffs

a, Response of a dopaminergic neuron during big-reward trials. b, Firing rate (mean ± SEM) vs. reward size (left) and in response to big-reward-predicting CS and big-reward US for each dopaminergic neuron (right). c, Histogram of CS-US index for dopaminergic neurons. d, CS-US index vs. day after the behaviour was learned. e, Average responses of dopaminergic and GABAergic neurons. f, Responses of a dopaminergic and GABAergic neuron for reward present (solid) and unexpectedly absent (dashed) on big-reward trials. g, Histograms of differences in firing rates during the outcome period (2-2.5 s) between rewarded and reward-omitted trials for dopaminergic (top) and GABAergic (bottom) neurons. Values are represented using auROC (<0.5, rewarded < omitted; 0.5, no difference; >0.5, rewarded > omitted). Significant values are filled (t-test, P < 0.05). h, Responses of a dopaminergic and GABAergic neuron during punishment trials. i, Histograms of auROC values during the airpuff (2-2.5 s) relative to baseline (<0.5, decrease; >0.5, increase from baseline).