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 co-terminated 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 re-acquiring 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.

Advances in understanding meso‐cortico‐limbic‐striatal systems mediating risky reward seeking

“…In the context of positive punishment risk, data generally support a role for the mOFC in opposing risk-seeking that is comparable to negative punishment-based tasks. The ability to use a conditioned stimulus to inhibit actions that could incur footshock punishment is impaired following lesioning (Ma et al, 2020) or inactivation (Verharen et al, 2019) of the rat mOFC. Compulsive (footshock resistant) alcohol seeking in mice has also been associated with alterations in the excitability of mOFC neurons and the expression of genes for specific NMDA-receptor subunits (Radke et al, 2017).…”

Does disrupting the orbitofrontal cortex alter sensitivity to punishment? A potential mechanism of compulsivity.

“…Verharen, van den Heuvel, Luijendijk, Vanderschuren, and Adan (2019) found that medial OFC inactivation increased the number of footshocks received by rats who entered a food port 'early' (before the end of a cue) to retrieve a sucrose pellet, whereas inactivation of the lateral OFC did not affect performance in this task (although it did appear to reduce task engagement). Most recently, we (Ma et al, 2020) found that lesions of the medial OFC prevented animals from learning to avoid a lever that earned footshock. We further demonstrated that this response was specific to the instrumental punishment contingency because Pavlovian fear of a stimulus that predicted footshock (as measured by conditioned suppression of lever pressing) was intact in the same animals.…”

“…Pavlovian studies examining such interactions that do not involve the punishment of an instrumental response, but do engage OFC (Bissonette, Gentry, Padmala, Pessoa, & Roesch, 2014;Morrison & Salzman, 2011). Again, however, the conclusion that OFC only regulates punishment learning due to regulating such interactions must again be approached with caution due to both the possible existence of unpublished studies that support this conclusion and the existence of studies that have explicitly separated the OFC's role in instrumental from Pavlovian conditioning (Balleine et al, 2011;Ma et al, 2020;Ostlund & Balleine, 2007).…”

Amygdala-cortical collaboration in reward learning and decision making

“…It does seem plausible, if not likely. Like the BLA, both lOFC and mOFC contribute to aversive behavior Orsini et al, 2015 ; Plassmann et al, 2010 ; Zimmermann et al, 2018 ; Ma et al, 2020 ; Verharen et al, 2019 ; Turner et al, 2021 ; Jean-Richard-Dit-Bressel and McNally, 2016 ; Ishikawa et al, 2020 ; Shih and Chang, 2021 ; Metereau and Dreher, 2015 ; O’Doherty et al, 2001 ; Fullana et al, 2016 . lOFC activity influences sensitivity to punishment.…”

“…In others, it is important for pursuing reward despite risk of punishment Orsini et al, 2015 ; Ishikawa et al, 2020 . mOFC is critical for sensitivity to punishment Ma et al, 2020 ; Verharen et al, 2019 , especially when it is infrequent requiring subjects to rely on their memory of the aversive outcome Ma et al, 2020 . Both lOFC and mOFC are also needed to use contexts to know when aversive events are and are not expected Shih and Chang, 2021 .…”