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Orbitofrontal neurons signal sensory associations underlying model-based inference in a sensory preconditioning task

  1. Brian F Sadacca
  2. Heather M Wied
  3. Nina Lopatina
  4. Gurpreet K Saini
  5. Daniel Nemirovsky
  6. Geoffrey Schoenbaum Is a corresponding author
  1. NIH, United States
  2. University of Maryland School of Medicine, United States
  3. Johns Hopkins School of Medicine, United States
Research Article
Cite as: eLife 2018;7:e30373 doi: 10.7554/eLife.30373
6 figures and 1 additional file


Rats learn to infer the value of a never-before rewarded cue in sensory preconditioning.

Panels illustrate the task design and show the percentage of time spent in the food cup during presentation of the cues for each of the three phases of the sensory preconditioning task. (A) In an initial preconditioning phase, rats (n = 21) learned to associate auditory cues in the absence of reinforcement; during this phase there is negligible food cup responding. (B) In a second conditioning phase, rats learn to associate cue B with reward; conditioned responding progressively increases across sessions (displayed as mean and SEM). (C) In a final test, rats were presented with a reminder of conditioning trials, followed by presentation of the two ‘unconditioned’ cues A and C alone. Responding to cue A over cue C is evident in the averaged responding across rats (right, displayed as mean and SEM; one way ANOVA across cues A and C, p>0.05).

Figure 2 with 1 supplement
Orbitofrontal neurons encode preconditioned pairs in the absence of reward.

(A) AUC normalized responding of all 266 neurons recorded across the two days of preconditioning for either A-B trials (blue, left) or C-D trials (red, right), sorted by for the relative response to cue pairs (cues AB vs CD). The plots show that different neurons seem to fire to the AB pair or the CD pair. (B) Cue-evoked firing in two individual neurons shows differential firing to either the AB or CD pair. (C) Correlations between individual neural responses to paired or unpaired cues above the neuron’s average responding. Plots reveal much greater correlated firing between paired than unpaired cues during preconditioning (A-B, top left; C-D, bottom right).

Figure 2—figure supplement 1
The correlation between pairs of cues is not solely determined by temporal contiguity.

To explore how dependent the correlation observed in Figure 2 is on the temporal adjacency of the cues, we compared the first half or second half of one of the cues presented on that trial with all other bins of that trial (scatter plots), and the first or second half of one cue with the mean firing during its paired cue (bar plots). We expected that if temporal adjacency explains much of the correlation, nearby bins should express substantially higher correlations. Here we display the results of such an analysis for both cues of a pair for neurons recorded on day 1 (left panels A and C) and 2 (right panels B and D) of preconditioning. While there is a modest difference between early vs late cue correlations, there is no significant difference between the temporal distance of early/late bins of one cue and the other cue of that pair.

Orbitofrontal neurons ability to reflect neutral associations becomes more reliable across conditioning.

(A) Pearson correlation of individual trials of OFC activity, calculated from all neurons recorded on preconditioning day 1 (left) or day 2 (right), shows that correlated firing between the paired cues spreads across trials conditioning (day 1 vs day 2). This spread does not occur for unpaired cues. (B) This effect is also evident in individual ensembles. An example of this is visualized for one ensemble of neurons in the two dimensions that best capture the population response from a principal components analysis on that ensemble from preconditioning day 1 (left) vs day 2 (right). On day 1, the ability to distinguish trial types via a linear discriminant classifier (indicated by the colored underlying grid; black indicating a likely B point, grey indicating D) does a much better job discriminating the paired cues (A and C) on day two than on day 1. (C) The classification illustrated in B is performed parametrically across randomly sampled pseudo-ensembles equal to the size of the population recorded on that day with replacement, and the classification of individual trials is displayed as a confusion matrix for all possible pairwise comparisons (e.g. cue A labeled as A, B, C or D). There is a notable decrease in correct classification and an increase in mis-classification within cue-pairs (e.g. cue A labeled as cue B) across days, resembling the results in panel A. (D) These results were then aggregated by error type (within or between pair) vs correctly labeled trials (mean ±SEM across 1000 resampled ensembles) to confirm the increase in within-pair classification across days. (E) Permutation tests performed on resampled ensembles showed that the increase in within-pair classification across days was unlikely to be obtained by chance.

Orbitofrontal neurons accumulate responding during conditioning.

(A) Normalized responding to cue B and reward (ordered by their relative responding to cue B vs cue D) shows an increased fraction and diversity of responses over the course of the six conditioning days, while (B) normalized responding to cue D on each conditioning day shows more modest changes across conditioning. (C) These differences are evident in the fraction of neurons responding to each cue across the 6 days of conditioning. There were significantly more neurons responding to cue B in the final day of conditioning than the first (p>0.05, chi-squared test), with no significant change in the fraction responding to cue D.

Orbitofrontal neurons distinctly encode preconditioned and conditioned cues in the final probe test.

(A) Activity to cues A (blue), C (red), B (black), or D (grey), across all 205 orbitofrontal neurons during the probe test, sorted by their relative responding to cue A vs cue C. Plots show a distinct pattern of responding to cues A and C. In addition, the firing to cue B, now rewarded, is substantially higher than to any of the other cues. While the population response to cue B has changed substantially, there is still some similarity between responding to cue A and cue B, such that neurons that respond strongly to cue A are more likely to respond strongly to cue B than are neurons that respond strongly to cue C. This is made explicit when we isolate activity from the 10% of the neurons responding most strongly to one or the other cue. (B) Neurons responding most strongly to C have modest firing to cue B that is similar to the activity observed to the other cues. (C) By contrast, neurons responding most strongly to A have substantial and somewhat unique firing to cue B.

Orbitofrontal neurons signal preconditioned associations in probe test in rats able to infer expectations of value.

(A) For the 150 neurons recorded in rats that showed evidence of preconditioning in the probe test, correlations between cues paired during preconditioning are well preserved and greater than between cues not paired during preconditioning (B) By contrast, for the 55 neurons recorded in rats that did not appear to precondition, the pattern is flipped, with greater correlations between the unpaired than the paired cues. (C–D) We attempted to classify trials based on this pattern of activity for rats that showed evidence of preconditioning (C) versus those that did not (D). For this, we trained a linear discriminant classifier on the evoked response of a pseudo ensemble of size equal to the population recorded (n = 205) to cues A and C and then tested the ability of this classifier to correctly identify the neural response to cues B and D. The mean success of this classifier at correctly identifying activity evoked by the paired cue was tested against that of a classifier trained and tested with shuffled cue labels (iterated 1000x, solid black line). The insets display the distribution of these results across iterations for one bin; classification in excess of 95% of shuffled resamples (dotted black line) was labeled significant (black circles). By this measure, classification accuracy for the ensemble recorded in rats that exhibited evidence of preconditioning was significantly above chance for the majority of bins during the second half of cue B, when cue B was co-presented with rewarding food pellets. By contrast classification accuracy for the ensemble recorded in rats that did not appear to precondition hovered near chance for all bins.


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