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Dorsal lateral striatum (DLS) is a highly associative structure that encodes relationships among environmental stimuli, behavioral responses, and predicted outcomes. DLS is known to be disrupted after chronic drug abuse; however, it remains unclear what neural signals in DLS are altered. Current theory suggests that drug use enhances stimulus-response processing at the expense of response- outcome encoding, but this has mostly been tested in simple behavioral tasks. Here, we investigated what neural correlates in DLS are affected by previous cocaine exposure as rats performed a complex reward-guided decision-making task in which predicted reward value was independently manipulated by changing the delay to or size of reward associated with a response direction across a series of trial blocks. After cocaine self-administration, rats exhibited stronger biases toward higher-value reward and firing in DLS more strongly represented action- outcome contingencies independent from actions subsequently taken rather than outcomes predicted by selected actions (chosen-outcome contingencies) and associations between stimuli and actions (stimulus-response contingencies). These results suggest that cocaine self-administration strengthens action- outcome encoding in rats (as opposed to chosen-outcome or stimulus- response encoding), which abnormally biases behavior toward valued reward when there is a choice between two options during rewardguided decision-making. [ABSTRACT FROM AUTHOR]

Cognitive flexibility is a hallmark of prefrontal cortical (PFC) function yet little is known about downstream area involvement. The medial dorsal striatum (mDS) receives major projections from the PFC and is uniquely situated to perform the integration of responses with rule information. In this study, we use a novel rule shifting task in rats that mirrors non-human primate and human studies in its temporal precision and counterbalanced responses. We record activity from single neurons in the mDS while rats switch between different rules for reward. Additionally, we pharmacologically inactivate mDS by infusion of a baclofen/muscimol cocktail. Inactivation of mDS impaired the ability to shift to a new rule and increased the number of regressive errors. While recording in mDS, we identified neurons modulated by direction whose activity reflected the conflict between competing rule information. We show that a subset of these neurons was also rule selective, and that the conflict between competing rule cues was resolved as behavioural performance improved. Other neurons were modulated by rule, but not direction. These neurons became selective before behavioural performance accurately reflected the current rule. These data provide an additional locus for investigating the mechanisms underlying behavioural flexibility. Converging lines of evidence from multiple human psychiatric disorders have implicated dorsal striatum as an important and understudied neural substrate of flexible cognition. Our data confirm the importance of mDS, and suggest a mechanism by which mDS mediates abstract cognition functions. [ABSTRACT FROM AUTHOR]

Background Cerebral cortical gamma-aminobutyric acidergic interneuron dysfunction is hypothesized to lead to cognitive deficits comorbid with human neuropsychiatric disorders, including schizophrenia, autism, and epilepsy. We have previously shown that mice that harbor mutations in the Plaur gene, which is associated with schizophrenia, have deficits in frontal cortical parvalbumin-expressing interneurons. Plaur mice have impaired reversal learning, similar to deficits observed in patients with schizophrenia. Methods We examined the role of parvalbumin interneurons in orbitofrontal cortex during reversal learning by recording single unit activity from 180 control and 224 Plaur mouse neurons during a serial reversal task. Neural activity was analyzed during correct and incorrect decision choices and reward receipt. Results Neurons in control mice exhibited strong phasic responses both during discrimination and reversal learning to decisions and rewards, and the strength of the response was correlated with behavioral performance. Although baseline firing was significantly enhanced in Plaur mice, neural selectivity for correct or erroneous decisions was diminished and not correlated with behavior, and reward encoding was downscaled. In addition, Plaur mice showed a significant reduction in the number of neurons that encoded expected outcomes across task phases during the decision period. Conclusions These data indicate that parvalbumin interneurons are necessary for the representation of outcomes in orbitofrontal cortex. Deficits in inhibition blunt selective neural firing during key decisions, contributing to behavioral inflexibility. These data provide a potential explanation for disorders of cognitive control that accompany the loss of these gamma-aminobutyric acidergic interneurons in human neuropsychiatric disorders, such as autism, epilepsy, and schizophrenia. [ABSTRACT FROM AUTHOR]

Highlights: [•] Loss of Plaur leads to reduced numbers of medial frontal cortical interneurons. [•] Excess HGF/SF increases hippocampal and medial frontal cortical interneurons. [•] Amygdalar interneurons are not affected by Plaur loss or excess HGF/SF. [•] Fear extinction and attentional set formation are dependent on interneuron number. [ABSTRACT FROM AUTHOR]

Background: The development of addiction is thought to reflect a transition from goal-directed to stimulus-response driven behavior, functions attributed to ventral (VS) and dorsal striatum (DS), respectively. In line with this theory, neuroadaptations that occur during prolonged drug use progress from VS to DS. Here we ask if VS dysfunction alone, independent of drug use, can affect neural selectivity in DS. Methods: To address this issue, we recorded from single neurons in DS while rats performed an odor-guided choice task for differently valued rewards in rats with and without unilateral VS lesions. In a separate group of animals, we used bilateral VS lesions to determine if VS was critical for performance on this task. Results: We describe data showing that unilateral lesions of VS enhance neural representations in DS during performance of a task that is dependent on VS. Furthermore, we show that VS is critical for reward-guided decision-making initially, but that rats regain function after several days. Conclusions: These results suggest that loss of VS function, independent of chronic drug use, can trigger stronger encoding in DS in a reward-guided decision-making task and that the transition from VS to DS governed behavior observed in addiction might be due, in part, to initial loss of VS function. [ABSTRACT FROM AUTHOR]

Highlights: [•] Thoroughly outline attentional set-shifting tasks across many animal models. [•] Summarize research findings in set-shifting literature. [•] Propose new directions and necessary experiments to fill in important gaps in literature. [ABSTRACT FROM AUTHOR]

Neurons in the ventral striatum (VS) fire to cues that predict differently valued rewards. It is unclear whether this activity represents the value associated with the expected reward or the level of motivation induced by reward anticipation. To distinguish between the two, we trained rats on a task in which we varied value independently from motivation by manipulating the size of the reward expected on correct trials and the threat of punishment expected upon errors. We found that separate populations of neurons in VS encode expected value and motivation. [ABSTRACT FROM AUTHOR]

Abstract: The ability to learn a rule to guide behavior is crucial for cognition and executive function. However, in a constantly changing environment, flexibility in terms of learning and changing rules is paramount. Research suggests there may be common underlying causes for the similar rule learning impairments observed in many psychiatric disorders. One of these common anatomical manifestations involves deficits to the GABAergic system, particularly in the frontal cerebral cortical regions. Many common anti-epileptic drugs and mood stabilizers activate the GABA system with the reported adverse side effects of cognitive dysfunction. The mouse reversal/set-shifting test was used to evaluate effects in mice given topiramate, which is reported to impair attention in humans. Here we report that in mice topiramate prevents formation of the attentional set, but does not alter reversal learning. Differences in the GABA system are also found in many neuropsychiatric disorders that are more common in males, including schizophrenia and autism. Initial findings with the reversal/set-shifting task excluded female subjects. In this study, female mice tested on the standard reversal/set-shifting task showed similar reversal learning, but were not able to form the attentional set. The behavioral paradigm was modified and when presented with sufficient discrimination tasks, female mice performed the same as male mice, requiring the same number of trials to reach criterion and form the attentional set. The notable difference was that female mice had an extended latency to complete the trials for all discriminations. In summary, the reversal/set-shifting test can be used to screen for cognitive effects of potential therapeutic compounds in both male and female mice. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a complex developmental disorder that presents challenges to modern neuroscience in terms of discovering etiology and aiding in effective treatment of afflicted humans. One approach is to divide the constellation of symptoms of human neuropsychiatric disorders into discrete units for study. Multiple animal models are used to study brain ontogeny, response to psychoactive compounds, substrates of defined behaviors. Frontal cortical areas have been found to have abnormal anatomy and neurotransmitter levels in postmortem brains from schizophrenic patients. The mouse model has the advantage of rather straightforward genetic manipulation and offers numerous genetic variations within the same species. However, until recently, the behavioral analyses in the mice lagged behind the primate and rat, especially with respect to testing of frontal cortical regions. Current reports of mouse prefrontal anatomy and function advocate the mouse as a feasible animal model to study prefrontal cortical function. This review highlights the most recent developments from behavioral paradigms for testing orbital and medial prefrontal cortical function in pharmacological and genetic models of human schizophrenia. This article is part of a special issue entitled ‘Schizophrenia’. [Copyright &y& Elsevier]

Many psychiatric and neurological disorders present persistent neuroanatomical abnormalities in multiple brain regions that may reflect a common origin for a developmental disturbance. In mammals, many of the local GABAergic inhibitory interneurons arise from a single subcortical source. Perturbations in the ontogeny of the GABAergic interneurons may be reflected in the adult by interneuron deficits in both frontal cerebral cortical and striatal regions. Disrupted GABAergic circuitry has been reported in patients with schizophrenia and frontal lobe epilepsy and may contribute to their associated impairments in behavioral flexibility. The present study demonstrates that one type of behavioral flexibility, reversal learning, is dependent upon proper numbers of GABAergic interneurons. Mice with abnormal interneuron ontogeny have reduced numbers of parvalbumin-expressing GABAergic local interneurons in the orbitofrontal cortical and striatal regions and impaired reversal leaning. Using a genetic approach, both the anatomical and functional deficiencies are restored with exogenous postnatal growth factor supplementation. These results show that GABAergic local circuitry is critical for modulating behavioral flexibility and that birth defects can be corrected by replenishing crucial growth factors. [ABSTRACT FROM AUTHOR]

Abstract: Disrupted ontogeny of forebrain inhibitory interneurons leads to neurological disorders, including epilepsy. Adult mice lacking the urokinase plasminogen activator receptor (Plaur) have decreased numbers of neocortical GABAergic interneurons and spontaneous seizures, attributed to a reduction of hepatocyte growth factor/scatter factor (HGF/SF). We report that by increasing endogenous HGF/SF concentration in the postnatal Plaur null mouse brain maintains the interneuron populations in the adult, reverses the seizure behavior and stabilizes the spontaneous electroencephalogram activity. The perinatal intervention provides a pathway to reverse potential birth defects and ameliorate seizures in the adult. [Copyright &y& Elsevier]

Many neuropsychiatric diseases are associated with cognitive rigidity linked to prefrontal dysfunction. For example, schizophrenia and Parkinson's disease are associated with performance deficits on the Wisconsin Card Sorting Test, which evaluates attentional set shifting. Although the genetic underpinnings of these disorders can be reproduced in mice, there are few models for testing the functional consequences. Here, we demonstrate that an analog of the Wisconsin Card Sorting Test, developed in marmosets and recently adapted to rats, is a behavioral model of prefrontal function in mice. Systematic analysis demonstrated that formation of the attentional set in mice is dependent on the number of problem sets. We found that mice, like rats and primates, exhibit both affective and attentional sets, and these functions are disrupted by neurotoxic damage to orbitofrontal and medial prefrontal cortical areas, respectively. These data are identical to studies in rats and similar to the deficits reported after prefrontal damage in a comparable task in marmosets. These results provide a behavioral model to assess prefrontal function in mice. [ABSTRACT FROM AUTHOR]

The authors discuss a study by Steiner and Redish which demonstrate that neural signals related to regret are encoded in orbitofrontal cortex (OFC) and ventral striatum in rats when making an economic decision task. They state that the OFC and ventral striatum encode the expected outcomes during economic decision-making. They say that OFC and ventral striatum activity also represents missed opportunities at foraging task that are cleverly designed to elicit regret in rats.

Recent computational models of sign tracking (ST) and goal tracking (GT) have accounted for observations that dopamine (DA) is not necessary for all forms of learning and have provided a set of predictions to further their validity. Among these, a central prediction is that manipulating the intertrial interval (ITI) during autoshaping should change the relative ST-GT proportion as well as DA phasic responses. Here, we tested these predictions and found that lengthening the ITI increased ST, i.e., behavioral engagement with conditioned stimuli (CS) and cue-induced phasic DA release. Importantly, DA release was also present at the time of reward delivery, even after learning, and DA release was correlated with time spent in the food cup during the ITI. During conditioning with shorter ITIs, GT was prominent (i.e., engagement with food cup), and DA release responded to the CS while being absent at the time of reward delivery after learning. Hence, shorter ITIs restored the classical DA reward prediction error (RPE) pattern. These results validate the computational hypotheses, opening new perspectives on the understanding of individual differences in Pavlovian conditioning and DA signaling. [ABSTRACT FROM AUTHOR]

Background: Neural activity in basolateral amygdala has recently been shown to reflect surprise or attention as predicted by the Pearce-Kaye-Hall model (PKH)—an influential model of associative learning. Theoretically, a PKH attentional signal originates in prediction errors of the kind associated with phasic firing of dopamine neurons. This requirement for prediction errors, coupled with projections from the midbrain dopamine system into basolateral amygdala, suggests that the PKH signal in amygdala may depend on dopaminergic input. Methods: To test this, we recorded single unit activity in basolateral amygdala in rats with 6-hydroxydopamine or sham lesions of the ipsilateral midbrain region. Neurons were recorded as the rats performed a task previously used to demonstrate both dopaminergic reward prediction errors and attentional signals in basolateral amygdala neurons. Results: We found that neurons recorded in sham lesioned rats exhibited the same attention-related PKH signal observed in previous studies. By contrast, neurons recorded in rats with ipsilateral 6-hydroxydopamine lesions failed to show attentional signaling. Conclusions: These results indicate a linkage between the neural instantiations of the basolateral complex of the amygdala attentional signal and dopaminergic prediction errors. Such a linkage would have important implications for understanding both normal and aberrant learning and behavior, particularly in diseases thought to have a primary effect on dopamine systems, such as addiction and schizophrenia. [ABSTRACT FROM AUTHOR]

Animals prefer an immediate over a delayed reward, just as they prefer a large over a small reward. Exposure to psychostimulants causes long-lasting changes in structures critical for this behavior and might disrupt normal time-discounting performance. To test this hypothesis, we exposed rats to cocaine daily for 2 weeks (30 mg/kg, i.p.). Approximately 6 weeks later, we tested them on a variant of a time-discounting task, in which the rats responded to one of two locations to obtain reward while we independently manipulated the delay to reward and reward magnitude. Performance did not differ between cocaine-treated and saline-treated (control) rats when delay lengths and reward magnitudes were equal at the two locations. However, cocaine-treated rats were significantly more likely to shift their responding when we increased the delay or reward size asymmetrically. Furthermore, they were slower to respond and made more errors when forced to the side associated with the lower value. We conclude that previous exposure to cocaine makes choice behavior hypersensitive to differences in the time to and size of available rewards, consistent with a general effect of cocaine exposure on reward valuation mechanisms. [ABSTRACT FROM AUTHOR]