Role of OFC-DS pathway

The orbitofrontal cortex (OFC) receives several sensory inputs; taste from the gustatory cortex, olfaction from the primary olfactory cortex and piriform cortex, vision from inferior temporal cortex, and touch from the somatosensory cortex (Rolls, 2004). The OFC is involved in learning association between neutral stimuli and primary reinforcers.

Interestingly, the lesions in the OFC does not impair the performance of Pavlovian conditioning task (Ostlund and Balleine, 2007), but reversal learning (Chudasama and Robbins, 2003). Indeed, OFC-lesioned animals continue to respond to the cue which was previously rewarded, even in the absence of rewarding consequences, which is in favor of the role of the OFC in cognitive flexibility. These effects of OFC lesions seem to be conserved in mammals. Indeed, monkeys with the lesions in the OFC are impaired in a Go/NoGo task, i.e. they also respond during NoGo trials (Iversen and Mishkin, 1970).

These data indicate that the OFC is specifically important for the update of the association between rewards and stimuli. To update the association, the OFC is particularly playing a critical role in imagining novel outcomes (Schoenbaum et al., 2016). This hypothesis was tested by using a task called Pavlovian over-expectation. The behavioral task comprises three phases; conditioning, compound training, and probe test. During the conditioning phase, at least two cues are paired with reward delivery. In the compound training phase, two cues are presented at the same time. Because the cues were associated with the reward during the conditioning, animals are supposed to expect a bigger reward. Typically, they show higher response to the compound cue. Note that even though animals have never been exposed to the compound cue, they display higher response. This means that animals can make a novel estimation based on their past experiences. During this compound phase, the same reward is delivered, without any change of its size. Because animals expect a bigger reward but the actual reward is the same, the discrepancy between the expectation and what they actually obtain results in extinction learning. This

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extinction learning is obvious during the probe test phase. In this phase, the previous compound cue is presented separately without any reward delivery. In this condition, animals display decrease of response when the cue is separated, indicating that the extinction learning occurs during the compound training. This extinction occurs due to the change of expectation, not due to the change of the reward size (Schoenbaum et al., 2016). The firing rate of the OFC neurons to the compound cue is increased significantly while the firing to the single cue does not change (Takahashi et al., 2013). In addition, the inactivation of the OFC during the compound training prevents the increase of the response during the compound training and abolishes extinction tested later in the probe test (Takahashi et al., 2009, 2013), indicating that the OFC neurons encode expected outcome (Schoenbaum et al., 2016). Interestingly, the increase of firing rate in the OFC to the compound cue and the behavioral effect is diminished after cocaine self-administration but not after sucrose self-self-administration (Lucantonio et al., 2014, 2015), suggesting that drug intake induces dysfunction of the OFC. Our data show that OFC to DS pathway was potentiated in perseverers, consistent with the previous results (Pascoli et al., 2018). This ‘gain of function’ at OFC-DS pathway looks puzzling. The Pavlovian over-expectation experiments indicate that cocaine self-administration causes the dysfunction of the OFC (Lucantonio et al., 2014, 2015), while our previous (Pascoli et al., 2018) data suggest that OFC to DS pathway is hyperactive in perseverers. Clinical studies show that addicted patients are less motivated to procure non-drug reward (Claus et al., 2011; Goldstein and Volkow, 2011). When animals are given chance to choose drug or non-drug reward (e.g. food or social interaction), most of them choose non-drug reward but a small population of animals drug reward (Guillem and Ahmed, 2018; Guillem et al., 2018; Venniro et al., 2018). Drug seeking at the expense of non-drug reward is used as a model of compulsivity also (Guillem and Ahmed, 2018; Guillem et al., 2018; Venniro et al., 2018). Drug rewarded and non-drug rewarded actions are encoded by non-overlapping neuronal populations in the OFC and relative size of the drug encoding population is positively correlated with the individual choices (Guillem and Ahmed, 2018; Guillem et al., 2018). One hypothesis is that the population size bias could increase the chance that preferred action-coding neuron fire during the choice, which leads to the bias toward corresponding choice (Guillem et al., 2018). Clinical fMRI data show that the blood oxygen

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level-dependent (BOLD) response in the OFC is higher when addicted patients are exposed to drug cue compared to non-drug cue (Claus et al., 2011). A preclinical study shows that inactivation of the OFC attenuates cue-induced relapse (Fanous et al., 2012).

These data suggest that the OFC contributes significantly to reward seeking and in addicted patients, the OFC does not respond to non-drugs reward as strongly as drug rewards. As a result, addicted patients often give up the non-drug rewards, procuring only drug rewards. This idea is consistent with the studies showing that Pavlovian over-expectation property is lost after cocaine self-administration (Lucantonio et al., 2014, 2015). Because in the over-expectation task, natural rewards are used as a reinforcer, it is well possible that animals are not motivated to seek them. Moreover, clinical data show that addicted patients are less interested in the change of size of non-drug rewards (Goldstein et al., 2007). In conclusion, the OFC is involved in the association between primary reinforcers and environmental cues and the seeking behavior evoked by the cues.

In our study, photometry experiment showed that the strong neuronal activity observed during baseline sessions at the end of seeking behaviour was diminished during punishment sessions in renouncers, while in perseverers it was unaltered. When the neurons in the striatum were silenced specifically at the end of the seeking behaviour, the compulsive reward seeking was attenuated. These results suggest that OFC to DS pathway encodes the value of the stimuli (e.g. retraction of a lever) and guides the behaviour in next trials. During baseline sessions, the retraction of the seek lever is always followed by the presentation of the take lever, meaning it is always rewarding. However, during punishment sessions, punishment is sometimes delivered immediately after the retraction of the seek lever, indicating it is not always predictive reward delivery anymore.

The reduction of amplitude of calcium signal at the end of the seeking behaviour in renouncing mice might reflect the degradation of the cue value of the seek lever retraction.

It is still open question why renouncing mice show the reduction of the signal while persevering mice do not. One possibility is that the rule of synaptic plasticity is different between renouncers and peseverers. It has been demonstrated that transition to addiction is associated with the impairment of synaptic plasticity (Kasanetz et al., 2010). This study suggests the possibility that the punishment induces depotentiation in renouncers, but not perseverers. This hypothesis needs to be tested empirically.

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