Ketamine-Induced Alteration of Working Memory Utility during Oculomotor Foraging Task in Monkeys

Sawagashira, Ryo; Tanaka, Masaki

doi:10.1523/eneuro.0403-20.2021

Cited by 8 publications

(14 citation statements)

References 89 publications

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“…It indicates that ketamine impairs the retrieval of well-learned abstract rules in the AVM task, which is in line with a previous study showing that anesthetic ketamine impaired the retrieval of information from post-training memory components (Boultadakis & Pitsikas, 2011). The ketamine-induced impairments in WM have been reported in many previous studies in rodents (Moosavi et al, 2012, Mathews et al, 2018, Pitsikas & Carli, 2020, monkeys (Sawagashira & Tanaka, 2021, Roussy et al, 2021, Condy et al, 2005, Skoblenick & Everling, 2012, Blackman et al, 2013 and humans (Ahn et al, 2003, Honey et al, 2004, Koychev et al, 2017. In this study, we found that the low doses of ketamine consistently reduced the correct percentage over 1 h in both AVM and AVM+WM tasks.…”

Section: Discussionsupporting

confidence: 91%

Low-Dose Ketamine-Induced Deficits in Arbitrary Visuomotor Mapping in Monkeys

Zhao

Nie²,

Jiang

et al. 2023

eNeuro

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Ketamine, an NMDA antagonist, is widely used in clinical settings, particularly for its promising role as a rapid antidepressant. Recently, low-dose ketamine has gained attention due to its potential therapeutic benefits. However, the effects of low-dose ketamine on brain function, particularly higher cognitive functions of primate brains, are not fully understood. In this study, we used two macaque monkeys as subjects and found that acute low-dose ketamine administration significantly impairs the ability for arbitrary visuomotor mapping, a form of associative learning essential for flexible behaviors, including executions of learned stimuli-response contingency or learning of new contingencies. We conducted in-depth analyses and identified intrinsic characteristics of these ketamine-induced functional deficits, including lowered accuracy, prolonged time for planning and movement execution, increased tendency to make errors when visual cues are changed from trial to trial, and stronger impact on the associative learning and another key higher cognitive function, working memory. Our results shed new light on how associative learning relies on the NMDA-mediated synaptic transmission of the brain and contribute to a better understanding of the potential acute side effects of low-dose ketamine on cognition, which can help facilitate its safe usage in medical practice.Significance StatementThis study found that acute low-dose ketamine significantly impairs the ability of arbitrary visual motor mapping, a critical form of associative learning for flexible behavior, including stimulus-response contingency learning or learning of new contingencies. We conducted a thorough analysis and identified intrinsic features of ketamine-induced functional deficits, including decreased accuracy, prolonged planning and motor execution time, increased error tendency when visual cues changed from trial to trial, and stronger impact on associative learning and another key higher-order cognitive function, working memory. These findings contribute to a better understanding of the potential acute cognitive side effects of low-dose ketamine and promote its safe use in medical practice.

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Section: Discussionsupporting

confidence: 91%

Low-Dose Ketamine-Induced Deficits in Arbitrary Visuomotor Mapping in Monkeys

Zhao

Nie²,

Jiang

et al. 2023

eNeuro

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“…We injected a subanesthetic dose of ketamine 0.5 mg/kg (Daiichi-Sankyo Co., Tokyo, Japan) intramuscularly for transient and reversible manipulation of schizophrenia symptoms. The dosage of ketamine was determined based on previous pharmacological studies in monkeys ( Pouget et al, 2010 ; Sawagashira and Tanaka, 2021 ) and marmosets ( Selvanayagam et al, 2021 ), so that marmosets could perform the free-viewing task. To avoid the development of the drug tolerance and cumulative effect, injections of ketamine were performed once a week.…”

Section: Methodsmentioning

confidence: 99%

“…Early human studies showed that high doses of ketamine strongly affected characteristics of eye movements ( Radant et al, 1998 ), and it was subsequently shown that even low doses reproduce some of the abnormalities seen in subjects with schizophrenia, such as reduced eye acceleration during initiation, reduced closed loop gain ( Weiler et al, 2000 ). Injections of subanesthetic dose of ketamine 0.3–0.5 mg/kg in non-human primates reproduce various sensory and cognitive dysfunctions of schizophrenia, such as dysfunction of the visual working memory ( Sawagashira and Tanaka, 2021 ) and impaired visual contextual integration ( Schielke and Krekelberg, 2021 ) in macaques, deficits in executive function in marmosets ( Kotani et al, 2016 ). Recently, it has been reported in marmosets that ketamine also induced disruption of scan paths, with limited effects on saccade motor control during free-viewing of face images ( Selvanayagam et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The effect of ketamine on eye movement characteristics during free-viewing of natural images in common marmosets

Polyakova

Iwase²,

Hashimoto³

et al. 2022

Front. Neurosci.

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Various eye movement abnormalities and impairments in visual information processing have been reported in patients with schizophrenia. Therefore, dysfunction of saccadic eye movements is a potential biological marker for schizophrenia. In the present study, we used a pharmacological model of schizophrenia symptoms in marmosets and compared the eye movement characteristics of marmosets during free-viewing, using an image set identical to those used for human studies. It contains natural and complex images that were randomly presented for 8 s. As a pharmacological model of schizophrenia symptoms, a subanesthetic dose of ketamine was injected intramuscularly for transient and reversible manipulation. Eye movements were recorded and compared under a ketamine condition and a saline condition as a control. The results showed that ketamine affected eye movement characteristics during free-viewing. Saccades amplitude and scanpath length were significantly reduced in the ketamine condition. In addition, the duration of saccades was longer under the ketamine condition than under the saline condition. A similar tendency was observed for the duration of fixations. The number of saccades and fixations tended to decrease in the ketamine condition. The peak saccades velocity also decreased after ketamine injection whereas there was no difference in the main sequence relationship between saccades amplitude and peak velocity. These results suggest that ketamine affected visual exploration but did not affect the oculomotor aspect of saccades in marmosets, consistent with studies in patients with schizophrenia. Therefore, we conclude that the subanesthetic dose of ketamine is a promising pharmacological model of schizophrenia symptoms in common marmosets and can be used in combination with free-viewing paradigms to establish “translatable markers” for schizophrenia in primates.

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“…In this previous study MIA increased the variability of the starting phase of precession; however, in both cases the consequence would be a decrease in the accuracy of sequential ordering during the theta sequences that may underlie aspects of sequential memory. While impairments in temporal processing and sequential ordering are well documented in individuals with schizophrenia, their first-degree relatives, and other at-risk individuals ( Ciullo et al, 2016 , 2018 ; Liu et al, 2020 ; Nour et al, 2021 ; Thoenes and Oberfeld, 2017 ), the effects of ketamine on such processes are less well investigated ( Brulé et al, 2021 ; Coull et al, 2011 ; Sawagashira and Tanaka, 2021 ). Ketamine is, however, known to induce several symptoms of schizophrenia in humans that could potentially involve a sequential component ( Malhotra et al, 1996 ; Morgan et al, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal phase precession is preserved under ketamine, but the range of precession across a theta cycle is reduced

Speers,

Sissons,

Cleland

et al. 2023

J Psychopharmacol

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Background: Hippocampal phase precession, which depends on the precise spike timing of place cells relative to local theta oscillations, has been proposed to underlie sequential memory. N-methyl-D-asparate (NMDA) receptor antagonists such as ketamine disrupt memory and also reproduce several schizophrenia-like symptoms, including spatial memory impairments and disorganized cognition. It is possible that these impairments result from disruptions to phase precession. Aims/methods: We used an ABA design to test whether an acute, subanesthetic dose (7.5 mg/kg) of ketamine disrupted phase precession in CA1 of male rats as they navigated around a rectangular track for a food reward. Results/outcomes: Ketamine did not affect the ability of CA1 place cells to precess despite changes to place cell firing rates, local field potential properties and locomotor speed. However, ketamine reduced the range of phase precession that occurred across a theta cycle. Conclusion: Phase precession is largely robust to acute NMDA receptor antagonism by ketamine, but the reduced range of precession could have important implications for learning and memory.

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Ketamine-Induced Alteration of Working Memory Utility during Oculomotor Foraging Task in Monkeys

Cited by 8 publications

References 89 publications

Low-Dose Ketamine-Induced Deficits in Arbitrary Visuomotor Mapping in Monkeys

Low-Dose Ketamine-Induced Deficits in Arbitrary Visuomotor Mapping in Monkeys

The effect of ketamine on eye movement characteristics during free-viewing of natural images in common marmosets

Hippocampal phase precession is preserved under ketamine, but the range of precession across a theta cycle is reduced

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