Ceftriaxone reverses diet-induced deficits in goal-directed control.

RATIONALE: Obesity is associated with numerous health risks and ever-increasing rates are a significant global concern. However, despite weight loss attempts many people have difficulty maintaining weight loss. Previous studies in animals have shown that chronic access to an obesogenic diet can disrupt goal-directed behavior, impairing the ability of animals to flexibly adjust food-seeking behavior following changes in the value of earned outcomes. Changes in behavioral control have been linked to disruption of glutamate transmission in the dorsal medial striatum (DMS), a region critical for the acquisition and expression of goal-directed behavior. OBJECTIVES: The goal of this study was to test whether ceftriaxone, a beta-lactam antibiotic shown elsewhere to upregulate the expression of the glutamate transporter GLT-1, would improve goal-directed control following long-term exposure to an obesogenic diet. METHODS: Male and female rats were given access to either standard chow or chow plus sweetened condensed milk (SCM) for 6 weeks. Access to SCM was ended and rats received daily injections of either ceftriaxone or saline for 6 days. Rats were then trained to press a lever to earn a novel food reward and, finally, were assessed for sensitivity to outcome devaluation. Histological analyses examined changes to GLT-1 protein levels and morphological changes to astrocytes, within the DMS. RESULTS: We found that ceftriaxone robustly restored goal-directed behavior in animals following long-term exposure to SCM. While we did not observe changes in protein levels of GLT-1 in the DMS, we observed that SCM induced changes in the morphology of astrocytes in the DMS, and that ceftriaxone mitigated these changes. CONCLUSIONS: These results demonstrate that long-term access to a SCM diet impairs goal-directed behavior while also altering the morphology of astrocytes in the DMS. Furthermore, these results suggest that ceftriaxone administration can reverse the impairment of goal-directed behavior potentially through its actions on astrocytes in decision-making circuitry.

The role of dorsomedial striatum adenosine 2A receptors in the loss of goal-directed behaviour.

RATIONALE: Adenosine A2A receptors (A2AR) in the dorsal striatum have been implicated in goal-directed behaviour. While activation of these receptors with several methods has resulted in an insensitivity to outcome devaluation, particular explanations for how they disrupt behaviour have not been explored. We both confirm a role for A2A receptors in goal-directed responding and evaluate additional behavioural aspects of goal-directed control to more fully understand the role of A2A receptors in instrumental behaviour. OBJECTIVES: To examine the effects of the adenosine A2A agonist CGS-21680 in the DMS on response-outcome encoding, updating representations of outcome value and on the ability to inhibit behaviour when reward is not available. METHODS: Male rats were trained to lever press for food reward. The A2AR agonist CGS-21680 was infused into the dorsomedial striatum either before an outcome devaluation test, prior to training with two distinct response-outcome associations or prior to a test of discriminative stimulus control over instrumental performance. RESULTS: Intra-DMS administration of CGS-21680 impaired sensitivity to outcome devaluation. CGS-21680 treatment did not impair acquisition of specific response-outcome associations, selective control of responding based on the presence of stimuli that signaled when reward was or was not available, discrimination between stimuli or lever choices nor did it influence the effect of devaluation on the amounts of food eaten in a consumption test. CONCLUSIONS: CGS-21680 impairs the ability to modulate responding based on recent changes to outcome value, an effect that is not accounted for by impairments in behavioural inhibition, discrimination, encoding the specific outcome of a response or the effectiveness of specific satiety.

Food for thought: diet-induced impairments to decision-making and amelioration by N-acetylcysteine in male rats.

RATIONALE: Attempts to lose weight often fail despite knowledge of the health risks associated with obesity and determined efforts. We previously showed that rodents fed an obesogenic diet displayed premature habitual behavioural control and weakened flexible decision-making based on the current value of outcomes produced by their behaviour. Thus, habitual control may contribute to failed attempts to modify eating behaviours. OBJECTIVES: To examine the effects of an obesogenic diet on behavioural control and glutamate transmission in dorsal striatum regions and to assess the ability of N-acetylcysteine (NAC) to reverse deficits. METHODS: Here, we examined diet-induced changes to decision-making and used in vitro electrophysiology to investigate the effects of diet on glutamate transmission within the dorsomedial (DMS) and dorsolateral (DLS) striatum, areas that control goal-directed and habitual behaviours, respectively. We administered NAC in order to normalize glutamate release and tested whether this would restore goal-directed performance following an obesogenic diet. RESULTS: We found that an obesogenic diet reduced sensitivity to outcome devaluation and increased glutamate release in the DMS, but not DLS. Administration of NAC restored goal-directed control and normalized mEPSCs in the DMS. Finally, NAC administered directly to the DMS was sufficient to reinstate sensitivity to outcome devaluation following an obesogenic diet. CONCLUSIONS: These data indicate that obesogenic diets alter neural activity in the basal ganglia circuit responsible for goal-directed learning and control which leads to premature habitual control. While the effects of diet are numerous and widespread, normalization of glutamatergic activity in this circuit is sufficient for restoring goal-directed behaviour.

Diet-induced deficits in goal-directed control are rescued by agonism of group II metabotropic glutamate receptors in the dorsomedial striatum.

Many overweight or obese people struggle to sustain the behavioural changes necessary to achieve and maintain weight loss. In rodents, obesogenic diet can disrupt goal-directed control of responding for food reinforcers, which may indicate that diet can disrupt brain regions associated with behavioural control. We investigated a potential glutamatergic mechanism to return goal-directed control to rats who had been given an obesogenic diet prior to operant training. We found that an obesogenic diet reduced goal-directed control and that systemic injection of LY379268, a Group II metabotropic glutamate receptor (mGluR2/3) agonist, returned goal-directed responding in these rats. Further, we found that direct infusion of LY379268 into the dorsomedial striatum, a region associated with goal-directed control, also restored goal-directed responding in the obesogenic-diet group. This indicates that one mechanism through which obesogenic diet disrupts goal-directed control is glutamatergic, and infusion of a mGluR2/3 agonist into the DMS is sufficient to ameliorate deficits in goal-directed control.

Intracerebellar infusion of an mGluR1/5 agonist enhances eyeblink conditioning.

Cerebellar metabotropic glutamate receptor 1 (mGluR1) expressed by Purkinje cells may play an important role in learning-related cerebellar plasticity. Eyeblink conditioning (EBC) is a well-studied form of Pavlovian learning that engages discrete areas of cerebellar cortex and deep cerebellar nuclei. EBC is impaired in mGluR1 knockout mice. Here, we show that infusion of the mGluR1/5 agonist DHPG into the lobulus simplex region of cerebellar cortex facilitates EBC in rats. Infusion was made prior to Sessions 1 and 2 of EBC but the facilitatory effects persisted throughout subsequent, noninfusion sessions. The facilitatory effects were confined to frequency of eyeblink conditioned responses (CRs); there were no effects on amplitude or latency of CRs. There were also no effects on reflexive responding to the tone conditioned stimulus or eyelid stimulation unconditioned stimulus. The current results provide further evidence that cerebellar mGluR1 plays a role in cerebellar-dependent associative learning and complement previous studies using mGluR1 knockout mice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Some factors that restore goal-direction to a habitual behavior.

Recent findings from our laboratory suggest that an extensively-practiced instrumental behavior can appear to be a goal-directed action (rather than a habit) when a second behavior is added and reinforced during intermixed final sessions (Shipman et al., 2018). The present experiments were designed to explore and understand this finding. All used the taste aversion method of devaluing the reinforcer to distinguish between goal-directed actions and habits. Experiment 1 confirmed that reinforcing a second response in a separate context (but not mere exposure to that context) can return an extensively-trained habit to the status of goal-directed action. Experiment 2 showed that training of the second response needs to be intermixed with training of the first response to produce this effect; training the second response after the first-response training was complete preserved the first response as a habit. Experiment 3 demonstrated that reinforcing the second response with a different reinforcer breaks the habit status of the first response. Experiment 4 found that free reinforcers (that were not response-contingent) were sufficient to restore goal-directed performance. Together, the results suggest that unexpected reinforcer delivery can render a habitual response goal-directed again.

Chemogenetic Silencing of Prelimbic Cortex to Anterior Dorsomedial Striatum Projection Attenuates Operant Responding.

Operant (instrumental) conditioning is a laboratory analog for voluntary behavior and involves learning to make a response for a reinforcing outcome. The prelimbic cortex (PL), a region of the rodent medial prefrontal cortex, and the dorsomedial striatum (DMS), have been separately established as important in the acquisition of minimally-trained operant behavior. Despite dense anatomical connections between the two regions, experimenters have only recently linked projections from the PL to the posterior DMS (pDMS) in the acquisition of an operant response. Yet, it is still unknown if these projections mediate behavioral expression, and if more anterior regions of the DMS (aDMS), which receive dense projections from the PL, are also involved. Therefore, we utilized designer receptors exclusively activated by designer drugs (DREADDs) to test whether or not projections from the PL to the aDMS influence the expression of operant behavior. Rats underwent bilateral PL-targeted infusions of either a DREADD virus (AAV8-hSyn-hM4D(Gi)-mCherry) or a control virus (AAV8-hSyn-GFP). In addition, guide cannulae were implanted bilaterally in the aDMS. Rats were tested with both clozapine-N-oxide (CNO) (DREADD ligand) and vehicle infusions into the aDMS. Animals that had received the DREADD virus, but not the control virus, showed attenuated responding when they received CNO microinfusions into the aDMS, compared to vehicle infusions. Patch clamp electrophysiology verified the inhibitory effect of CNO on DREADDs-expressing PL neurons in acute brain slices. GFP-expressing control PL neurons were unaffected by CNO. The results add to the recent literature suggesting that connections between the PL and aDMS are important for the expression of minimally-trained operant responding.

Cerebellum and cognition: Does the rodent cerebellum participate in cognitive functions?

There is a widespread, nearly complete consensus that the human and non-human primate cerebellum is engaged in non-motor, cognitive functions. This body of research has implicated the lateral portions of lobule VII (Crus I and Crus II) and the ventrolateral dentate nucleus. With rodents, however, it is not so clear. We review here approximately 40 years of experiments using a variety of cerebellar manipulations in rats and mice and measuring the effects on executive functions (working memory, inhibition, and cognitive flexibility), spatial navigation, discrimination learning, and goal-directed and stimulus-driven instrumental conditioning. Our conclusion is that there is a solid body of support for engagement of the rodent cerebellum in tests of cognitive flexibility and spatial navigation, and some support for engagement in working memory and certain types of discrimination learning. Future directions will involve determining the relevant cellular mechanisms, cerebellar regions, and precise cognitive functions of the rodent cerebellum.

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.

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.

Selective hippocampal lesions impair acquisition of appetitive trace conditioning with long intertrial and long trace intervals.

Whereas hippocampal lesions clearly impair performance on aversive trace conditioning tasks, recent evidence suggests that such lesions do not affect performance on appetitive trace conditioning tasks with trace intervals from 2 seconds up to 20 seconds. The current study first demonstrated that intact rats can learn trace conditioning tasks with longer trace intervals (8 s) when the average intertrial interval (intertrial interval [ITI]) was lengthened from 150-s to 300-s. In two subsequent experiments with longer ITIs (420-s and 825-s), hippocampal-lesioned rats performed similarly to intact controls in an appetitive trace conditioning task with 20-s trace interval but were impaired in an appetitive trace conditioning task with a 60-s trace interval. These results suggest that the training ITI and the trace interval are important variables to consider in appetitive trace conditioning, and the hippocampus may play an important role in appetitive trace conditioning when the ITI and trace intervals are both sufficiently long.