Medial prefrontal cortex involvement in the expression of extinction and ABA renewal of instrumental behavior for a food reinforcer
Introduction
Conditioned instrumental (operant) behaviors are voluntary actions that are controlled by their consequences. Animals readily acquire behaviors (e.g., lever pressing) to obtain a desirable outcome (e.g., food pellet or drug delivery) and likewise learn to suppress behavior when the reinforcer is withheld. This extinction of instrumental responding is an important and fundamental component of behavioral change (Bouton, 2014, Bouton and Todd, 2014). However, extinguished behaviors can re-emerge through several manipulations and mechanisms, including renewal. Renewal occurs when an animal is tested in a context different from the extinction context (Bouton & Bolles, 1979), resulting in a return of extinguished responding. This return of responding demonstrates that extinction is not erasure of the original learning. A major challenge in successful treatment of behavioral disorders in humans (e.g., addiction) is the susceptibility of these behaviors to relapse.
Instrumental renewal has been reliably demonstrated with several different reinforcers and across different paradigms. ABA renewal (conditioning in context A, extinction in context B, testing in context A) has been shown with food reinforcers (e.g., Nakajima, Tanaka, Urushihara, & Imada, 2000) and different drug reinforcers (e.g., alcohol, cocaine, heroin) (e.g. (Bossert et al., 2004, Chaudhri et al., 2009, Fuchs et al., 2007, Hamlin et al., 2008). Additionally, AAB and ABC renewal have also been observed in instrumental conditioning (Bouton, Todd, Vurbic, & Winterbauer, 2011) and show that removal from the extinction context is sufficient to elicit renewal of responding; return to the acquisition context is not necessary. Such results suggest that extinction at least partly involves learning to inhibit the response in the extinction context.
There are several possible mechanisms that may underlie renewal (e.g., Bouton, 1993). However, Todd (2013) found that when the renewal test occurred in a context that was associated with extinction of a separate response, renewal was not affected. Additionally, in a discriminated operant situation in which responses were controlled by different discriminative stimuli, renewal of a response was reduced if the same response, but not a different response, had previously been extinguished in the test context (Todd, Vurbic, & Bouton, 2014b). Thus, renewal is due at least partly to the release from context specific response inhibition that develops during extinction, rather than negative occasion setting or context-outcome inhibition. It is worth noting that when renewal tests are conducted in context A, the original acquisition context, the test context might also engage excitatory mechanisms learned there during acquisition (see Section 4).
A number of brain regions appear to play a role in ABA renewal of extinguished instrumental behavior for drug reinforcers (Bossert, Marchant, Calu, & Shaham, 2013). Many of these brain regions are important regardless of the type of drug reinforcer. For example, inactivation of the nucleus accumbens shell, or infusion of a D1R antagonist there, reduced ABA renewal of extinguished lever-pressing for cocaine (Fuchs, Ramirez, & Bell, 2008), alcohol (Chaudhri et al., 2009), or heroin (Bossert, Poles, Wihbey, Koya, & Shaham, 2007). However, the picture is not as clear for the medial prefrontal cortex. For example, inactivation of the dorsomedial prefrontal cortex (primarily the prelimbic cortex) reduced expression of ABA renewal of extinguished lever pressing for cocaine; inactivation of ventromedial prefrontal cortex (primarily the infralmbic cortex) had no effect (Fuchs et al., 2005). Similarly, inactivation of the dmPFC reduced expression of ABA renewal of extinguished nose-poking for alcoholic beer; inactivation of vmPFC had no effect (Willcocks & McNally, 2013). In contrast, inactivation of dmPFC had no effect on the expression of ABA renewal of extinguished lever pressing for heroin, whereas inactivation of the vmPFC reduced it (Bossert et al., 2011). Thus, inactivation of dmPFC (but not vmPFC) attenuated ABA renewal of extinguished instrumental behavior for cocaine or alcohol, while inactivation of vmPFC (but not dmPFC) attenuated ABA renewal of extinguished instrumental behavior for heroin. Further evidence that different drug reinforcers might involve different brain regions is provided by results showing that the renewal context activates vmPFC neurons projecting to the nucleus accumbens shell when heroin has been the reinforcer (Bossert et al., 2012) but not when alcohol has been the reinforcer (Hamlin, Clemens, Choi, & McNally, 2009).
While neither the dmPFC nor vmPFC appears to be important for the learning of instrumental extinction (Mendoza et al., 2015, Peters et al., 2008), there is some evidence that vmPFC is important for its consolidation and expression. For example, Peters et al. (2008) gave rats 11 sessions of extinction of lever-pressing for cocaine. Inactivation of vmPFC prior to session 12 of extinction impaired expression of extinguished lever-pressing (i.e., increased responding) (Peters et al., 2008). In contrast, inactivation of dmPFC did not produce the same increase in extinguished responding and inactivation of nucleus accumbens shell increased responding on both an extinguished and an inactive lever. LaLumiere, Niehoff, and Kalivas (2010) performed post-session inactivation of the dmPFC or the vmPFC after each of five short (30 min) sessions of extinction of lever-pressing for cocaine; vmPFC inactivation impaired expression of extinction during subsequent longer (2 h), inactivation-free sessions of extinction, suggesting impaired consolidation of extinction learning, while dmPFC inactivation was without effect. Although the results of Peters et al. (2008) and LaLumiere et al. (2010) suggest that the vmPFC may be required for suppression of responding in extinction after cocaine reinforcement, Willcocks and McNally (2013) did not find any effect of vmPFC inactivation on expression of extinguished nose-poking for alcoholic beer, and Bossert et al. (2011) did not find any effect of vmPFC inactivation on expression of extinguished lever-pressing for heroin.
In comparison to renewal of extinguished instrumental responding for drug reinforcers, we are reaching a relatively good understanding of the behavioral mechanisms that underlie renewal of extinguished instrumental responding for a food reinforcer (e.g., Bouton & Todd, 2014). This might make the food reinforcement paradigm more analytically powerful for exploring the contributions of different brain regions. Here we therefore extend the investigation of the role of the dmPFC and the vmPFC in relapse by inactivating each of these regions just prior to test in an appetitive instrumental ABA renewal paradigm, using a sucrose pellet reinforcer. Our studies include several controls (e.g., off-site cannula placements; use of fluorescent muscimol to map infusion spread; angled cannula placement in the vmPFC to avoid dmPFC damage) that improve interpretation and application of our results. It was hypothesized that if the vmPFC and dmPFC are underlying suppression and promotion (respectively) of appetitive instrumental behavior, then inactivation of the vmPFC would attenuate expression of extinction, while dmPFC inactivation would attenuate ABA renewal. Both of these predictions were confirmed in the current experiments using a food reinforcer, which represents the first time that both effects have been observed in a single study. However, given previous results showing that vmPFC is important for ABA renewal of extinguished lever-pressing for heroin (Bossert et al., 2011), we were not surprised to also observe an attenuation of ABA renewal with inactivation of the vmPFC.
Section snippets
Subjects
A total of 95 adult male Wistar rats (57–61 days old at delivery) obtained from Charles River Canada were used. Of this total, 4 rats were eliminated based on an inability to locate one or both cannulas, leaving a total of 91 rats (25 rats in Experiment 1, 42 rats in Experiment 2, 25 rats as off-site controls). Animals were housed in a temperature and humidity controlled colony room, and kept on a 12/12 hr light/dark schedule. Rats were maintained at approximately 90% of their free-feeding
Experiment 1: Dorsomedial prefrontal cortex
There were no differences between groups in acquisition (vehicle group mean ± SEM = 16.5 ± 2.0 lever presses per minute in the final session; B/M group mean ± SEM = 19.7 ± 1.5 lever presses per minute in the final session) or extinction (vehicle group mean ± SEM = 6.3 ± 0.6 lever presses per minute in first session and 1.2 ± 0.2 lever presses per minute in the final session; B/M group mean ± SEM = 7.1 ± 0.9 lever presses per minute in the first session and 1.0 ± 0.2 lever presses per minute in the final session), as
Discussion
We examined the role of the dmPFC and the vmPFC in ABA renewal following extinction of instrumental behavior with a sucrose reward. Renewal in context A was reduced by inactivation of the dmPFC (Experiment 1) or vmPFC (Experiment 2). Conversely, although dmPFC inactivation had no impact on responding in context B (extinction context), inactivation of the vmPFC increased responding in this context.
Several controls/techniques were implemented that strengthen the interpretation of our results and
Acknowledgments
Supported by NIH R01 MH082893 to JTG and NIH 5 P30 RR032135 from the COBRE Program of the National Center for Research Resources and 8 P30 GM 103498 from the National Institute of General Medical Sciences.
References (41)
- et al.
Imaging the spread of reversible brain inactivations using fluorescent muscimol
Journal of Neuroscience Methods
(2008) - et al.
Goal-directed instrumental action: Contingency and incentive learning and their cortical substrates
Neuropharmacology
(1998) Why behavior change is difficult to sustain
Preventative Medicine
(2014)- et al.
A fundamental role for context in instrumental learning and extinction
Behavioural Processes
(2014) - et al.
The role of prelimbic cortex in instrumental conditioning
Behavioural Brain Research
(2003) - et al.
Inactivation of the infralimbic prefrontal cortex reinstates goal-directed responding in overtrained rats
Behavioural Brain Research
(2003) - et al.
Renewal of extinguished cocaine-seeking
Neuroscience
(2008) Occasion setting in Pavlovian conditioning
- et al.
Inactivating the infralimbic but not prelimbic medial prefrontal cortex facilitates the extinction of appetitive Pavlovian conditioning in Long-Evans rats
Neurobiology of Learning and Memory
(2015) - et al.
Renewal of extinguished lever-press responses upon return to the training context
Learning and Motivation
(2000)
Targeting cocaine versus heroin memories: Divergent roles within ventromedial prefrontal cortex
Trends in Pharmacological Sciences
Behavioral and neurobiological mechanisms of extinction in Pavlovian and instrumental learning
Neurobiology of Learning and Memory
Contextual control of appetite. Renewal of inhibited food-seeking behavior in sated rats after extinction
Appetite
A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking
Journal of Neuroscience
The reinstatement model of drug relapse: Recent neurobiological findings, emerging research topics, and translational research
Psychopharmacology (Berl)
Differential effects of blockade of dopamine D1-family receptors on nucleus accumbens core or shell on reinstatement of heroin seeking induced by contextual and discrete cues
Journal of Neuroscience
Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin
Nature Neuroscience
Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking
Journal of Neuroscience
Context, time, and memory retrieval in the interference paradigms of Pavlovian learning
Psychological Bulletin
Role of conditioned contextual stimuli in reinstatement of extinguished fear
Journal of Experimental Psycholology: Animal Behavior Processes
Cited by (29)
Sex differences in the rodent medial prefrontal cortex – What Do and Don't we know?
2024, NeuropharmacologyPrelimbic cortex inactivation prevents ABA renewal based on satiety state
2023, Neurobiology of Learning and MemoryThe rodent medial prefrontal cortex and associated circuits in orchestrating adaptive behavior under variable demands
2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :These findings are in accord with lesion and pharmacological studies showing that contextual control over discriminative cue responding for reward is impacted by PL or IL inactivation both under reinforced, and extinction conditions (Ashwell and Ito, 2014; Riaz et al., 2019). The PL and IL are also recruited in the use of contextual cues to disambiguate between conflicting cue-outcome contingencies under extinction and guiding instrumental responding for food (Eddy et al., 2016; Haddon and Killcross, 2005; Laurent et al., 2016; Marquis et al., 2007). Taken together, these findings suggest that the PL and IL act cooperatively to detect and disambiguate multiple cues in the environment (context/discrete cue/valence), to enable the deployment of the most appropriate behavioral response in a given situation.
New functions of the rodent prelimbic and infralimbic cortex in instrumental behavior
2021, Neurobiology of Learning and MemoryCitation Excerpt :Our results showing that inactivation of IL reduced ABA renewal of extinguished food-seeking also replicated findings of Bossert et al. (2011) for ABA renewal of extinguished heroin-seeking. The results of Eddy et al. (2016) raised several important questions. One is whether PL involvement in ABA renewal of extinguished instrumental responding is due to the PL specifically mediating the response-enhancing effects of the acquisition context A or whether it might play a role whenever the organism shows renewal when it has merely detected that it is no longer in the extinction context B.
Beyond the hippocampus: The role of parahippocampal-prefrontal communication in context-modulated behavior
2021, Neurobiology of Learning and MemoryCitation Excerpt :The mPFC also contributes to context renewal. Suppressing either the PL or IL diminishes renewal of a food-seeking response in its original acquisition context, i.e. in ABA renewal (Eddy et al., 2016), but PL inactivation has no effect when the renewal test is conducted in a third, novel context, i.e. in ABC renewal (Trask, Shipman, et al., 2017). This suggests that the PL particularly supports instrumental responding in the context where initial acquisition occurs, possibly through retrieving context-dependent action-outcome associations (Trask, Shipman, et al., 2017).
Inactivation of the prelimbic cortex attenuates operant responding in both physical and behavioral contexts
2020, Neurobiology of Learning and MemoryCitation Excerpt :The role of context in behavioral control has generally been attributed to the prefrontal cortex (PFC) (Miller & Cohen, 2001). Notably, the prelimbic subregion of the PFC has been identified as being involved in context-appropriate responding in choice paradigms (Haddon & Killcross, 2006; Marquis, Killcross, & Haddon, 2007) and context-based renewal of extinguished operant behaviors (Bossert et al., 2011; Eddy, Todd, Bouton, & Green, 2016; Fuchs, Eaddy, Su, & Bell, 2007; Fuchs et al., 2005; Palombo et al., 2017; Trask et al., 2017; Willcocks & McNally, 2013). Our work has suggested that rather than having a general role in renewal of extinguished behaviors, the PL selectively promotes the performance of operant behaviors in the context in which they are learned (i.e., acquisition context) (Trask et al., 2017).