The dorsal raphe nucleus is integral to negative prediction errors in Pavlovian fear

Abstract

Prediction errors are central to modern learning theories. While brain regions contributing to reward prediction errors have been uncovered, the sources of aversive prediction errors remain largely unknown. Here we used probabilistic and deterministic reinforcement procedures, followed by extinction, to examine the contribution of the dorsal raphe nucleus to negative, aversive prediction errors in Pavlovian fear. Rats with dorsal raphe lesions were able to acquire fear and reduce fear to a non-reinforced deterministic cue. However, dorsal raphe lesions impaired the reduction of fear to a probabilistic cue and fear extinction to a deterministic cue, both of which involve the use of negative prediction errors. The results point to an integral role for the dorsal raphe nucleus in negative prediction error signaling in Pavlovian fear.

Keywords: conditioned suppression; learning; omission; rat.

Figure 1. Summary of behavioral procedures

A summary of behavioral procedures is shown. Briefly, each rat was trained to nose poke for pellet delivery which was maintained for the entirety of pre-exposure, discrimination and extinction. Following pre-exposure to the three auditory cues each rat received discrimination sessions in which one cue deterministically predicted shock occurrence ‘D100’, a second deterministically predicted shock absence ‘D0’, and a third probabilistically predicted occurrence or omission ‘PR’. In extinction all cues were presented in the absence of shock.

Figure 2. Histology

Rats were first randomly assigned to the Control or DRN lesion condition. (A) Sections 7.80 mm (left) and 8.00 mm (right) posterior to bregma are shown. Minimal lesion extent is indicated by the filled red areas. Maximal lesion extent is indicated by red outlines. Representative photomicrographs of (B) surgical Control and (C) DRN lesion are shown. The area outlined contains gliosis and cell loss – evidence of neurotoxic damage. Abbreviations: Aq – aqueduct, DRd – dorsal raphe dorsal, DRv – dorsal raphe ventral, DRd – dorsal raphe ventrolateral, and vlPAG – ventrolateral periaqueductal grey.

Figure 3. Fear in discrimination

(A) Mean suppression ratios to the ‘D100’ (black fill), ‘PR’ (grey fill) and ‘D0’ cues (white fill) are shown for Control (black outlines) rats on the final pre-exposure session (‘p’ on x axis) and the 12 discrimination sessions. The horizontal line indicates a suppression ratio of 0.0, meaning no fear is observed to the cue. The first vertical line separates the last pre-exposure session from the first discrimination session. The second vertical line marks the transition from 50% shock reinforcement of the ‘PR’ cue to 38% reinforcement. (B) Conditioned suppression data from DRN-lesioned (red outlines) rats plotted exactly as in (A). (C) Mean ± SEM suppression ratios for discrimination session 12 are shown for each group and cue. Meaning of colors maintained from (A & B). Asterisk indicates a significant, between-subject t test result comparing Control and DRN-lesioned rats. *p<0.05.

Figure 4. Fear in extinction

(A, left) Mean suppression ratios to the ‘D100’ cue are shown for Control (black outlines) and DRN-lesioned rats (red lines) on the reminder session (‘r’ on x axis) and the four extinction sessions. The horizontal line indicates a suppression ratio of 0.0, meaning no fear is observed to the cue. The vertical line separates the reminder session from the first extinction session. (A, right) Mean ± SEM suppression ratios to the ‘D100’ cue for extinction sessions 1 and 2 are shown for Control and DRN-lesioned rats. Meaning of colors maintained from (A). Asterisk indicates a significant, between-subject t test result comparing Control and DRN-lesioned rats. (B) The correlation between mean suppression ratio to the ‘PR’ cue on discrimination session 8 (x axis) and to the ‘D100’ cue on the first two extinction sessions is plotted for Control (Con, black) and DRN-lesioned rats (DRN, red). Each marker represents an individual. Trend line, R² and p-value of correlation are shown. (C) The correlation between mean suppression ratio to the ‘PR’ cue on discrimination session 12 (x axis) and to the ‘D100’ cue on the first two extinction sessions is plotted. Formatting same as (B). *p<0.05.