The neurotensin receptor agonist NT69L suppresses sucrose-reinforced operant behavior in the rat

NT69L is a neurotensin analog that can be administered peripherally. It blocks amphetamine- and cocaine-induced hyperactivity in rats. It also blocks nicotine-induced locomotor activity and has shown sustained efficacy in a rat model of nicotine-induced sensitization. The present study tested the effect of NT69L on responding for sucrose reinforcement on a continuous reinforcement schedule (CRF) and incrementing (FR1-FR5) discrimination schedule. Male Sprague-Dawley rats, on restricted food intake, were trained to press a lever for sucrose pellets on a CRF and incrementing discrimination schedule of reinforcement. On the following day, the testing session was followed by an extinction session, where lever pressing was not reinforced. Immediately after extinction, a reversal to CRF was implemented to test for relapse. Trained rats were injected with NT69L (1 mg/kg) or saline 30 min before each testing session. Dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels were determined. NT69L significantly suppressed the lever pressing behavior for sucrose reinforcement on CRF which measures the "hedonic" value of the reward. NT69L also suppressed sucrose self-administration on the incrementing discrimination schedule of reinforcement (FR3-FR5) that is analogous to the motivational incentive. Reversal to CRF was significantly reduced by pretreatment with NT69L. The suppression of sucrose self-administration behavior by pretreatment with NT69L had a pattern similar to that for extinction. The effect of NT69L on dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels is discussed relative to changes occurring during extinction.     

Measuring threshold of reinforcing brain stimulation by the method of constant stimuli

A new method for measuring threshold of reinforcing electrical brain stimulation is described and results of a parametric study using this method are presented. Two groups of rats were trained under a concurrent FR-CRF (fixed ratio-continuous reinforcement) schedule of reinforcement provided by electrical stimulation of the lateral hypothalamus. The invariant intermittent FR schedule of reinforcement was used to maintain a baseline of behavior while a superimposed concurrent CRF schedule was used to measure reinforcement magnitude by varying the intensity of the CRF stimulus between zero and a maximum. Increasing and decreasing stimulus intensity on the CRF schedule leads to a gradual disappearance, respectively reappearance, of post-reinforcement pauses (PRPs) on the concurrent FR schedule, providing a criterion for changeover in schedule control, and thus, for threshold of reinforcement. To illustrate the measurement of threshold according to psychophysical requirements of the Method of Constant Stimuli, different CRF intensities were given in a randomized order. In one group of animals FR and CRF stimuli were given through the same electrode. Another group received FR and CRF stimuli through separate electrodes implanted in different hemispheres of the brain. For both groups the duration of the PRP was used as the dependent variable. The data of both groups showed a high negative correlation between the intensity of the CRF stimulus and the duration of the PRP, which is consistent with the results of experiments in which a Method of Limits procedure was used. On the basis of this relationship between CRF current intensity and PRP duration a threshold for reinforcing brain stimulation was calculated.     

Acquisition and extinction of continuously and partially reinforced running in rats with lesions of the dorsal noradrenergic bundle

Local injection of 6-hydroxydopamine was used to selectively destroy the dorsal ascending noradrenergic bundle (DB) in rats. Two lesion procedures were used, differing in the extent of depletion of forebrain noradrenaline they produced (>90% or 77%). In Experiments 1–3 the rats were run in a straight alley for food reward on continuous (CR) or partial (PR) reinforcement schedules. The smaller lesion reduced and the larger lesion eliminated the partial reinforcement acquisition effect (i.e. the faster start and run speeds produced by PR during training) and the partial reinforcement extinction effect (PREE, i.e. the greater resistance to extinction produced by PR training); these changes were due to altered performance only in the PR condition. Abolition of the PREE by the larger DB lesion occurred with 50 acquisition trials, but with 100 trials the lesion had no effect. In Experiment 4 rats were run in a double runway with food reward on CR in the second goal box, and on CR, PR or without reinforcement in the first. The larger lesion again eliminated the PREE in the first runway, but did not block the frustration effect in the second runway (i.e. the faster speeds observed in the PR condition after non-reward than after reward in the first goal box). These results are consistent with the hypothesis that DB lesions alter behavioural responses to signals of non-reward, but not to non-reward itself. They cannot be predicted from two other hypotheses: that the DB mediates responses to reward or that it subserves selective attention. Since septal and hippocampal, but not amygdalar, lesions have been reported to produce similar behavioural changes, it is proposed that the critical DB projection for the effects observed in these experiments is to the septo-hippocampal system.     

Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory

Functional dissociations between the medial septal area (MSA) and the nucleus basalis magnocellularis (NBM) were examined using the concepts and experimental procedures developed by scalar timing theory. Rats were tested in variations of a signalled discrete-trial peak-interval schedule of reinforcement in which the response rate functions identified the time when the rats expected reinforcement. The variations assessed aspects of both reference and working memory for information obtained from prior trials and from the current trial. A double dissociation was found in reference memory. Rats with NBM lesions, like those with frontal cortex (FC) lesions, remembered the time of reinforcement as having occurred later than it actually did; rats with MSA lesions, like those with fimbria-fornix (FF) lesions, remembered the time of reinforcement as having occurred earlier than it did. A single dissociation was found in working memory. MSA lesions and FF lesions impaired working memory, while NBM and FC lesions had no effect on it. These data begin to identify the brain mechanisms underlying temporal memory; they indicate that the frontal and hippocampal systems are both involved, but in complementary ways; and they provide information that helps specify more clearly the functions of the frontal and hippocampal systems.     

Extinction of cocaine self-administration produces alterations in corticotropin releasing factor gene expression in the paraventricular nucleus of the hypothalamus

The long-term effect of cocaine self-administration on corticotropin releasing factor (CRF) mRNA content in the hypothalamic CRF-containing neurons has not yet been established. The purpose of this study was to examine the time course effects of the extinction of cocaine self-administration behavior on CRF gene expression in the paraventricular nucleus of the hypothalamus (PVN) using in situ hybridization histochemistry (IHHS). Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (a) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT), (b) non-contingent injections of either 1 mg/kg/injection of cocaine (NONCONT) or (c) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a fixed ratio 5 (FR5) schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (Day 0) and 1, 5 and 10 days after the second extinction period, animal brains in each triad were removed to be processed for IHHS. CRF mRNA levels in the PVN were significantly lower in the NONCONT cocaine group at Day 0 compared to CONT or SALINE groups. On Day 1, hypothalamic CRF gene expression significantly decreased in the CONT cocaine group with respect to the SALINE group, but there were no differences between the cocaine groups or among the NONCONT cocaine and SALINE groups. After 5 and 10 days of extinction, no differences were found in CRF mRNA content in the PVN between the three conditions of this study. These results suggest that, after the extinction of cocaine self-administration, changes in hypothalamic CRF gene expression are differentially affected depending upon the type of cocaine administration, and that the stages of cocaine withdrawal might not be associated with enduring changes in hypothalamic CRF mRNA levels.     

Metabolic mapping of brain regions associated with behavioral extinction in preweanling rats

Fluorodeoxyglucose autoradiography, quantitative image analysis, and a multivariate tool (partial least squares) were used to assess distributed patterns of brain activation in postnatal day 17 and day 12 rat pups engaged in extinction of instrumental behavior. Pups were trained in a straight alley runway on an alternating reward schedule, or on a pseudorandom reward schedule, injected with fluorodeoxyglucose, and then shifted to continuous nonreward (extinction). Another group at each age served as handled controls. Day 17 pups trained on the alternating schedule demonstrated faster extinction rates compared to those trained on the pseudorandom schedule, a phenomenon known as the partial reinforcement extinction effect. No differences were found between day 12 groups. Partial least-squares analysis revealed age-related increases in fluorodeoxyglucose uptake across all three training conditions in the cingulate and frontal cortices, amygdala, midline thalamic nuclei, cerebellum, and in several brainstem regions. Training-related increases common to both age groups were found in the orbital frontal cortex, limbic thalamus, gigantocellular reticular nucleus, the somatosensory system, and cerebellum. Age-dependent training effects were found in the interpositus and medial cerebellar nuclei wherein fluorodeoxyglucose uptake increased in the day 12 alternation and pseudorandom groups relative to controls. Day 12 pups trained on the alternating schedule demonstrated increased uptake in the anterior dorsal thalamus relative to pseudorandom and control pups. Hence, a large-scale neural system comprised by somatosensory, cerebellar, and brainstem regions govern extinction behavior in preweanling rats. Recruitment of limbic structures may allow the older pups to modify extinction behavior based on prior learning.     

The effects of interpolated reinforcement on resistance to extinction in children diagnosed with autism: a preliminary investigation

Studies on the "interpolation of reinforcement" effect (IRE) suggest that switching from an intermittent (INT) to a continuous (CRF) reinforcement schedule may result in less resistance to extinction than if extinction had followed INT alone. The finding has been examined with both human and animal participants using both free- and restricted-operant research preparations with equivocal results. In the present study, the IRE was examined in four young children diagnosed with autism using a free-operant preparation. Participants were matched into pairs and were exposed, in a counterbalanced order, to extinction following CRF "interpolated" between INT and extinction, and to extinction following INT alone. Resistance to extinction was examined by comparing the number of responses emitted during extinction and the number of sessions required to reach an extinction criterion. Responding may be less resistant to extinction following interpolated CRF reinforcement than following INT alone. Methodological refinements necessary for more conclusively demonstrating the IRE are discussed.     

T-maze alternation,response patterning,and septo-hippocampal circuitry in rats

The effects of small electrolytic lesions in the posterodorsal septal area (aimed at the precommissural fornix) on acquisition and retention of either a spatio-temporal task (contingently reinforced T-maze alternation) or a temporal task (response patterning in a straight runway) were investigated in Long-Evans rats. Acquisition of T-maze alternation was impaired following posterodorsal septal lesions, but with extensive training there was evidence of learning. Postoperative retention of T-maze alternation was also impaired by posterodorsal septal lesions but, again, with continued practice the experimental animals relearned the task and came to perform as well as controls. Postoperative acquisition of response patterning in a runway was significantly but not greatly impaired by posterodorsal septal lesions. The experimental animals did pattern, but not as well as controls, even after substantial practice. Retention of response patterning was severely impaired following lesions in the posterodorsal septum but, as in the T-maze task, experimental animals improved significantly in performance with postoperative practice. The results were interpreted in the light of two recent formulations of the functions of the septo-hippocampal system: cognitive mapping and working memory. However, the data are not conclusive and suggest that inhibition theories of septo-hippocampal function are possibly relevant.     

The effects of varying schedules of time-out on aggressive behavior of a retarded girl

Three schedules of time-out were compared for suppressing aggressive behavior in a 7-yr-old retarded girl. The schedules (FR5, FR2, CRF) were time-out after every 5th, 2nd or every aggressive act. The FR5 schedule had no effect on rate of aggressive behavior while the FR2 and CRF schedules both produced significant reductions, the CRF being more effective. This reduction was maintained at follow-up after 5 weeks. It appears that time-out may be effective proportionate to the percentage of target behaviors it follows, and that some success can be achieved with less than continuous application.     

A comparison of two behaviour reduction procedures: traditional extinction alone and interpolated reinforcement followed by extinction

ABSTRACT. Extinction responding of children with severe retardation was compared when one component of a multiple schedule (VR-20/VR-20) was interpolated with one session of additional reinforcement. Either variable ratio 10 (VR-10), variable ratio 5 (VR-5) or continuous reinforcement (CRF) were interpolated in one component prior to extinction in both. Interpolated reinforcement resulted in an extinction process at least as efficient as traditional methods. Total responding in the VR-10 and VR-5 components was less than in the comparable unchanged components. Results support and extend research with animals and humans. Results also suggest the feasibility of using such a procedure to gain control of behaviours that are controlled by intermittent schedules of reinforcement, are under multiple or inconsistent stimulus control or occur infrequently.     

Effects of excitotoxic lesions of the basolateral amygdala on conditional discrimination learning with primary and conditioned reinforcement

Rats with excitotoxic lesions of the basolateral amygdala (BLA) were not impaired in the acquisition of an appetitive visuospatial conditional discrimination between stimuli varying in temporal frequency that has previously been shown to be sensitive to the effects of lesions of the striatum and cingulate cortex. After asymptotic performance was attained, discrimination was reinforced according to a fixed ratio (FR) schedule under which n presentations of sucrose were provided following n correct responses; each correct response also being reinforced immediately by a light acting as a conditioned reinforcer. Under these conditions of reinforcement when FR_n=5, BLA-lesioned rats initially showed transient impairments in several aspects of performance, but rapidly attained control levels over subsequent test sessions. No further impairments occurred when FR_n=10/20. However, in various conditions of extinction, further differences in performance were revealed between the BLA-lesioned and control groups, notably a significantly enhanced resistance to extinction when both sucrose and conditioned reinforcement were omitted. The results are discussed in terms of limbic-striatal mechanisms in the control of discrimination learning and the possible role of the amygdala in the mediation of different aspects of conditioned reinforcement.     

Striatal injections of kainic acid selectively impair serial memory performance in the rat

Rats with bilateral injections of kainic acid into the striatum were trained on a schedule of either singly alternated or continuous reinforcement in a runway. Both the acquisition and the extinction rates of the kainate-treated rats did not significantly differ from those of control rats with either reinforcement schedule. However, the kainate-treated rats ran significantly more slowly than the controls, especially at the onset of the training sessions, and, in contrast to the controls, failed to show reliable speed alternation in the late trials of the sessions with reward alternation, thus indicating both a locomotor impairment and an impairment of serial memory performance. In addition to severe loss of striatal neurons, the kainate injections induced partial neuronal loss in the neocortex, globus pallidus, hippocampus, and pyriform cortex. The similarity of the kainate-induced behavioral and pathological alterations to those of Huntington's disease is discussed.     

The effect of early‐life stress on memory systems supporting instrumental behavior

People experiencing early‐life stress (ELS) exhibit increased incidence of behaviors that lead to addiction and obesity as adults. Many of these behaviors may be viewed as resulting from an overreliance on habits as opposed to goal‐directed instrumental behavior. This increased habitization may result from alterations in the interactions between dorsolateral striatum‐dependent and hippocampus‐dependent learning systems. As an initial examination of this idea, we investigated the effect of ELS on instrumental learning and extinction. In Experiment 1, we examined the effect of ELS in two groups of people, one trained on a continuous reinforcement schedule and one trained on a partial reinforcement schedule. We found that people who experienced ELS had a diminished effect of the partial reinforcement schedule on extinction. In Experiment 2, we again manipulated reinforcement schedule and also challenged declarative memory by requiring subjects to perform a concurrent task. We found that the declarative challenge did not affect extinction responding in the non‐ELS group. In a moderate‐ELS group, we observed a diminished sensitivity to the reinforcement schedule during extinction only under divided attention. In the high‐ELS group, we observed a reduced sensitivity to reinforcement schedule even in the absence of the declarative memory challenge, consistent with Experiment 1. Our results suggest that ELS reduces the tendency to use declarative, hippocampus‐dependent memory in instrumental tasks in favor of habits. ELS may affect hippocampal development, thus altering the interaction between memory systems and potentially contributing to poor health outcomes. © 2013 Wiley Periodicals, Inc.     

Electrolytic lesions of the medial septum enhance latent inhibition in a conditioned taste aversion paradigm

The effects of medial septal lesions on latent inhibition (LI) were assessed in a conditioned taste aversion paradigm. Animals were tested in a LI paradigm 2 weeks after receiving medial septal or sham lesions. The LI paradigm involved a pre-exposure phase in which water-deprived rats were allowed access to either water (non-pre-exposed; NPE) or 5% sucrose (pre-exposed; PE), followed by a conditioning phase in which animals were allowed access to sucrose and subsequently injected with lithium chloride, and a test phase in which animals were allowed access to both sucrose and water. LI was assessed by comparing the %-sucrose consumed in PE and NPE groups on the test day. There was a significantly greater LI effect in the lesion group than in the sham group, suggesting that electrolytic lesions to the medial septum can enhance LI in a CTA paradigm.     

Effects of CP 154,526, a CRF1 receptor antagonist, on behavioral responses to cocaine in rats

We examined the influence of CP 154,526, a selective antagonist of corticotropin-releasing factor (CRF)1 receptors, in the locomotor, sensitizing, discriminative stimulus and rewarding effects of cocaine, as well as on the cocaine-induced reinstatement of cocaine-seeking behavior in male Wistar rats. CP 154,526 in doses of 5, 10 and 20 mg/kg, which did not affect basal locomotor activity, dose-dependently reduced the hyperactivation evoked by cocaine. To assess the effects of CP 154,526 on the expression of cocaine sensitization, the rats were injected with either saline or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) after pretreatment with saline or CP 154,526 on day 5 of withdrawal. The cocaine-induced hyperactivity in sensitized rats was reduced by CP 154,526 (10 and 20 mg/kg). In rats trained to discriminate cocaine (10 mg/kg) from saline, pretreatment with CP 154,526 (5-20 mg/kg) did not affect the cocaine (1.25-10 mg/kg)-induced discriminative stimulus effects. In a self-administration model, the rats were trained to self-administer cocaine (0.5 mg/kg/infusion) in the FR 5 schedule of reinforcement. Administration of CP 154,526 (10-20 mg/kg) did not alter the rewarding effects of cocaine, assessed as the number of active-lever presses and infusions; however, following a 10-day extinction phase, CP 154,526 (5-20 mg/kg) significantly decreased in a dose-dependent manner the cocaine (10 mg/kg) priming-induced reinstatement of cocaine-seeking behavior. The present study implies that CRF1 receptors control the expression of cocaine hyperactivation and sensitization as well as the cocaine-induced relapse behavior, but do not play any role in cocaine discrimination and self-administration. These findings may suggest that CRF1 receptor antagonists should be considered as possible medications in the treatment of cocaine addiction.     

Effects of septal lesions on responding for delayed brain stimulation reinforcement

Rats with medial septal lesions were unable to learn in a situation where lateral hypothalamic stimulation reinforcement was delayed for 10 sec following each response. Rats with lateral septal lesions and rats with no lesions were able to learn under these conditions. All subjects in all groups exhibited high rates of responding for stimulation delivered concurrently with the response. The data suggest that a fiber system (possibly adrenergic) ascending from lateral hypothalamus through the medial septal area is involved in the mediation of brain stimulation reinforcement of complex tasks; and that some other neural mechanism which mediates the reinforcement of simple tasks must also exist.     

The effects of delaying reward on choice preference in rats with hippocampal or selective septal lesions

Two experiments are reported in which rats were trained to choose one of two goal arms in a Y-maze, for water reward. In one arm, the rats always received water (the continuously reinforced-CRF-arm). In the other arm the rats only sometimes received water (the partially reinforced-PRF-arm). During the critical test phase in both experiments, we delayed the reward in the CRF arm only by 10 s. Experiment 1 tested intact rats given saline injections, or injections of chlordiazepoxide hydrochloride (Librium, 5 mg/kg), and rats with hippocampal or cortical control lesions. When reward was immediate in both arms all rats preferred the CRF arm. Once reward was delayed, the rats with hippocampal lesions switched their preference to the PRF arm, while the rats in the other treatment groups did not. Experiment 2 tested rats with medial septal lesions, lateral septal lesions or control operations in the same way. The rats with medial septal lesions, and to a lesser extent those with lateral septal lesions, switched their preference to the PRF arm when compared to the sham-operated controls. We conclude that damage to the hippocampus or its afferent pathway from the septum increases rats' sensitivity to temporal discontiguities between the outcome of a response and its emission.     

The effects of lesions in the lateral septal and hippocampal areas on the humoral immune response of adult female rats

There are interactions between the immune and the endocrine systems. A major role for adrenal steroids in the modulation of the immune system is well documented and the immune system can apparently activate the adrenal axis at the hypothalamic and/or pituitary level. Sex steroids modify immune function and sex differences in immune function suggest that there are also major interactions between the reproductive system and the immune system. To the extent that the endocrine system is integrated with the immune system, many of the brain areas and neural mechanisms implicated in psychoneuroendocrine processes may be involved in the regulation of psychoneuroimmune processes. We have proposed that the septal region represents an important extrahypothalamic and now propose that the septal region may also represent an important component in the central regulation of psychoneuroimmune processes. We have tested the effects of electrolytic and kainic acid (KA) lesions in the lateral septal area of female rats and have compared the effects of KA lesions in the lateral septal area with KA lesions in the hippocampal region on antibody production following immunization with 100 micrograms ovalbumin in complete Freund's adjuvant. Blood samples were collected on Days 0, 7, 14, 17, and 28 following immunization in the first experiment and on Days 0, 7, 14, and 28 in the second study. All animals were injected again with ovalbumin on Day 14. The IgG, IgA, and IgM antibody titers were then measured by an enzyme-amplified ELISA assay. KA lesions in the lateral septal area produced extensive cell loss in this region and produced a concurrent loss of cell bodies in the CA 3-CA 4 hippocampal areas. Compared to sham and electrolytic septal lesioned rats, KA lesions of the lateral septal area significantly reduced IgG titers on Days 7 and 17 with a trend for Day 14. Similarly, the IgA and IgM titers were significantly lower on Days 7, 14, and 17 for the rats with KA lesions in the lateral septal area. In addition, the KA septal lesioned rats gained more body weight and had higher thymus weights, relative to the electrolytic lesioned and sham groups. In addition, the rats with KA lesions in the hippocampal area showed significantly higher IgM titers on Day 7, elevated IgG titers on Day 14, and lower IgA titers on Day 28, relative to the sham group.(ABSTRACT TRUNCATED AT 250 WORDS)     

The partial reinforcement extinction effect in humans: effects of schizophrenia,schizotypy and low doses of amphetamine

The partial reinforcement extinction effect (PREE) was studied in human subjects. It has been suggested that the PREE depends on neural mechanisms critical to the cognitive dysfunction which underlines acute schizophrenia. We therefore predicted that the PREE should be reduced, through decreased resistance to extinction in the partial reinforcement (PR) condition, in various types of individual: (a) healthy volunteers given low doses of oral amphetamine; (b) those in the acute (but not chronic) phase of a schizophrenic illness and; (c) healthy volunteers with high scores on personality measures of schizotypy. Despite obtaining robust demonstrations of PREE in all experiments, none of these predictions were confirmed. A single, low dose, of amphetamine had no effect on either continuous reinforcement (CR) or partial reinforcement (PR). Acute and chronic schizophrenic patients showed a reduced PREE compared to controls. However this was due to increased resistance to extinction in the CR groups. Finally, high schizotypy scores were associated with greater PREE, attributable to both decreased extinction in the CR condition and increased extinction in the PR condition. The results of these experiments on human PREE provide no support that PREE is a valid paradigm with which to explore the cognitive dysfunction underlying schizophrenia.     

Dissociable regulation of instrumental action within mouse prefrontal cortex

Evaluation of the behavioral 'costs', such as effort expenditure relative to the benefits of obtaining reward, is a major determinant of goal-directed action. Neuroimaging evidence suggests that the human medial orbitofrontal cortex (mOFC) is involved in this calculation and thereby guides goal-directed and choice behavior, but this region's functional significance in rodents is unknown despite extensive work characterizing the role of the lateral OFC in cue-related response inhibition processes. We first tested mice with mOFC lesions in an instrumental reversal task lacking discrete cues signaling reinforcement; here, animals were required to shift responding based on the location of the reinforced aperture within the chamber. Mice with mOFC lesions acquired the reversal but failed to inhibit responding on the previously reinforced aperture, while mice with prelimbic prefrontal cortex lesions were unaffected. When tested on a progressive ratio schedule of reinforcement, mice with prelimbic cortical lesions were unable to maintain responding, resulting in declining response levels. Mice with mOFC lesions, by contrast, escalated responding. Neither lesion affected sensitivity to satiety-specific outcome devaluation or non-reinforcement (i.e. extinction), and neither had effects when placed after animals were trained on a progressive ratio response schedule. Lesions of the ventral hippocampus, which projects to the mOFC, resulted in similar response patterns, while lateral OFC and dorsal hippocampus lesions resulted in response acquisition, though not inhibition, deficits in an instrumental reversal. Our findings thus selectively implicate the rodent mOFC in braking reinforced goal-directed action when reinforcement requires the acquisition of novel response contingencies.