Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice

Izquierdo, Alicia; Wiedholz, Lisa M.; Millstein, Rachel; Yang, Rebecca; Bussey, Timothy J.; Saksida, Lisa M.; Holmes, Andrew

doi:10.1016/j.bbr.2006.03.029

Cited by 112 publications

(106 citation statements)

References 48 publications

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“…There are few D1 agonists or antagonists with sufficient selectivity for use in human subjects, and ours is the first study to examine the effects of a D1 antagonist on reversal learning in the non-human primate. We find that SCH23390 failed to impair performance; however, in mice, the D1-like receptor agonist SKF81297 was reported to impair reversal learning, using an automated touch-screen procedure (Izquierdo et al, 2006). In essence, it is possible that subphysiological activation of D1-like receptors by DA does not affect reversal learning, whereas supra-normal stimulation does.…”

Section: -Like Receptor Mechanisms In Executive Functionmentioning

confidence: 75%

Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys

Lee

Groman

London

et al. 2007

Neuropsychopharmacol

140

123

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Converging evidence supports a role for mesocorticolimbic dopaminergic systems in a subject's ability to shift behavior in response to changing stimulus-reward contingencies. To characterize the dopaminergic mechanisms involved in this function, we quantified the effects of subtype-specific dopamine (DA) receptor antagonists on acquisition, retention, and reversal of a visual discrimination task in nonhuman primates (Chlorocebus aethiops sabaeus). We used a modified Wisconsin General Test Apparatus that was equipped with three food boxes, each fitted with a lid bearing a unique visual cue; one of the cues concealed a food reward, whereas the other two concealed an empty box. The monkeys were trained first to acquire a novel discrimination (eg A + , B À , C À ) in a single session, before experiencing either a reversal of the discrimination (eg A À , B + , C À ) or the acquisition of a completely new discrimination (eg D + , E À , F À ), on the following day. Systemic administration of the D 2 /D 3 receptor antagonist raclopride (0.001-0.03 mg/kg) failed to significantly affect the performance of reversal learning when reversal sessions were run without a retention session. But, raclopride (0.03 mg/kg) significantly impaired performance under the reversal condition when reversal sessions were run right after a retention session; however, it did not affect acquisition of a novel visual discrimination. Specifically, raclopride significantly increased the number of reversal errors made before reaching the performance criterion in the reversal, but not in new learning sessions. In contrast, the D 1 /D 5 receptor antagonist SCH 23390 did not significantly modulate acquisition of a novel discrimination or reversal learning at doses (0.001-0.03 mg/kg, i.m.) that did not suppress behavior generally. In addition, none of the drug treatments affected retention of a previously learned discrimination. The results strongly suggest that D 2 /D 3 receptors, but not D 1 /D 5 receptors, selectively mediate reversal learning, without affecting the capacity to learn a new stimulus-reward association. These data support the hypothesis that phasic DA release, acting through D 2 -like receptors, mediates behavioral flexibility.

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Section: -Like Receptor Mechanisms In Executive Functionmentioning

confidence: 75%

Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys

Lee

Groman

London

et al. 2007

Neuropsychopharmacol

140

123

View full text Add to dashboard Cite

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“…Mice were trained to discriminate between 2 novel stimuli presented in a spatially pseudorandomized manner over 30-trial sessions, with the correct vs incorrect designation switched for reversal training (64,65).…”

Section: Methodsmentioning

confidence: 99%

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

DePoy

Daut

Brigman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

178

193

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Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptordependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism.lcoholism is a highly prevalent disorder with a massive and growing impact on public health (1). The course of alcoholism and other chronic drug addictions has been conceptualized as involving the progressive deterioration of executive control of behavior and the corresponding emergence of compulsive drug seeking (2, 3). At the neural systems level, this shift is associated with a "devolution" away from prefrontal cortical (PFC) regulation of behavior in favor of greater control by subcortical regions including the dorsal striatum (DS) (2, 4).Consistent with this scheme, alcohol-dependent individuals show impairments on PFC-mediated cognitive measures, such as impulse control and reversal learning (5, 6), but exaggerated neural responses in the DS when, for example, presented with alcohol-associated cues (7-9). Along similar lines, rodents chronically exposed to ethanol (EtOH) exhibit deficits in PFC-and hippocampal-mediated tasks, including spatial and reversal learning, set-shifting, and fear extinction, that in some cases are linked to cortical cell death (10-17).These observations are consistent with an EtOH-induced impairment in various PFC-related cognitive behaviors but do not address the possibility of concomitant changes in processes mediated by the DS. In this context, recent studies in rats have found that ch...

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“…These measures are known to be dependent on the prefrontal cortex across multiple species including humans, non-human primates and rats (Robbins, 2000;Brown and Bowman, 2002;Royall et al 2002;Miller et al 2002), and while studies in mice have thus been less expansive, the literature available to date suggests at least a functional homology to rats in equivalent cognitive tests (Lidow et al 2003;Greco et al 2005;Izquierdo et al 2006). In addition to these prefrontal-related tasks, two measures of hippocampal-dependent learning were included to help clarify previous conflicting findings.…”

Section: Introductionmentioning

confidence: 99%

Assessment of cognitive function in the heterozygous reeler mouse

et al. 2006

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RATIONALE-The heterozygous reeler mouse has been proposed as a genetic mouse model of schizophrenia, based on several neuroanatomical and behavioral similarities between these mice and patients with schizophrenia. However, the effect of reelin haploinsufficiency on one of the cardinal symptoms of schizophrenia, the impairment of prefrontal cortex-dependent cognitive function, has yet to be determined.OBJECTIVE-Here, we investigated multiple aspects of cognitive function in heterozygous reeler mice that are known to be impaired in schizophrenic patients.METHODS-Heterozygous reeler mice were assessed for (1) cognitive flexibility in an instrumental reversal learning task; (2) impulsivity in an inhibitory control task; (3) attentional function in a threechoice serial reaction time task; and (4) working memory in a delayed matching-to-position task.RESULTS-No differences were found between heterozygous reeler mice and wild-type littermate controls in any prefrontal-related cognitive measures. However, heterozygous reeler mice showed deficits in the acquisition of two operant tasks, consistent with a role for reelin in certain forms of learning.CONCLUSIONS-These findings suggest that heterozygous reeler mice may not be an appropriate model for the core prefrontal-dependent cognitive deficits observed in schizophrenia, but may model more general learning deficits that are associated with many psychiatric disorders.

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Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice

Cited by 112 publications

References 48 publications

Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys

Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

Assessment of cognitive function in the heterozygous reeler mouse

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