Inactivation of the Prelimbic Cortex Attenuates Context-Dependent Operant Responding.

Operant responding in rats provides an analog to voluntary behavior in humans and is used to study maladaptive behaviors, such as overeating, drug taking, or relapse. In renewal paradigms, extinguished behavior recovers when tested outside the context where extinction was learned. Inactivation of the prelimbic (PL) region of the medial prefrontal cortex by baclofen/muscimol (B/M) during testing attenuates renewal when tested in the original acquisition context after extinction in another context (ABA renewal). Two experiments tested the hypothesis that the PL is important in context-dependent responding learned during conditioning. In the first, rats learned to lever-press for a sucrose-pellet reward. Following acquisition, animals were infused with either B/M or vehicle in the PL and tested in the acquisition context (A) and in a different context (B). All rats showed a decrement in responding when switched from Context A to Context B, but PL inactivation decreased responding only in Context A. Experiment 2a examined the effects of PL inactivation on ABC renewal in the same rats. Here, following reacquisition of the response, responding was extinguished in a new context (C). Following infusions of B/M or vehicle in the PL, responding was tested in Context C and another new context (D). The rats exhibited ACD renewal regardless of PL inactivation. Experiment 2b demonstrated that PL inactivation attenuated the ABA renewal effect in the same animals, replicating earlier results and demonstrating that cannulae were still functional. The results suggest that, rather than attenuating renewal generally, PL inactivation specifically affects ABA renewal by reducing responding in the conditioning context.SIGNIFICANCE STATEMENT Extinguished operant behavior can recover ("renew") when tested outside the extinction context. This suggests that behaviors, such as overeating or drug taking, might be especially prone to relapse following treatment. In rats, inactivation of the prelimbic cortex (PL) attenuates renewal. However, we report that PL inactivation after training attenuates responding in the context in which responding was acquired, but not in another one. A similar inactivation has no impact on renewal when testing occurs in a new, rather than the original, context following extinction. The PL thus has a more specific role in controlling contextually dependent operant behavior than has been previously reported.

Trask S ，Shipman ML ，Green JT ，Bouton ME ... -  《-》

Medial prefrontal cortex involvement in the expression of extinction and ABA renewal of instrumental behavior for a food reinforcer.

Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of responding for a food reinforcer. The role of the medial prefrontal cortex in renewal in the original conditioning context may depend in part on control over excitatory context-response or context-(response-outcome) relations that might be learned in acquisition. The role of the vmPFC in expression of extinction may depend on its control over inhibitory context-response or context-(response-outcome) relations that are learned in extinction.

Eddy MC ，Todd TP ，Bouton ME ，Green JT ... -  《-》

Inactivation of prelimbic and infralimbic cortex respectively affects minimally-trained and extensively-trained goal-directed actions.

Several studies have examined a role for the prelimbic cortex (PL) and infralimbic cortex (IL) in free operant behavior. The general conclusion has been that PL controls goal-directed actions (instrumental behaviors that are sensitive to reinforcer devaluation) whereas IL controls habits (instrumental behaviors that are not sensitive to reinforcer devaluation). To further examine the involvement of these regions in the expression of instrumental behavior, we first implanted male rats with bilateral guide cannulae into their PL, then trained two responses to produce a sucrose pellet reinforcer, R1 and R2, each in a distinct context. R1 received extensive training and R2 received minimal training. Rats then received lithium chloride injections either paired or unpaired with sucrose pellets in both contexts until paired rats rejected all pellets. Following acquisition, in Experiment 1, rats received either an infusion of saline or baclofen/muscimol into the PL and were tested (in extinction) on both R1 and R2. In vehicle controls, both responses were goal-directed actions, as indicated by their sensitivity to reinforcer devaluation. PL inactivation decreased expression of the minimally-trained action without affecting expression of the extensively-trained action. Experiment 2 utilized the same experimental design but with IL inactivation at test. The extensively-trained response was again a goal-directed action. However, now expression of the extensively-trained goal-directed action was suppressed by IL inactivation. The overall pattern of results suggests that the PL is involved in expression of minimally trained goal-directed behavior while the IL is involved in expression of extensively trained goal-directed behavior. This implies that the PL does not control all types of actions and the IL can control some types of actions. These results expand upon the traditional view that the PL controls action while the IL controls habit.

Shipman ML ，Trask S ，Bouton ME ，Green JT ... -  《-》

Inactivating the infralimbic but not prelimbic medial prefrontal cortex facilitates the extinction of appetitive Pavlovian conditioning in Long-Evans rats.

The infralimbic medial prefrontal cortex (IL) has been posited as a common node in distinct neural circuits that mediate the extinction of appetitive and aversive conditioning. However, appetitive extinction is typically assessed using instrumental conditioning procedures, whereas the extinction of aversive conditioning is customarily studied using Pavlovian assays. The role of the IL in the extinction of appetitive Pavlovian conditioning remains underexplored. We investigated the involvement of the IL and prelimbic medial prefrontal cortex (PrL) in appetitive extinction in Pavlovian and instrumental conditioning assays in male, Long-Evans rats. Following acquisition, a gamma-aminobutyric acid agonist solution (0.03 nmol muscimol; 0.3 nmol baclofen; 0.3 μl/side) was bilaterally microinfused into the IL or PrL to pharmacologically inactivate each region before the first extinction session. Compared to saline, PrL inactivation did not affect the acquisition of extinction or the recall of extinction memory 24-h later. IL inactivation caused a more rapid extinction of Pavlovian conditioning, but had no effect on the extinction of instrumental conditioning or extinction recall. IL inactivation during a Pavlovian conditioning session in which conditioned stimulus (CS) trials were paired with sucrose did not affect CS-elicited behaviour, but increased responding during intervals that did not contain the CS. The same manipulation did not impact lever pressing for sucrose. These findings suggest that the IL may normally maintain Pavlovian conditioned responding when an anticipated appetitive CS is unexpectedly withheld, and that this region has distinct roles in the expression of Pavlovian conditioning when an appetitive unconditioned stimulus is either presented or omitted.

Mendoza J ，Sanio C ，Chaudhri N 《-》

The role of medial prefrontal cortex in extinction and reinstatement of alcohol-seeking in rats.

The prelimbic (PL) and infralimbic (IL) medial prefrontal cortex (mPFC) are thought to play opposing roles in drug-seeking behaviour. Specifically, the PL promotes drug-seeking whereas the IL is necessary for the inhibition of drug-seeking during extinction. We studied the roles of the PL, IL and dorsal peduncular PFC (DP) in the expression of context-induced reinstatement, reacquisition and extinction of alcoholic beer-seeking. In context-induced reinstatement (renewal), animals were trained to nosepoke for alcoholic beer (context A), extinguished (context B) and then tested in context A and B. In reacquisition, animals received the same instrumental training and extinction without any contextual manipulation. On test, alcoholic beer was again available and responding was compared with naive controls. Just prior to the test, rats received bilateral infusion of baclofen/muscimol into the PL, IL or DP. Reversible inactivation of the PL attenuated ABA renewal but augmented reacquisition. Reversible inactivation of IL had no effect on the reinstatement or reacquisition of alcoholic beer-seeking and had no effect on extinction expression (ABB and AAA). IL inactivation did, however, increase the latencies with which animals responded on test but only when animals were tested in the extinction context. DP inactivation had no effect on reinstatement or reacquisition. These studies are inconsistent with the view that PL and IL exert opposing effects on drug-seeking. Rather, they support the view that PL is important for retrieval of drug-seeking contingency information and that the use of contextual information is enhanced with IL manipulation.

Willcocks AL ，McNally GP 《-》