Animal neuropsychology: Validation of the Intra-Dimensional Extra-Dimensional set shifting task for mice

Garner, Joseph P.; Thogerson, C. M.; Würbel, Hanno; Murray, James D.; Mench, Joy A.

doi:10.1016/j.bbr.2006.06.002

Cited by 131 publications

(158 citation statements)

References 41 publications

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“…As illustrated in Figures 1 and 2, saline-treated animals made significantly more errors to reach the criterion level of six consecutive correct trials in the EDS than in the IDS (po0.001), demonstrating that they had formed an attentional set towards the relevant dimension before the EDS stage (Birrell and Brown, 2000;Garner et al, 2006 Performance of both saline-(white bars) and MAM-treated rats (gray bars) in the attentional set-shifting task (N ¼ 8 per group). Graph bars represent the mean ± SEM of the number of errors made to reach the criterion of six correct consecutive trials in each test discrimination (a) and the average number of perseverative vs regressive errors made within the first two reversal learning discriminations (b).…”

Section: Resultsmentioning

confidence: 90%

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

Gastambide

Côtel

Gilmour

et al. 2011

Neuropsychopharmacol

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Based on the glutamatergic hypothesis of schizophrenia we assessed the effects of a novel mGlu5 positive allosteric modulator, LSN2463359 [N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide] on deficits in cognitive flexibility in two distinct rodent models of schizophrenia, the neurodevelopmental MAM E17 model and the acute PCP model. Cognitive flexibility was measured with the intra-dimensional and extra-dimensional set-shifting and reversal learning digging paradigm. Regional effects of MAM on the expression of parvalbumin-positive cells (PV) and mGlu5 receptors were also examined, to further characterize the model. Results showed that LSN2463359 selectively attenuated reversal learning deficits in the MAM but not acute PCP model. Whilst both models led to deficits in reversal learning and extra-dimensional set-shifting, the reversal impairments were qualitatively distinct, with MAM increasing perseverative responding, whereas the PCP deficit was mainly due to the inability of rats to maintain reinforced choice behavior. Reduction of PV and mGlu5 expression was found in the MAM model in several regions of importance in schizophrenia, such as the orbitofrontal and medial prefrontal cortex, which also mediate reversal learning and extra-dimensional set-shifting. The present findings confirm that the positive modulation of mGlu5 receptors may have beneficial effects in the treatment of certain aspects of cognitive impairment associated with schizophrenia. This study also illustrates the importance of studying putative cognitive enhancing drug effects in a number of models which may have implications for the future development of the compound.

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Section: Resultsmentioning

confidence: 90%

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

Gastambide

Côtel

Gilmour

et al. 2011

Neuropsychopharmacol

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“…Testing: we used the same experimental protocol adopted by Garner et al (2006). Briefly, a trial was initiated by raising the sliding wall to give the mouse access to the two digging bowls, only one of which was baited.…”

Section: Attentional Set-shifting Testmentioning

confidence: 99%

“…For the reversal, the exemplars and the relevant dimension were unchanged: the mouse had to learn that the previously correct stimulus was now incorrect. Stimulus presentation and counterbalancing was identical to the one used by Garner et al (2006). A stage was considered complete when the mouse achieved a criterion of 8 correct trials out of 10 (Garner et al, 2006).…”

Section: Dimensionmentioning

confidence: 99%

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Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

Macrı̀

Biamonte

Romano

et al. 2010

Psychoneuroendocrinology

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Summary According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly explain the skewed sex ratio found in Autism Spectrum Disorders (ASD). Correcting this testosterone imbalance by increasing estrogen levels may mitigate the abnormal phenotype. Accordingly, while control heterozygous reeler (rl/+) male mice -a putative model of neuroanatomical and behavioral endophenotypes in ASD -show a decreased number of Purkinje cells (PC) compared to control wild-type (+/+) littermates, neonatal estradiol administration has been shown to correct this deficit in the short-term (i.e. on postnatal day 15). Here, we further investigated the neuroanatomical and behavioral abnormalities of rl/+ male mice and the potential compensatory effects of neonatal treatment with estradiol. In a longitudinal study, we observed that: i) infant rl/+ mice showed reduced motivation for social stimuli; ii) adult rl/+ male mice showed reduced cognitive flexibility; iii) the number of amygdalar parvalbuminpositive GABAergic interneurons were remarkably reduced in rl/+ mice; iv) neonatal estradiol administration into the cisterna magna reverted the abnormal profile both at the behavioral and at the neuroanatomical level in the amygdala but did not compensate for the cerebellar abnormalities in adulthood. This study supports the view that an increased excitation-toinhibition ratio in the cerebellum and in the amygdala during a critical window of development could be crucial to the social and cognitive phenotype of male rl/+ mice, and that acute estradiol treatment during this critical window may mitigate symptoms' severity. #

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“…Autism also shows us how to resolve this problem-sometimes we may have to pick different species for different components of the diagnosis. Developmental delay and repetitive behaviors can be meaningfully modeled in mice 83 , but we will have to turn to species that do possess complex social cognition in order to model the social dimension of the disorder 55 .…”

Section: Focus On Reproducibilitymentioning

confidence: 99%

Introducing Therioepistemology: the study of how knowledge is gained from animal research

et al. 2017

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We are honored to write the opening article of this focus issue of Lab Animal. This focus issue could not occur at a more important time for biomedical research and the use of animals in science in general. The progressive worsening of success rates in human trials (currently 1 in 9 drugs entering human trials will succeed) 1-4 , combined with the explosion of interest in the reproducibility crisis 5-8 and the recognition that most drugs fail in human trials due to insufficient efficacy 1,2,4 , has led to a growing suspicion that the failure of translation from animal work to human outcomes may in some way reflect issues in animal research itself 5-19 -after all, every drug that fails in humans "worked" in an animal model. Indeed pharmaceutical companies continue to disinvest in internal animal R&D, a trend begun in the last decade, passing on the cost and risk to academia and startups 5,20 . Even this approach is not foolproof as pharmaceutical companies often cannot replicate the results of published work from academia 5,8,13 . Accordingly, there is a growing trend to focus on human, not animal, work for basic discovery 17 .Discarding animal research entirely is not the answer. When properly used, animal models have incredible value, not least the ability to follow biomarkers from birth to disease onset in a year or less (in the case of mice), which is impossible in humans 17,18 . There are patterns and principles that can help us identify models and results that are more or less likely to translate, and there are also easily realized, simple changes in the execution of animal work that will inherently improve translation [16][17][18] . This isn't a new concept; looking back over the last 10-15 years we can see many authors have been candid about the merits, strengths, weaknesses, reproducibility, and translatability of various animal models 1,2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . Our goal with this article is to unite the common themes in this broader emerging literature and this special issue.Thus, the central point is that we (i.e., refs. 17,18,26-28,39,41) do not represent a voice in the wilderness, but one voice in a chorus and that this emerging literature 1,2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]42,43 reflects a nascent discipline which can be codified as the study of how knowledge is gained from animal research. We propose the title "Therioepistemology" This focus issue of Lab Animal coincides with a tipping point in biomedical research. For the first time, the scale of the reproducibility and translatability crisis is widely understood beyond the small cadre of researchers who have been studying it and the pharmaceutical and biotech companies who have been living it. Here we argue that an emerging literature, including the papers in this focus issue, has begun to congeal around a set of recurring themes, which themselves represent a paradigm shift. This paradigm shift can be c...

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Animal neuropsychology: Validation of the Intra-Dimensional Extra-Dimensional set shifting task for mice

Cited by 131 publications

References 41 publications

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

Introducing Therioepistemology: the study of how knowledge is gained from animal research

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