Reversal learning and attentional set-shifting in mice

Bissonette, Gregory B.; Powell, Elizabeth M.

doi:10.1016/j.neuropharm.2011.03.011

Cited by 95 publications

(87 citation statements)

References 99 publications

(145 reference statements)

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“…We know OFC is critical for reversal learning (19,24,30,38–40), and Plaur mice have reversal deficits that we have hypothesized are due to disrupted encoding of decisions in OFC (17). Thus, we predict that activity in OFC should be correlated with decision-making, specifically during reversal decisions, with activity corresponding to task difficulty.…”

Section: Resultsmentioning

confidence: 94%

Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Bissonette

Schoenbaum

Roesch

et al. 2015

Biological Psychiatry

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Background Cerebral cortical GABAergic interneuron dysfunction is hypothesized to lead to cognitive deficits co-morbid 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 (OFC) during reversal learning by recording single unit activity from 180 control and 224 Plaur mouse neurons during a serial reversal task. Neural activity was analysed 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 behaviour, and reward encoding was downscaled. In addition, Plaur mice showed a significant reduction in the number of neurons that encoded expected outcomes across tasks phases during the decision period. Conclusions These data indicate that parvalbumin interneurons are necessary for the representation of outcomes in OFC. 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 accompanies the loss of these GABAergic interneurons in human neuropsychiatric disorders, such as autism, epilepsy, and schizophrenia.

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Section: Resultsmentioning

confidence: 94%

Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Bissonette

Schoenbaum

Roesch

et al. 2015

Biological Psychiatry

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“…A paradigm equivalent to the Wisconsin Card Sorting Test has been adapted to mice and permitted the evaluation of the prefrontal cortex function in mice [74]. These tests can finely decipher the brain areas and neurotransmitters involved in reversal and attentional set-shifting abilities, as reviewed by Bissonette and Powell [75], and could be highly useful in bvFTD modeling.…”

Section: The Ftd Symptoms and Corresponding Tests In Micementioning

confidence: 99%

Evaluating Behavior in Mouse Models of the Behavioral Variant of Frontotemporal Dementia: Which Test for Which Symptom?

Vernay

Sellal²,

Frydman³

2015

Neurodegener Dis

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The behavioral variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease affecting people in their early sixties, characterized by dramatic changes in individual and social behavior. Despite the heterogeneity in the presentation of the clinical symptoms of bvFTD, some characteristic changes can be highlighted. Social disinhibition, changes in food preferences as well as loss of empathy and apathy are commonly described. This is accompanied by a characteristic and dramatic atrophy of the prefrontal cortex with the accumulation of protein aggregates in the neurons in this area. Several causative mutations in different genes have been discovered, allowing the development of transgenic animal models, especially mouse models. In mice, attention has been focused on the histopathological aspects of the pathology, but now studies are taking interest in assessing the behavioral phenotype of FTD models. Finding the right test corresponding to human symptoms is quite challenging, especially since the frontal cortex is much less developed in mice than in humans. Although challenging, the ability to detect relevant prefrontal cortex impairments in mice is crucial for therapeutic approaches. In this review, we aim to present the approaches that have been used to model the behavioral symptoms of FTD and to explore other relevant approaches to assess behavior involving the prefrontal cortex, as well as the deficits associated with FTD.

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“…The basic loop helix (bHLH) transcription factors SHARP1 (DEC2/BHLHE41) and SHARP2 (DEC1/BHLHE40) are modulators of the circadian system and of the core clock factors circadian locomotor output cycles kaput (CLOCK) and NPAS2 and have been implicated in the control of homeostatic sleep, neuronal plasticity, and working memory (20)(21)(22)(23)(24). In this study, we analyzed wild type (WT), Sharp1 and -2 single (S1 −/− and S2 −/− ) and double knockout mice and observed exclusively in double mutants strongly enhanced cognitive performance in remote fear memory and reversal learning tasks that have been associated with the ACC and the orbitofrontal cortex as parts of the prefrontal cortex in rodents (1,25,26). In parallel, insulin-related growth factor 2 (IGF2) and MAPK signaling was elevated in the ACx of S1/2 −/− mice and adeno-associated virus type 2 (AAV2)-mediated expression of Igf2 and IGF binding protein 5 (Igfbp5) in the ACC caused improved and impaired remote fear memory formation in wild-type mice, respectively.…”

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confidence: 99%

Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex

Shahmoradi

Radyushkin

Rossner

2015

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

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The bHLH transcription factors SHARP1 and SHARP2 are partially redundant modulators of the circadian system. SHARP1/DEC2 has been shown to control sleep length in humans and sleep architecture is also altered in double mutant mice (S1/2 −/− ). Because of the importance of sleep for memory consolidation, we investigated the role of SHARP1 and SHARP2 in cognitive processing. S1/2 −/− mice show enhanced cortex (Cx)-dependent remote fear memory formation as well as improved reversal learning, but do not display alterations in hippocampus (Hi)-dependent recent fear memory formation. SHARP1 and SHARP2 single null mutants do not display any cognitive phenotype supporting functional redundancy of both factors. Molecular and biochemical analyses revealed elevated insulin-related growth factor 2 (IGF2) signaling and increased phosphorylation of MAPK and S6 in the Cx but not the Hi of S1/2 −/− mice. No changes were detected in single mutants. Moreover, adenoassociated virus type 2-mediated IGF2 overexpression in the anterior cingulate cortex enhanced remote fear memory formation and the analysis of forebrain-specific double null mutants of the Insulin and IGF1 receptors revealed their essential function for memory formation. Impaired fear memory formation in aged S1/2 −/− mice indicates that elevated IGF2 signaling in the long term, however, has a negative impact on cognitive processing. In summary, we conclude that the bHLH transcription factors SHARP1 and SHARP2 are involved in cognitive processing by controlling Igf2 expression and associated signaling cascades. Our analyses provide evidence that the control of sleep and memory consolidation may share common molecular mechanisms.cortex | memory consolidation | insulin-like signaling | aging | MAPK signaling T he hippocampus (Hi) and anterior cortex (ACx) have been associated with different aspects of cognitive processes controlling, for example, recent and remote long-term fear memory formation, respectively (1). Current concepts suggest that longterm fear memory consolidation involves a gradual transfer of memory traces from hippocampal networks into stable cortical modules integrated by the anterior cingulate cortex (ACC) (2). Long-term memory consolidation is considered a highly dynamic process involving different cortical areas and is thought to be shaped already during encoding, storage, but also reconsolidation processes (3, 4). The gradual transfer of memory traces from the Hi to cortical structures is thought to be dependent on different aspects of sleep (5) such as the sleep-dependent memory replay between the Hi and the cortex (6). Thus, the controls of sleep and memory consolidation appear to be interconnected processes. It is well known that many aspects of sleep-wakerelated behavior are controlled by clock genes and emerging evidence suggests an involvement of the circadian system in cognitive processes (7). Several signaling pathways have been studied in the context of hippocampal learning (8-14), among those, the circadian timing of mitogen-activated prot...

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Reversal learning and attentional set-shifting in mice

Cited by 95 publications

References 99 publications

Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Evaluating Behavior in Mouse Models of the Behavioral Variant of Frontotemporal Dementia: Which Test for Which Symptom?

Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex

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