Medial Orbitofrontal Cortex Regulates Instrumental Conditioned Punishment, but not Pavlovian Conditioned Fear

Abstract

Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsive disorders and related behaviors. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here, we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment; a core characteristic of many compulsive disorders. In our first experiment, we demonstrated that mOFC lesions prevented rats from learning to avoid a lever that was punished with a stimulus that coterminated with footshock. Our second experiment demonstrated that retrieval of punishment learning is also somewhat mOFC-dependent, as lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent rats from reacquiring the ability to avoid a punished lever when it was learned prior to lesions being administered. In both experiments, Pavlovian fear conditioning to the stimulus was intact for all animals. Together, these results reveal that the mOFC regulates punishment learning and retrieval in a manner that is separate from any role in Pavlovian fear conditioning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.

Keywords: Pavlovian conditioned fear; conditioned punishment; medial orbitofrontal cortex; passive avoidance.

Figure 1

Excitotoxic lesions of medial orbitofrontal cortex prevent conditioned punishment learning. (A–D) Representative photomicrographs of (A) a sham anterior mOFC placement, (B) an excitotoxic anterior mOFC lesion (both +5.64 mm from bregma, (C) a sham posterior mOFC placement, and (D) a posterior mOFC lesion (+4 mm from bregma). Scale bars = 100 μm. (E) Diagrammatic representation of overlapping anterior mOFC lesion placements in Experiment 1, (F) diagrammatic representation of overlapping posterior mOFC lesion placements in Experiment 1, (G) Mean (±1 SEM) lever presses per min during initial lever press acquisition, (H) Mean (±1 SEM) lever presses per min during conditioned punishment training for group SHAM, (I) Mean (±1 SEM) lever presses per min during conditioned punishment training for group mOFC, (J) Mean (±1 SEM) lever presses per min during VI-30s conditioned punishment training for group SHAM, (K) Mean (±1 SEM) lever presses per min during VI-30S conditioned punishment training for group mOFC, note that although graphed separately, groups SHAM and mOFC groups were compared statistically (group × punishment interaction for the data displayed in Fig. 1H–I, P < 0.05, group × punishment interaction for data displayed in Fig. 1J–K, P > 0.05). ^*P < 0.05, n.s. = nonsignificant, P > 0.05.

Figure 2

Excitotoxic lesions of medial orbitofrontal cortex leave Pavlovian fear conditioning intact. (A) Mean (±1 SEM) conditioned suppression ratios to CS− and CS+ for group SHAM during conditioned punishment training, (B) Mean (±1 SEM) conditioned suppression ratios to CS− and CS+ for group mOFC during conditioned punishment training, (C) Mean (±1 SEM) conditioned suppression ratios to CS− and CS+ for group SHAM during VI-30s conditioned punishment training, (D) Mean (±1 SEM) conditioned suppression ratios to CS− and CS+ for group mOFC during VI-30s conditioned punishment training. Note that although graphed separately, groups SHAM and mOFC were compared statistically at each stage (group × Pavlovian conditioning interaction for data displayed in Fig. 2A,B, P > 0.05, for data displayed in Fig. 2C,D, P > 0.05). ^*P < 0.05.

Figure 3

Excitotoxic lesions of medial orbitofrontal cortex impair extended conditioned punishment retrieval. (A) Diagrammatic representation of anterior lesion placements in Experiment 2, (B) diagrammatic representation of posterior lesion placements in Experiment 2, (C) Mean (±1 SEM) lever presses per min during initial lever press acquisition, (D) Mean (±1 SEM) lever presses per min during presurgery conditioned punishment training for group SHAM, (E) Mean (±1 SEM) lever presses per min during presurgery conditioned punishment training for group mOFC, (F) Mean lever presses per min for both groups during the 5-min extinction retrieval test, (G) Mean lever presses per min for both groups during the 10-min pellet-only retrieval test, (H) Mean (±1 SEM) lever presses per min during conditioned punishment retraining for group SHAM, (I) Mean (±1 SEM) lever presses per min during conditioned punishment retraining for group mOFC, (J) Mean (±1 SEM) lever presses per min during the 20-min pellet-only retrieval test, separated into 5 min bins. Note that although sometimes graphed separately, groups SHAM and mOFC were compared statistically at each stage (group × punishment interactions for data displayed in Fig. 3D,E, P > 0.05, for data displayed in Fig. 3H,I, P > 0.05). ^*P < 0.05, n.s. = nonsignificant, P > 0.05.

Figure 4

Excitotoxic lesions of medial orbitofrontal cortex leave Pavlovian fear conditioning intact. (A) Mean (±1 SEM) conditioned suppression ratios to CS− and CS+ for group SHAM during presurgery conditioned punishment training, (B) Mean (±1 SEM) conditioned suppression ratios to CS− and CS+ for group mOFC during presurgery conditioned punishment training, (C) Mean (±1 SEM) conditioned suppression ratios to CS− and CS+ for group SHAM during conditioned punishment retraining, (D) Mean (±1 SEM) conditioned suppression ratios to CS− and CS+ for group mOFC during conditioned punishment retraining. Note that although graphed separately, groups SHAM and mOFC were compared statistically at each stage (group × Pavlovian conditioning interaction for data displayed in Fig. 4A,B, P > 0.05, for data displayed in Fig. 4C,D, P > 0.05). ^*P < 0.05.