Short- and Long-Term High-Fat Diet Exposure Differentially Alters Phasic and Tonic GABAergic Signaling onto Lateral Orbitofrontal Pyramidal Neurons.

The chronic consumption of caloric dense high-fat foods is a major contributor to increased body weight, obesity, and other chronic health conditions. The orbitofrontal cortex (OFC) is critical in guiding decisions about food intake and is altered with diet-induced obesity. Obese rodents have altered morphologic and synaptic electrophysiological properties in the lateral orbitofrontal cortex (lOFC). Yet the time course by which exposure to a high-fat diet (HFD) induces these changes is poorly understood. Here, male mice are exposed to either short-term (7 d) or long-term (90 d) HFD. Long-term HFD exposure increases body weight, and glucose signaling compared with short-term HFD or a standard control diet (SCD). Both short and long-term HFD exposure increased the excitability of lOFC pyramidal neurons. However, phasic and tonic GABAergic signaling was differentially altered depending on HFD exposure length, such that tonic GABAergic signaling was decreased with early exposure to the HFD and phasic signaling was changed with long-term diet exposure. Furthermore, alterations in the short-term diet exposure were transient, as removal of the diet restored electrophysiological characteristics similar to mice fed SCD, whereas long-term HFD electrophysiological changes were persistent and remained after HFD removal. Finally, we demonstrate that changes in reward devaluation occur early with diet exposure. Together, these results suggest that the duration of HFD exposure differentially alters lOFC function and provides mechanistic insights into the susceptibility of the OFC to impairments in outcome devaluation.SIGNIFICANCE STATEMENT This study provides mechanistic insight on the impact of short-term and long-term high-fat diet (HFD) exposure on GABAergic function in the lateral orbitofrontal cortex (lOFC), a region known to guide decision-making. We find short-term HFD exposure induces transient changes in firing and tonic GABA action on lOFC pyramidal neurons, whereas long-term HFD induces obesity and has lasting changes on firing, tonic GABA and inhibitory synaptic transmission onto lOFC neurons. Given that GABAergic signaling in the lOFC can influence decision-making around food, these results have important implications in present society as palatable energy dense foods are abundantly available.

Cortico-striatal white-matter connectivity underlies the ability to exert goal-directed control.

The balance between goal-directed and habitual control has been proposed to determine the flexibility of instrumental behaviour, in both humans and animals. This view is supported by neuroscientific studies that have implicated dissociable neural pathways in the ability to flexibly adjust behaviour when outcome values change. A previous Diffusion Tensor Imaging study provided preliminary evidence that flexible instrumental performance depends on the strength of parallel cortico-striatal white-matter pathways previously implicated in goal-directed and habitual control. Specifically, estimated white-matter strength between caudate and ventromedial prefrontal cortex correlated positively with behavioural flexibility, and posterior putamen-premotor cortex connectivity correlated negatively, in line with the notion that these pathways compete for control. However, the sample size of the original study was limited, and so far, there have been no attempts to replicate these findings. In the present study, we aimed to conceptually replicate these findings by testing a large sample of 205 young adults to relate cortico-striatal connectivity to performance on the slips-of-action task. In short, we found only positive neural correlates of goal-directed performance, including striatal connectivity (caudate and anterior putamen) with the dorsolateral prefrontal cortex. However, we failed to provide converging evidence for the existence of a neural habit system that puts limits on the capacity for flexible, goal-directed action. We discuss the implications of our findings for dual-process theories of instrumental action.

Response-independent outcome presentations dissociate stimulus and value based choice: Instrumental degradation and specific PIT.

A stimulus that predicts the delivery of a specific food outcome can bias performance towards instrumental actions that earn that same outcome in a phenomenon known as specific Pavlovian-instrumental transfer (PIT). The precise mechanism by which the specific instrumental action is selected under these circumstances has remained elusive. The present set of experiments explored whether treatments that undermine the response-outcome (R-O) association also affect the expression of specific PIT. Consistent with previous work, in Experiment 1 we showed that specific PIT remains intact after an instrumental degradation treatment that attempted to undermine R-O associations. However, we additionally demonstrated that outcome-devaluation sensitivity also persisted after degradation, suggesting that R-O associations were impervious to the degradation treatment, and precluding any conclusions about the necessity of R-O associations for specific PIT expression. Nevertheless, given the two-lever two-outcome design of this experiment it is possible that R-O associations were indeed undermined by degradation and that the devaluation effect was driven by distinct, incidental Pavlovian lever-outcome associations. To nullify the obscuring effects of these incidental Pavlovian associations, we used a bidirectional lever for instrumental conditioning that could be pushed to the left or the right for distinct outcomes. In Experiment 2 we demonstrated that specific PIT could be observed on this bidirectional manipulandum whether the subjects were hungry or sated, consistent with the literature. The critical third Experiment used an identical design to Experiment 1 except that the two instrumental responses were made on the single bidirectional manipulanda. Here, specific PIT was intact after instrumental degradation and, crucially, we saw no evidence of outcome devaluation sensitivity in these same subjects, suggesting that the R-O associations were weakened or undermined by this treatment. We conclude that the expression of specific PIT is resistant to treatments that undermine R-O associations and disrupt value based choice, and discuss how these findings contribute to our understanding of the associative framework supporting behavioral control.

Investigating habits in humans with a symmetrical outcome-revaluation task.

The translation of the outcome-devaluation paradigm to study habit in humans has yielded interesting insights but proven to be challenging. We present a novel, outcome-revaluation task with a symmetrical design, in the sense that half of the available outcomes are always valuable and the other half not-valuable. In the present studies, during the instrumental learning phase, participants learned to respond (Go) to certain stimuli to collect valuable outcomes (and points) while refraining to respond (NoGo) to stimuli signaling not-valuable outcomes. Half of the stimuli were short-trained, while the other half were long-trained. Subsequently, in the test phase, the signaled outcomes were either value-congruent with training (still-valuable and still-not-valuable), or value-incongruent (devalued and upvalued). The change in outcome value on value-incongruent trials meant that participants had to flexibly adjust their behavior. At the end of the training phase, participants completed the self-report behavioral automaticity index - providing an automaticity score for each stimulus-response association. We conducted two experiments using this task, that both provided evidence for stimulus-driven habits as reflected in poorer performance on devalued and upvalued trials relative to still-not-valuable trials and still-valuable trials, respectively. While self-reported automaticity increased with longer training, behavioral flexibility was not affected. After extended training (Experiment 2), higher levels of self-reported automaticity when responding to stimuli signaling valuable outcomes were related to more 'slips of action' when the associated outcome was subsequently devalued. We conclude that the symmetrical outcome-revaluation task provides a promising paradigm for the experimental investigation of habits in humans.

Effects of Motivational Downshifts on Specific Pavlovian-Instrumental Transfer in Rats.

BACKGROUND: Pavlovian stimuli predictive of appetitive outcomes can exert a powerful influence on the selection and initiation of action, a phenomenon termed outcome-selective Pavlovian-instrumental transfer (sPIT). Rodent studies suggest that sPIT is insensitive to motivational downshift induced by outcome devaluation, an effect that is, however, relatively underexplored. METHODS: Here we examined in detail the effects of distinct shifts in motivation from hunger to a state of relative satiety on sPIT in rats. RESULTS: A motivational downshift by outcome-specific devaluation immediately prior to testing markedly reduced overall lever responding and magazine entries but left intact the sPIT effect. A motivational downshift prior testing by (1) giving ad libitum rather than restricted access to maintenance diet in the home cage for 24 hours or by (2) a systemic blockade of hormone secretagogue receptor subtype 1A receptors to inhibit orexigenic actions of ghrelin both reduced overall lever responding and magazine entries. Moreover, these latter motivational downshifts reduced the sPIT effect; however, the sizes of the sPIT effects were still large. CONCLUSIONS: Collectively, our rodent findings indicate that major effects of various motivational downshifts are overall inhibition of lever pressing and magazine approach, possibly reflecting reduced general motivation. The observed effects of motivational downshifts on sPIT have implications with regard to the role of general motivating effects in sPIT and to the contribution of Pavlovian-instrumental interactions to excessive food seeking as well as obesity in humans.

Fractionating the all-or-nothing definition of goal-directed and habitual decision-making.

Goal-directed and habitual decision-making are fundamental processes that support the ongoing adaptive behavior. There is a growing interest in examining their disruption in psychiatric disease, often with a focus on a disease shifting control from one process to the other, usually a shift from goal-directed to habitual control. However, several different experimental procedures can be used to probe whether decision-making is under goal-directed or habitual control, including outcome devaluation and contingency degradation. These different experimental procedures may recruit diverse behavioral and neural processes. Thus, there are potentially many opportunities for these disease phenotypes to manifest as alterations to both goal-directed and habitual controls. In this review, we highlight the examples of behavioral and neural circuit divergence and similarity, and suggest that interpretation based on behavioral processes recruited during testing may leave more room for goal-directed and habitual decision-making to coexist. Furthermore, this may improve our understanding of precisely what the involved neural mechanisms underlying aspects of goal-directed and habitual behavior are, as well as how disease affects behavior and these circuits.

Prefrontal Corticostriatal Disconnection Blocks the Acquisition of Goal-Directed Action.

The acquisition of goal-directed action requires encoding of the association between an action and its specific consequences or outcome. At a neural level, this encoding has been hypothesized to involve a prefrontal corticostriatal circuit involving the projection from the prelimbic cortex (PL) to the posterior dorsomedial striatum (pDMS); however, no direct evidence for this claim has been reported. In a series of experiments, we performed functional disconnection of this pathway using targeted lesions of the anterior corpus callosum to disrupt contralateral corticostriatal projections with asymmetrical lesions of the PL and/or pDMS to block plasticity in this circuit in rats. We first demonstrated that unilaterally blocking the PL input to the pDMS prevented the phosphorylation of extracellular signal-related kinase/mitogen activated protein kinase (pERK/pMAPK) induced by instrumental training. Next, we used a full bilateral disconnection of the PL from the pDMS and assessed goal-directed action using an outcome-devaluation test. Importantly, we found evidence that rats maintaining an ipsilateral and/or contralateral connection between the PL and the pDMS were able to acquire goal-directed actions. In contrast, bilateral PL-pDMS disconnection abolished the acquisition of goal-directed actions. Finally, we used a temporary pharmacological disconnection to disrupt PL inputs to the pDMS by infusing the NMDA antagonist dl-2-amino-5-phosphonopentanoic acid into the pDMS during instrumental training and found that this manipulation also disrupted goal-directed learning. These results establish that, in rats, the acquisition of new goal-directed actions depends on a prefrontal-corticostriatal circuit involving a connection between the PL and the pDMS.SIGNIFICANCE STATEMENT It has been hypothesized that the prelimbic cortex (PL) and posterior dorsomedial striatum (pDMS) in rodents interact in a corticostriatal circuit to mediate goal-directed learning. However, no direct evidence supporting this claim has been reported. Using targeted lesions, we performed functional disconnection of the PL-pDMS pathway to assess its role in goal-directed learning. In the first experiment, we demonstrated that PL input to the pDMS is necessary for instrumental training-induced neuronal activity. Next, we disrupted ipsilateral, contralateral, or bilateral PL-pDMS connections and found that only bilateral PL-pDMS disconnection disrupted the acquisition of goal-directed actions, a finding we replicated in our final study using a pharmacological disconnection procedure.

Intact goal-directed control in treatment-seeking drug users indexed by outcome-devaluation and Pavlovian to instrumental transfer: critique of habit theory.

Animal studies have demonstrated that chronic exposure to drugs of abuse impairs goal-directed control over action selection indexed by the outcome-devaluation and specific Pavlovian to instrumental transfer procedures, suggesting this impairment might underpin addiction. However, there is currently only weak evidence for impaired goal-directed control in human drug users. Two experiments were undertaken in which treatment-seeking drug users and non-matched normative reference samples (controls) completed outcome-devaluation and specific Pavlovian to instrumental transfer procedures notionally translatable to animal procedures (Experiment 2 used a more challenging biconditional schedule). The two experiments found significant outcome-devaluation and specific Pavlovian to instrumental transfer effects overall and there was no significant difference between groups in the magnitude of these effects. Moreover, Bayes factor supported the null hypothesis for these group comparisons. Although limited by non-matched group comparisons and small sample sizes, the two studies suggest that treatment-seeking drug users have intact goal-directed control over action selection, adding uncertainty to already mixed evidence concerning the role of habit learning in human drug dependence. Neuro-interventions might seek to tackle goal-directed drug-seeking rather than habit formation in drug users.

Thalamic Control of Dorsomedial Striatum Regulates Internal State to Guide Goal-Directed Action Selection.

We (Bradfield et al., 2013) have demonstrated previously that parafascicular thalamic nucleus (PF)-controlled neurons in the posterior dorsomedial striatum (pDMS) are critical for interlacing new and existing action-outcome contingencies to control goal-directed action. Based on these findings, it was suggested that animals with a dysfunctional PF-pDMS pathway might suffer a deficit in creating or retrieving internal contexts or "states" on which such information could become conditional. To assess this hypothesis more directly, rats were given a disconnection treatment using contralateral cytotoxic lesions of the PF and pDMS (Group CONTRA) or ipsilateral control lesions (Group IPSI) and trained to press a right and left lever for sucrose and pellet outcomes, after which these contingencies were reversed. The rats were then given an outcome devaluation test (all experiments) and a test of outcome-specific reinstatement (Experiments 1 and 3). We found that devaluation performance was intact for both groups after training of initial contingencies, but impaired for Group CONTRA after reversal. However, performance was restored by additional reversal training. Furthermore, when tested a second time after reversal training, rats in both groups demonstrated responding in accordance with the original contingencies, providing direct evidence of modulation of action selection by state. Finally, we found that external context could substitute for internal state and so could rescue responding in Group CONTRA, but only in the reinstatement test. Together, these findings suggest that animals use internal state information to guide action selection and that this information is modulated by the PF-pDMS pathway.SIGNIFICANCE STATEMENT Individuals with Parkinson's disease dementia often suffer a characteristic deficit in "cognitive flexibility." It has been suggested that neurodegeneration in the pathway between the centromedian/parafascicular thalalmic nucleus (PF) and striatum might underlie such deficits (Smith et al., 2014). In rats, we have similarly observed that a functional disconnection of the PF-posterior dorsomedial striatal pathway produces a specific impairment in the ability to alter goal-directed actions (Bradfield et al., 2013). It was suggested that this impairment could be a result of a deficit in state modulation. Here, we present four experiments that provide evidence for this hypothesis and suggest several ways (e.g., extended practice, providing external cues) in which this state modulation can be rescued.

Inferring action-dependent outcome representations depends on anterior but not posterior medial orbitofrontal cortex.

Although studies examining orbitofrontal cortex (OFC) often treat it as though it were functionally homogeneous, recent evidence has questioned this assumption. Not only are the various subregions of OFC (lateral, ventral, and medial) hetereogeneous, but there is further evidence of heterogeneity within those subregions. For example, several studies in both humans and monkeys have revealed a functional subdivision along the anterior-posterior gradient of the medial OFC (mOFC). Given our previous findings suggesting that, in rats, the mOFC is responsible for inferring the likelihood of unobservable action outcomes (Bradfield, Dezfouli, van Holstein, Chieng, & Balleine, 2015), and given the anterior nature of the placements of our prior manipulations, we decided to assess whether the rat mOFC also differs in connection and function along its anteroposterior axis. We first used retrograde tracing to compare the density of efferents from mOFC to several structures known to contribute to goal-directed action: the mediodorsal thalamus, basolateral amygdala, posterior dorsomedial striatum, nucleus accumbens core and ventral tegmental area. We then compared the functional effects of anterior versus posterior mOFC excitotoxic lesions on tests of Pavlovian-instrumental transfer, instrumental outcome devaluation and outcome-specific reinstatement. We found evidence that the anterior mOFC had greater connectivity with the accumbens core and greater functional involvement in goal-directed action than the posterior mOFC. Consistent with previous findings across species, therefore, these results suggest that the anterior and posterior mOFC of the rat are indeed functionally distinct, and that it is the anterior mOFC that is particularly critical for inferring unobservable action outcomes.

The effect of high-fat diet consumption on appetitive instrumental behavior in rats.

Evidence now indicates that the chronic consumption of high-calorie foods, such as a high-fat diet (HFD), is associated with impaired control over food-seeking, yet the extent of this alteration is not fully understood. Using different reinforcement schedules, we evaluated whether HFD intake from weaning to adulthood modifies instrumental responding and induces a shift from goal-directed actions to habitual responding. We first observed reduced instrumental performance and motivation for a food reward in HFD-fed rats trained under schedules of reinforcement that facilitate habitual responding [Random Interval (RI)]. However, this deficit was alleviated if rats trained under RI were subsequently trained with reinforcement schedules that promote goal-directed strategies [Random Ratio (RR)]. Using an outcome devaluation procedure, we then demonstrated that consumption of a HFD promoted habitual behavior in rats trained under RI but not RR schedules. Finally, extended HFD exposure did not interfere with the ability of RR training to overcome impaired RI instrumental performance and to favor goal-directed behavior. These results indicate that chronic consumption of a HFD changes the co-ordination of goal-directed actions and habits and that alteration of food-seeking may be reversed under particular behavioral conditions.

Intermittent feeding alters sensitivity to changes in reward value.

The influence of binge-like feeding schedules on subsequent food-related behavior is not well understood. We investigated the effect of repeated cycles of restriction and refeeding on two food-related behaviors; goal-directed responding for a palatable food reward and sensory-specific satiety. Hungry rats were trained to perform two instrumental actions for two distinct food outcomes and were then subjected to repeated cycles of restricted and unrestricted access to their maintenance chow for 30-days or were maintained on food restriction. Goal-directed control was then assessed using specific satiety-induced outcome devaluation. Rats were given 1 h access to one of theoutcomes and were then immediately given a choice between the two actions. Rats maintained on restriction responded more for the valued than the devalued reward but rats with a history of restriction and refeeding failed to show this effect. Importantly, all rats showed sensory-specific satiety when offered a choice between the two foods, indicating that pre-feeding selectively reduced the value of the pre-fed food. By contrast, sensory-specific satiety was not observed in rats with a history of intermittent feeding when the foods were offered sequentially. These results indicate that, similar to calorically dense diets, intermittent feeding patterns can impair the performance of goal-directed actions as well as the ability to reject a pre-fed food when it is offered alone.

Interaction of insular cortex and ventral striatum mediates the effect of incentive memory on choice between goal-directed actions.

The anterior insular cortex (IC) and the nucleus accumbens (NAc) core have been separately implicated in the selection and performance of actions based on the incentive value of the instrumental outcome. Here, we examined the role of connections between the IC and the NAc core in the performance of goal-directed actions. Rats were trained on two actions for distinct outcomes, after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed the projection from the IC to the NAc core and then disconnected these structures via asymmetrical excitotoxic lesions before training. Contralateral, but not ipsilateral, disconnection of the IC and NAc core disrupted outcome devaluation. We hypothesized that communication between the IC and NAc core is necessary for the retrieval of incentive value at test. To test this, we infused the GABAA agonist muscimol into the IC and the µ-opioid receptor antagonist CTAP into the contralateral NAc before the choice extinction test. As expected, inactivation of the IC in one hemisphere and blocking µ-opioid receptors in the contralateral NAc core abolished outcome-selective devaluation. These results suggest that the IC and NAc core form part of a circuit mediating the retrieval of outcome values and the subsequent choice between goal-directed actions based on those values.

Habitual Alcohol Seeking: Neural Bases and Possible Relations to Alcohol Use Disorders.

Loss of flexible control over alcohol use may contribute to the development of alcohol use disorders. An increased contribution of response habits to alcohol-related behaviors may help explain this loss of control. Focusing on data from outcome devaluation and Pavlovian-instrumental transfer procedures, we review evidence for loss of goal-directed control over alcohol seeking and consumption drawing from both preclinical findings and clinical data where they exist. Over the course of extended alcohol self-administration and exposure, the performance of alcohol-seeking responses becomes less sensitive to reduction in the value of alcohol and more vulnerable to the influences of alcohol-predictive stimuli. These behavioral changes are accompanied by a shift in the corticostriatal circuits that control responding from circuits centered on the dorsomedial to those centered on the dorsolateral striatum. These changes in behavioral and neural control could help explain failures to abstain from alcohol despite intention to do so. Understanding and ultimately ameliorating these changes will aid development of more effective treatment interventions.

Binge-like consumption of a palatable food accelerates habitual control of behavior and is dependent on activation of the dorsolateral striatum.

Access to highly palatable and calorically dense foods contributes to increasing rates of obesity worldwide. Some have made the controversial argument that consumption of such foods can lead to "food addiction," yet little is known about how long-term access to highly palatable foods might alter goal-directed learning and decision making. In the following experiments, rats were given 5 weeks of continuous or restricted daily access to sweetened condensed milk (SCM) before instrumental training for food reward. Subsequently we examined whether goal-directed performance was impaired in these groups using the outcome-devaluation task. Control rats reduced responding following devaluation of the earned outcome as did those with previous continuous access to SCM. Of interest, rats with previous restricted access to SCM responded similarly under the devalued and nondevalued conditions, indicating loss of goal-directed control of responding. To identify whether the loss of goal-directed control was accompanied by differences in neuronal activity, we used c-Fos immunohistochemistry to examine the patterns of activation during devaluation testing. We observed greater c-Fos immunoreactivity in the dorsolateral striatum (DLS) and associated cortical regions in the group that received previous restricted access to SCM and demonstrated a lack of sensitivity to outcome devaluation. Infusion of the AMPA-receptor antagonist CNQX or dopamine D1-receptor antagonist SCH-23390 into the DLS before testing restored goal-directed performance in the restricted SCM group, confirming that this region is essential for habit-based performance. These results indicate that previous diet can alter subsequent learning and activity in the neural circuits that support performance.

Dorsal and ventral streams: the distinct role of striatal subregions in the acquisition and performance of goal-directed actions.

Considerable evidence suggests that distinct neural processes mediate the acquisition and performance of goal-directed instrumental actions. Whereas a cortical-dorsomedial striatal circuit appears critical for the acquisition of goal-directed actions, a cortical-ventral striatal circuit appears to mediate instrumental performance, particularly the motivational control of performance. Here we review evidence that these distinct mechanisms of learning and performance constitute two distinct 'streams' controlling instrumental conditioning. From this perspective, the regulation of the interaction between these 'streams' becomes a matter of considerable importance. We describe evidence that the basolateral amygdala, which is heavily interconnected with both the dorsal and ventral subregions of the striatum, coordinates this interaction providing input to the final common path to action as a critical component of the limbic-motor interface.

Goal-directed behavior in Tenebrio molitor larvae.

Can signs of intentional behavior be traced in an insect larva, traditionally thought to be driven only by mere reflexes? We trained Tenebrio molitor coleoptera larvae in a uniform Y-maze to prefer one target branch to get access to food, observing their ability to learn and retain access to the reward-associated side for up to 24 h. During reward devaluation, the reward food (experimental group) and a different food (control group) were paired with an aversive stimulus in a new environment. When tested again in the Y-maze, mealworms of the experimental group significantly reduced their visits to the target branch, whereas mealworms of the control group did not. Importantly, we found that the larvae did not have to experience the unpleasant consequences directly in the target branch to halt their behavior, as the exposure to the aversive taste occurred in a separate unfamiliar context. This is evidence that the mealworms formed a mental representation of action-consequence relationships, demonstrating flexible control of their actions to achieve desired outcomes at an early stage of their development.

Striatal dopamine release tracks the relationship between actions and their consequences.

The acquisition and performance of goal-directed actions has long been argued to depend on the integration of glutamatergic inputs to the posterior dorsomedial striatum (pDMS) under the modulatory influence of dopamine. Nevertheless, relatively little is known about the dynamics of striatal dopamine during goal-directed actions. To investigate this, we chronically recorded dopamine release in the pDMS as rats acquired two actions for distinct outcomes as these action-outcome associations were incremented and then subsequently degraded or reversed. We found that bilateral dopamine release scaled with action value, whereas the lateralized dopamine signal, i.e., the difference in dopamine release ipsilaterally and contralaterally to the direction of the goal-directed action, reflected the strength of the action-outcome association independently of changes in movement. Our results establish, therefore, that striatal dopamine activity during goal-directed action reflects both bilateral moment-to-moment changes in action value and the long-term action-outcome association.

Outcome devaluation by sensory-specific satiety alters Pavlovian-conditioned behavior in male and female rats.

Goal-directed behavior relies on accurate mental representations of the value of expected outcomes. Disruptions to this process are a central feature of several neuropsychiatric disorders, including addiction. Goal-directed behavior is most frequently studied using instrumental paradigms paired with outcome devaluation, but cue-evoked behaviors in Pavlovian settings can also be goal-directed and therefore sensitive to changes in outcome value. Emerging literature suggests that male and female rats may differ in the degree to which their Pavlovian-conditioned responses are goal-directed, but interpretation of these findings is complicated by the tendency of female and male rats to engage in distinct types of Pavlovian responses when trained with localizable cues. Here, we used outcome devaluation via sensory-specific satiety to assess the behavioral responses in male and female Long Evans rats trained to respond to an auditory CS (conditioned stimulus) in a Pavlovian-conditioning paradigm. We found that satiety-induced devaluation led to a decrease in behavioral responding to the reward-predictive CS, with males showing an effect on both port entry latency and probability and females showing an effect only on port entry probability. Overall, our results suggest that outcome devaluation affects Pavlovian-conditioned responses in both male and female rats, but that females may be less sensitive to outcome devaluation.

Sex-biased effects of outcome devaluation by sensory-specific satiety on Pavlovian-conditioned behavior.

Goal-directed behavior relies on accurate mental representations of the value of expected outcomes. Disruptions to this process are a central feature of several neuropsychiatric disorders, including addiction. Goal-directed behavior is most frequently studied using instrumental paradigms paired with outcome devaluation, but cue-evoked behaviors in Pavlovian settings can also be goal-directed and therefore sensitive to changes in outcome value. Emerging literature suggests that male and female rats may differ in the degree to which their Pavlovian-conditioned responses are goal-directed, but interpretation of these findings is complicated by the tendency of female and male rats to engage in distinct types of Pavlovian responses when trained with localizable cues. Here, we used outcome devaluation via sensory-specific satiety to assess the behavioral responses in male and female Long Evans rats trained to respond to an auditory CS (conditioned stimulus) in a Pavlovian-conditioning paradigm. We found that satiety-induced devaluation led to a decrease in behavioral responding to the reward-predictive CS, with males showing an effect on both port entry latency and probability and females showing an effect only on port entry probability. Overall, our results suggest that outcome devaluation affects Pavlovian-conditioned responses in both male and female rats, but that females may be less sensitive to outcome devaluation.