Adolescent‐onset GABAAα1 silencing regulates reward‐related decision making

The GABA_A receptor mediates fast, inhibitory signaling, and cortical expression of the α1 subunit increases during postnatal development. Certain pathological stimuli such as stressors or prenatal cocaine exposure can interfere with this process, but causal relationships between GABA_Aα1 deficiency and complex behavioral outcomes remain unconfirmed. We chronically reduced GABA_Aα1 expression selectively in the medial prefrontal cortex (prelimbic subregion) of mice using viral‐mediated gene silencing of Gabra1. Adolescent‐onset Gabra1 knockdown delayed the acquisition of a cocaine‐reinforced instrumental response but spared cocaine seeking in extinction and in a cue‐induced reinstatement procedure. To determine whether response acquisition deficits could be associated with impairments in action–outcome associative learning and memory, we next assessed behavioral sensitivity to instrumental contingency degradation. In this case, the predictive relationship between familiar actions and their outcomes is violated. Adolescent‐onset knockdown, although not adult‐onset knockdown, delayed the expression of goal‐directed response strategies in this task, resulting instead in inflexible habit‐like modes of response. Thus, the maturation of medial prefrontal cortex GABA_Aα1 systems during adolescence appears necessary for goal‐directed reward‐related decision making in adulthood. These findings are discussed in the light of evidence that prolonged Gabra1 deficiency may impair synaptic plasticity.     

Involvement of the rodent prelimbic and medial orbitofrontal cortices in goal-directed action: A brief review

Goal-directed action refers to selecting behaviors based on the expectation that they will be reinforced with desirable outcomes. It is typically conceptualized as opposing habit-based behaviors, which are instead supported by stimulus–response associations and insensitive to consequences. The prelimbic prefrontal cortex (PL) is positioned along the medial wall of the rodent prefrontal cortex. It is indispensable for action–outcome-driven (goal-directed) behavior, consolidating action–outcome relationships and linking contextual information with instrumental behavior. In this brief review, we will discuss the growing list of molecular factors involved in PL function. Ventral to the PL is the medial orbitofrontal cortex (mOFC). We will also summarize emerging evidence from rodents (complementing existing literature describing humans) that it too is involved in action–outcome conditioning. We describe experiments using procedures that quantify responding based on reward value, the likelihood of reinforcement, or effort requirements, touching also on experiments assessing food consumption more generally. We synthesize these findings with the argument that the mOFC is essential to goal-directed action when outcome value information is not immediately observable and must be recalled and inferred.     

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.     

Dissociable contributions of the ventral hippocampus and orbitofrontal cortex to decision‐making with a delayed or uncertain outcome

In this study, we examined how risk and delay influence rats' decision‐making, and the role of the ventral hippocampus (VHC) and orbitofrontal cortex (OFC) in the valuation of these two factors. We used a touchscreen testing method in which rats with VHC lesions, OFC lesions and sham control surgery made choices in two decision‐making tasks. In the delay discounting task, rats chose between two visual stimuli, one of which indicated a small, immediate reward, and the other of which indicated a large, delayed reward. In the probability discounting task, two stimuli indicated, instead, a small, certain reward or a large, uncertain reward. The two lesion groups showed a double dissociation with respect to the two tasks. Rats with VHC lesions were intolerant of delay, and were strongly biased towards the small, immediate reward. However, the same rats were indistinguishable from sham controls in the probability discounting task. The opposite pattern was observed for rats with OFC lesions; they performed normally in the delay discounting task, but showed a reduced tolerance for uncertainty as compared with sham‐operated controls. These data support the conclusion that the VHC and OFC contribute differentially to decision‐making that involves delayed or uncertain outcomes. This provides a means for understanding the neural basis of a range of neurological and psychiatric patients who show impaired decision‐making and executive dysfunction.     

Neurophysiological correlates of collective perceptual decision‐making

Humans frequently perform tasks collaboratively in daily life. Collaborating with others may or may not result in higher task performance than if one were to complete the task alone (i.e., a collective benefit). A recent study on collective benefits in perceptual decision‐making showed that dyad members with similar individual performances attain collective benefit. However, little is known about the physiological basis of these results. Here, we replicate this earlier work and also investigate the neurophysiological correlates of decision‐making using EEG. In a two‐interval forced‐choice task, co‐actors individually indicated presence of a target stimulus with a higher contrast and then indicated their confidence on a rating scale. Viewing the individual ratings, dyads made a joint decision. Replicating earlier work, we found a positive correlation between the similarity of individual performances and collective benefit. We analyzed event‐related potentials (ERPs) in three phases (i.e., stimulus onset, response and feedback) using explorative cluster mass permutation tests. At stimulus onset, ERPs were significantly linearly related to our manipulation of contrast differences, validating our manipulation of task difficulty. For individual and joint responses, we found a significant centro‐parietal error‐related positivity for correct versus incorrect responses, which suggests that accuracy is already evaluated at the response level. At feedback presentation, we found a significant late positive fronto‐central potential elicited by incorrect joint responses. In sum, these results demonstrate that response‐ and feedback‐related components elicited by an error‐monitoring system differentially integrate conflicting information exchanged during the joint decision‐making process.     

Thalamic afferents to prefrontal cortices from ventral motor nuclei in decision‐making

The focus of this literature review is on the three interacting brain areas that participate in decision‐making: basal ganglia, ventral motor thalamic nuclei, and medial prefrontal cortex, with an emphasis on the participation of the ventromedial and ventral anterior motor thalamic nuclei in prefrontal cortical function. Apart from a defining input from the mediodorsal thalamus, the prefrontal cortex receives inputs from ventral motor thalamic nuclei that combine to mediate typical prefrontal functions such as associative learning, action selection, and decision‐making. Motor, somatosensory and medial prefrontal cortices are mainly contacted in layer 1 by the ventral motor thalamic nuclei and in layer 3 by thalamocortical input from mediodorsal thalamus. We will review anatomical, electrophysiological, and behavioral evidence for the proposed participation of ventral motor thalamic nuclei and medial prefrontal cortex in rat and mouse motor decision‐making.     

Pathological Gambling in Parkinson's disease: Autonomic measures supporting impaired decision‐making

According to the somatic marker hypothesis, autonomic measures and arousal modulation can reveal a difference in subgroups of patients developing impaired decision‐making because of addictions. Previously, pathological gambling (PG) and Parkinson's disease (PD) have been associated with differential arousal levels during gambling behavior. However, no research considered the specific autonomic responses of Parkinson's disease patients with pathological gambling and with a previous history of gambling. Thus, this study investigated skin conductance responses (SCRs), skin conductance level (SCL) and heart rate (HR) during the Iowa Gambling Task (IGT) in two groups of PD patients with gambling disorder, active (PD Gamblers; n = 14) or remitted (PD Non‐Gamblers; n = 13) and a control group of patients with Parkinson's disease only (n = 13). Anticipatory autonomic responses to disadvantageous decks and advantageous decks during the Iowa Gambling Task were measured for each participant. The PD Gamblers group performed worse than the PD Non‐Gamblers and the control groups at the IGT task and exhibited lower SCRs, SCL, and HR during the decision‐making processing of cards belonging to disadvantageous decks. The role of autonomic and behavioral measures was considered.     

The role of the dorsomedial striatum in instrumental conditioning

Considerable evidence suggests that, in instrumental conditioning, rats learn the relationship between actions and their specific consequences or outcomes. The present study examined the role of the dorsomedial striatum (DMS) in this type of learning after excitotoxic lesions and reversible, muscimol-induced inactivation. In three experiments, rats were first trained to press two levers for distinct outcomes, and then tested after training using a variety of behavioural assays that have been established to detect action-outcome learning. In Experiment 1, pre-training lesions of the posterior DMS abolished the sensitivity of rats' instrumental performance to both outcome devaluation and contingency degradation when tested in extinction, whereas lesions of the anterior DMS had no effect. In Experiment 2, both pre-training and post-training lesions of the posterior DMS were equally effective in reducing the sensitivity of performance both to devaluation and degradation treatments. In Experiment 3, the infusion of muscimol into the posterior DMS selectively abolished sensitivity of performance to devaluation and contingency degradation without impairing the ability of rats to discriminate either the instrumental actions performed or the identity of the earned outcomes. Taken together, these results suggest that the posterior region of the DMS is a crucial neural substrate for the acquisition and expression of action-outcome associations in instrumental conditioning.     

Unilateral medial frontal cortex lesions cause a cognitive decision‐making deficit in rats

The medial frontal cortex (MFC) is critical for cost–benefit decision‐making. Generally, cognitive and reward‐based behaviour in rodents is not thought to be lateralised within the brain. In this study, however, we demonstrate that rats with unilateral MFC lesions show a profound change in decision‐making on an effort‐based decision‐making task. Furthermore, unilateral MFC lesions have a greater effect when the rat has to choose to put in more effort for a higher reward when it is on the contralateral side of space to the lesion. Importantly, this could not be explained by motor impairments as these animals did not show a turning bias in separate experiments. In contrast, rats with unilateral dopaminergic midbrain lesions did exhibit a motoric turning bias, but were unimpaired on the effort‐based decision‐making task. This rare example of a cognitive deficit caused by a unilateral cortical lesion in the rat brain indicates that the MFC may have a specialised and lateralised role in evaluating the costs and benefits of actions directed to specific spatial locations.     

The subthalamic nucleus during decision‐making with multiple alternatives

Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre‐SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple‐alternative decision‐making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia. Hum Brain Mapp 36:4041–4052, 2015. © 2015 Wiley Periodicals, Inc.     

The top‐down regulation from the prefrontal cortex to insula via hypnotic aversion suggestions reduces smoking craving

Hypnosis has been shown to have treatment effects on nicotine addiction. However, the neural basis of these effects is poorly understood. This preliminary study investigated the neural mechanisms of hypnosis‐based treatment on cigarette smoking, specifically, whether the hypnosis involves a top‐down or bottom‐up mechanism. Two groups of 45 smokers underwent a smoking aversion suggestion and viewed smoking‐related pictures and neutral pictures. One group underwent functional magnetic resonance imaging scanning twice (control and hypnotic states), whereas the other group underwent two electroencephalograph sessions. Our study found that self‐reported smoking craving decreased in both groups following hypnosis. Smoking cue‐elicited activations in the right dorsal lateral prefrontal cortex (rDLPFC) and left insula (lI) and the functional connectivity between the rDLPFC and lI were increased in the hypnotic state compared with the control state. The delta band source waveforms indicated the activation from 390 to 862 ms at the rDLPFC and from 490 to 900 ms at the lI was significantly different between the smoking and neutral conditions in the hypnotic state, suggesting the activation in the rDLPFC preceded that in the lI. These results suggest that the decreased smoking craving via hypnotic aversion suggestions may arise from the top‐down regulation of the rDLPFC to the lI. Our findings provide novel neurobiological evidence for understanding the therapeutic effects of hypnosis on nicotine addiction, and the prefrontal–insula circuit may serve as an imaging biomarker to monitor the treatment efficacy noninvasively.     

The role of the right temporo–parietal junction in social decision‐making

Identifying someone else's noncooperative intentions can prevent exploitation in social interactions. Hence, the inference of another person's mental state might be most pronounced in order to improve social decision‐making. Here, we tested the hypothesis that brain regions associated with Theory of Mind (ToM), particularly the right temporo–parietal junction (rTPJ), show higher neural responses when interacting with a selfish person and that the rTPJ‐activity as well as cooperative tendencies will change over time. We used functional magnetic resonance imaging (fMRI) and a modified prisoner's dilemma game in which 20 participants interacted with three fictive playing partners who behaved according to stable strategies either competitively, cooperatively or randomly during seven interaction blocks. The rTPJ and the posterior–medial prefrontal cortex showed higher activity during the interaction with a competitive compared with a cooperative playing partner. Only the rTPJ showed a high response during an early interaction phase, which preceded participants increase in defective decisions. Enhanced functional connectivity between the rTPJ and the left hippocampus suggests that social cognition and learning processes co‐occur when behavioral adaptation seems beneficial.     

The hypocretin–orexin system regulates cocaine self‐administration via actions on the mesolimbic dopamine system

Recent evidence suggests that the hypocretin–orexin system participates in the regulation of reinforcement processes. The current studies examined the extent to which hypocretin neurotransmission regulates behavioral and neurochemical responses to cocaine, and behavioral responses to food reinforcement. These studies used a combination of fixed ratio, discrete trials, progressive ratio and threshold self‐administration procedures to assess whether the hypocretin 1 receptor antagonist, SB‐334867, reduces cocaine self‐administration in rats. Progressive ratio sucrose self‐administration procedures were also used to assess the extent to which SB‐334867 reduces responding to a natural reinforcer in food‐restricted and food‐sated rats. Additionally, these studies used microdialysis and in vivo voltammetry in rats to examine whether SB‐334867 attenuates the effects of cocaine on dopamine signaling within the nucleus accumbens core. Furthermore, in vitro voltammetry was used to examine whether hypocretin knockout mice display attenuated dopamine responses to cocaine. Results indicate that when SB‐334867 was administered peripherally or within the ventral tegmental area, it reduced the motivation to self‐administer cocaine and attenuated cocaine‐induced enhancement of dopamine signaling. SB‐334867 also reduced the motivation to self‐administer sucrose in food‐sated but not food‐restricted rats. Finally, hypocretin knockout mice displayed altered baseline dopamine signaling and reduced dopamine responses to cocaine. Combined, these studies suggest that hypocretin neurotransmission participates in reinforcement processes, likely through modulation of the mesolimbic dopamine system. Additionally, the current observations suggest that the hypocretin system may provide a target for pharmacotherapies to treat cocaine addiction.     

The anterior insula bidirectionally modulates cost‐benefit decision‐making on a rodent gambling task

Deficits in cost‐benefit decision‐making, as assessed in the Iowa Gambling Task (IGT), are commonly observed in neuropsychiatric disorders such as addiction. There is considerable variation in the maximization of rewards on such tasks, both in the general population and in rodent models, suggesting individual differences in decision‐making may represent a key endophenotype for vulnerability to neuropsychiatric disorders. Increasing evidence suggests that the insular cortex, which is involved in interoception and emotional processes in humans, may be a key neural locus in the control of decision‐making processes. However, the extent to which the insula contributes to individual differences in cost‐benefit decision‐making remains unknown. Using male Sprague Dawley rats, we first assessed individual differences in the performance over the course of a single session on a rodent analogue of the IGT (rGT). Rats were matched for their ability to maximize reward and received bilateral excitotoxic or sham lesions of the anterior insula cortex (AIC). Animals were subsequently challenged on a second rGT session with altered contingencies. Finally, animals were also assessed for instrumental conditioning and reversal learning. AIC lesions produced bidirectional alterations on rGT performance; rats that had performed optimally prior to surgery subsequently showed impairments, and animals that had performed poorly showed improvements in comparison with sham‐operated controls. These bidirectional effects were not attributable to alterations in behavioural flexibility or in motivation. These data suggest that the recruitment of the AIC during decision‐making may be state‐dependent and help guide response selection towards subjectively favourable options.     

Small gray matter volume in orbitofrontal cortex in Prader‐Willi syndrome: A voxel‐based MRI study

Prader‐Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder presenting with behavioral symptoms including hyperphagia, disinhibition, and compulsive behavior. The behavioral problems in individuals with PWS are strikingly similar to those in patients with frontal pathologies, particularly those affecting the orbitofrontal cortex (OFC). However, neuroanatomical abnormalities in the frontal lobe have not been established in PWS. The aim of this study was to look, using volumetric analysis, for morphological changes in the frontal lobe, especially the OFC, of the brains of individuals with PWS. Twelve adults with PWS and 13 age‐ and gender‐matched control subjects participated in structural magnetic resonance imaging (MRI) scans. The whole‐brain images were segmented and normalized to a standard stereotactic space. Regional gray matter volumes were compared between the PWS group and the control group using voxel‐based morphometry. The PWS subjects showed small gray‐matter volume in several regions, including the OFC, caudate nucleus, inferior temporal gyrus, precentral gyrus, supplementary motor area, postcentral gyrus, and cerebellum. The small gray‐matter volume in the OFC remained significant in a separate analysis that included total gray matter volume as a covariate. These preliminary findings suggest that the neurobehavioral symptoms in individuals with PWS are related to structural brain abnormalities in these areas. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Functional magnetic resonance imaging responses during perceptual decision‐making at 3 and 7 T in human cortex,striatum, and brainstem

While functional magnetic resonance imaging (fMRI) at ultra‐high field (7 T) promises a general increase in sensitivity compared to lower field strengths, the benefits may be most pronounced for specific applications. The current study aimed to evaluate the relative benefit of 7 over 3 T fMRI for the assessment of responses evoked in different brain regions by a well‐controlled cognitive task. At 3 and 7 T, the same participants made challenging perceptual decisions about visual motion combined with monetary rewards for correct choices. Previous work on this task has extensively characterized the underlying cognitive computations and single‐cell responses in cortical and subcortical structures. We quantified the evoked fMRI responses in extrastriate visual cortical areas, the striatum, and the brainstem during the decision interval and the post‐feedback interval of the task. The dependence of response amplitudes on field strength during the decision interval differed between cortical, striatal, and brainstem regions, with a generally bigger 7 versus 3 T benefit in subcortical structures. We also found stronger responses during relatively easier than harder decisions at 7 T for dopaminergic midbrain nuclei, in line with reward expectation. Our results demonstrate the potential of 7 T fMRI for illuminating the contribution of small brainstem nuclei to the orchestration of cognitive computations in the human brain.     

Prostaglandin E receptor EP1 enhances GABA‐mediated inhibition of dopaminergic neurons in the substantia nigra pars compacta and regulates dopamine level in the dorsal striatum

Dopamine (DA) is a neuromodulator that is critical for sensory‐motor, cognitive and emotional functions. We previously found that mice lacking prostaglandin E receptor EP1 showed impulsive emotional behaviors accompanied by enhanced DA turnover in the frontal cortex and striatum. Given that these behavioral phenotypes were corrected by DA receptor antagonists, we hypothesized that EP1 deficiency causes a hyperdopaminergic state for its behavioral phenotype. Here we tested this hypothesis by examining the EP1 action in the nigrostriatal dopaminergic system. We first used microdialysis and found an elevated extracellular DA level in the dorsal striatum of EP1‐deficient mice compared with wild‐type mice. Despite the EP1 expression in the striatum, neither deficiency nor activation of EP1 altered the intrastriatal control for DA release, uptake or degradation. Immunohistochemistry revealed punctate EP1 signals apposed with dopaminergic neurons in the substantia nigra pars compacta (SNc). Many EP1 signals were colocalized with a marker for GABAergic synapses. Further, an EP1 agonist enhanced GABA_A‐mediated inhibitory inputs to SNc dopaminergic neurons in midbrain slices. Therefore, the prostaglandin E₂‐EP1 signaling directly enhances GABAergic inputs to SNc dopaminergic neurons. The lack of this EP1 action may lead to a hyperdopaminergic state of EP1‐deficient mice.     

The small‐conductance calcium‐activated potassium channel is a key modulator of firing and long‐term depression in the dorsal striatum

The striatum is considered to be critical for the control of goal‐directed action, with the lateral dorsal striatum (latDS) being implicated in modulation of habits and the nucleus accumbens thought to represent a limbic–motor interface. Although medium spiny neurons from different striatal subregions exhibit many similar properties, differential firing and synaptic plasticity could contribute to the varied behavioral roles across subregions. Here, we examined the contribution of small‐conductance calcium‐activated potassium channels (SKs) to action potential generation and synaptic plasticity in adult rat latDS and nucleus accumbens shell (NAS) projection neurons in vitro. The SK‐selective antagonist apamin exerted a prominent effect on latDS firing, significantly decreasing the interspike interval. Furthermore, prolonged latDS depolarization increased the interspike interval and reduced firing, and this enhancement was reversed by apamin. In contrast, NAS neurons exhibited greater basal firing rates and less regulation of firing by SK inhibition and prolonged depolarization. LatDS neurons also had greater SK currents than NAS neurons under voltage‐clamp. Importantly, SK inhibition with apamin facilitated long‐term depression (LTD) induction in the latDS but not the NAS, without alterations in glutamate release. In addition, SK activation in the latDS prevented LTD induction. Greater SK function in the latDS than in the NAS was not secondary to differences in sodium or inwardly rectifying potassium channel function, and apamin enhancement of firing did not reflect indirect action through cholinergic interneurons. Thus, these data demonstrate that SKs are potent modulators of action potential generation and LTD in the dorsal striatum, and could represent a fundamental cellular mechanism through which habits are regulated.     

Rostrocaudal functional gradient among the pre‐dorsal premotor cortex,dorsal premotor cortex and primary motor cortex in goal‐directed motor behaviour

The dorsal premotor cortex residing in the dorsolateral aspect of area 6 is a rostrocaudally elongated area that is rostral to the primary motor cortex (M1) and caudal to the prefrontal cortex. This region, which is subdivided into rostral [pre‐dorsal premotor cortex (pre‐PMd)] and caudal [dorsal premotor cortex proper (PMd)] components, probably plays a central role in planning and executing actions to achieve a behavioural goal. In the present study, we investigated the functional specializations of the pre‐PMd, PMd, and M1, because the synthesis of the specific functions performed by each area is considered to be essential. Neurons were recorded while monkeys performed a conditional visuo‐goal task designed to include separate processes for determining a behavioural goal (reaching towards a right or left potential target) on the basis of visual object instructions, specifying actions (direction of reaching) to be performed on the basis of the goal, and preparing and executing the action. Neurons in the pre‐PMd and PMd retrieved and maintained behavioural goals without encoding the visual features of the visual object instructions, and subsequently specified the actions by multiplexing the goals with the locations of the targets. Furthermore, PMd and M1 neurons played a major role in representing the action during movement preparation and execution, whereas the contribution of the pre‐PMd progressively decreased as the time of the actual execution of the movement approached. These findings revealed that the multiple processing stages necessary for the realization of an action to accomplish a goal were implemented in an area‐specific manner across a functional gradient from the pre‐PMd to M1 that included the PMd as an intermediary.     

Central thalamic inactivation impairs the expression of action‐ and outcome‐related responses of medial prefrontal cortex neurons in the rat

The mediodorsal (MD) and adjacent intralaminar (IL) and midline nuclei provide the main thalamic input to the medial prefrontal cortex (mPFC) and are critical for associative learning and decision‐making. MD neurons exhibit activity related to actions and outcomes that mirror responses of mPFC neurons in rats during dynamic delayed non‐match to position (dDNMTP), a variation of DNMTP where start location is varied randomly within an open octagonal arena to avoid confounding behavioral events with spatial location. To test whether the thalamus affects the expression of these responses in mPFC, we inhibited the central thalamus unilaterally by microinjecting muscimol at doses and sites found to affect decision‐making when applied bilaterally. Unilateral inactivation reduced normalized task‐related responses in the ipsilateral mPFC without disrupting behavior needed to characterize event‐related neuronal activity. Our results extend earlier findings that focused on delay‐related activity by showing that central thalamic inactivation interferes with responses related to actions and outcomes that occur outside the period of memory delay. These findings are consistent with the broad effects of central thalamic lesions on behavioral measures of reinforcement‐guided responding. Most (7/8) of the prefrontal response types affected by thalamic inactivation have also been observed in MD during dDNMTP. These results support the hypothesis that MD and IL act as transthalamic gates: monitoring prefrontal activity through corticothalamic inputs; integrating this information with signals from motivational and sensorimotor systems that converge in thalamus; and acting through thalamocortical projections to enhance expression of neuronal responses in the PFC that support adaptive goal‐directed behavior.