Temporal prediction error triggers amygdala-dependent memory updating in appetitive operant conditioning in rats

Abstract

Reinforcement learning theories postulate that prediction error, i.e., a discrepancy between the actual and expected outcomes, drives reconsolidation and new learning, inducing an updating of the initial memory. Pavlovian studies have shown that prediction error detection is a fundamental mechanism in triggering amygdala-dependent memory updating, where the temporal relationship between stimuli plays a critical role. However, in contrast to the well-established findings in aversive situations (e.g., fear conditioning), only few studies exist on prediction error in appetitive operant conditioning, and even less with regard to the role of temporal parameters. To explore if temporal prediction error in an appetitive operant paradigm could generate an updating and consequent reconsolidation and/or new learning of temporal association, we ran four experiments in adult male rats. Experiment 1 verified whether an unexpected delay in the time of reward's availability (i.e., a negative temporal prediction error) in a single session produces an updating in long-term memory of temporal expectancy in an appetitive operant conditioning. Experiment 2 showed that negative prediction errors, either due to the temporal change or through reward omission, increased in the basolateral amygdala nucleus (BLA) the activation of a protein that is critical for memory formation. Experiment 3 revealed that the presence of a protein synthesis inhibitor (anisomycin) in the BLA during the session when the reward was delayed (Error session) affected the temporal updating. Finally, Experiment 4 showed that anisomycin, when infused immediately after the Error session, interfered with the long-term memory of the temporal updating. Together, our study demonstrated an involvement of BLA after a change in temporal and reward contingencies, and in the resulting updating in long-term memory in appetitive operant conditioning.

Keywords: basolateral amygdala; negative prediction error; omission effect; reconsolidation; timing.

FIGURE 1

Temporal prediction error generated a long-lasting memory updating of temporal expectancy. Responses average (+ SEM) during the 18-s tone, per 2 s, for No Change (Black columns; n = 14) and Temporal Change (White Columns, n = 13) groups. (A) Error session of No Change Group during FI 6 s LH 12 s signaled schedule (*p < 0.05, post hoc intra-group differences from 2 s). (B) Error session of Temporal Change group during FI 12 s LH 6 s signaled schedule during which the FI time was changed from 6 to 12 s to obtain the reinforcement (*p < 0.05, post hoc intra-group differences from 2 s). (C) Test session of reinforcement omission effect (ROE) during FI 6 s LH 12 s signaled schedule in which the reinforcement was omitted in 50% of trials (*p < 0.05, post hoc intra-group differences from 6 s). FI: fixed-interval; LH: limited hold; R: Reinforcement; N: non-reinforcement.

FIGURE 2

Basolateral amygdala nuclei are activated by the prediction error due to a change in the temporal rule and reinforcement omission. (A) Error session: responses average (+ SEM) during the 18 s tone, per 2 s, for three groups: No Change (Black columns; n = 9) during FI 6 s LH 12 s signaled schedule (*p < 0.05, post hoc intra-group differences from 2 s); Temporal Change (White columns; n = 10) during FI 12 s LH 6 s signaled schedule during which the FI time was delayed to 12 s to obtain the reward (*p < 0.05, post hoc intra-group differences from 2 s); reinforcement omission effect (ROE) (Gray columns; n = 10) during FI 6 s LH 12 s signaled schedule during which the reward was omitted in 50% of trials (*p < 0.05, post hoc intra-group differences from 6 s). (B) Activity-regulated cytoskeletal (ARC) activation: Quantification of the number of Arc-positive cells per square millimeter (mean ± SEM) across basolateral (BLA), lateral (LA) and central (CeA) posterior amygdala nuclei of No Change (Black columns), Temporal Change (White columns) and ROE (Gray columns) groups in animals perfused 90 min from the beginning of the Error session. Arc expression is increased in the BLA when the time to reward was changed from 6 to 12 s, as well as when the reinforcement was omitted (*p < 0.05, post hoc differences from No Change group). FI, fixed-interval; LH, limited hold; R, Reinforcement; N, non-reinforcement.

FIGURE 3

Anisomycin infusion before the Error session affected responding when a temporal prediction error was detected. Responses average (+SEM) during the 18 s tone, per 2 s, for Vehicle (White columns; n = 15) and Anisomycin (Red columns; n = 16) groups. (A) Retraining session during FI 6 s LH 12 s signaled schedule (*p < 0.05, intra-group differences from 2 s). (B) Error session of Temporal Change during FI 12 s LH 6 s signaled schedule during which the time was changed from 6 to 12 s to obtain the reward, and the vehicle or anisomycin were infused in the BLA 10 min before the session (*p < 0.05, intra-group differences from 2 s). (C) Reinforcement omission effect (ROE) Test session under FI 6 s LH 12 s signaled schedule during which the reward was omitted in 50% of trials (*p < 0.05, intra-group differences from 6 s). FI, fixed-interval; LH, limited hold; R, Reinforcement; N, non-reinforcement.

FIGURE 4

Anisomycin infusion after the Error session interfered with long-term memory of temporal updating. Responses average (+ SEM) during the 18 s tone, per 2 s, for Vehicle (White columns; n = 8) and Anisomycin (Red columns; n = 7) groups. (A) Retraining session during FI 6 s LH 12 s signaled schedule (*p < 0.05, intra-group differences from 2 s). (B) Error session of Temporal Change during FI 12 s LH 6 s signaled schedule during which the FI time was changed from 6 to 12 s to obtain the reward, and vehicle or anisomycin infusions were performed immediately after session (*p < 0.05, intra-group differences from 2 s). (C) Reinforcement omission effect (ROE) Test session under FI 6 s LH 12 s during which the reinforcement was omitted in 50% of trials (*p < 0.05, differences from 6 s). FI, fixed-interval; LH, limited hold; R, Reinforcement; N, non-reinforcement.