MK-801 impairs working memory on the Trial-Unique Nonmatch-to-Location test in mice, but this is not exclusively mediated by NMDA receptors on PV+ interneurons or forebrain pyramidal cells

Sokolenko, Elysia; Nithianantharajah, Jess; Jones, Nigel C.

doi:10.1016/j.neuropharm.2020.108103

Cited by 11 publications

(15 citation statements)

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“…Zebrafish have homologues of each of these neurotransmitter systems (Horzmann & Freeman, 2016), and results from the present study support findings from human and rodent studies of impaired working memory as a result of pharmacologically blocking glutamatergic, cholinergic and dopaminergic receptors (K. A. Ellis & Nathan, 2001;Myhrer, 2003;Shapiro & Caramanos, 1990;Sokolenko et al, 2020;van der Staay et al, 2011), thus highlighting the suitability of zebrafish as a behavioural model for assessing working memory.…”

Section: Discussionsupporting

confidence: 84%

The Free-movement pattern Y-maze: A cross-species measure of working memory and executive function

et al. 2020

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Numerous neurodegenerative and psychiatric disorders are associated with deficits in executive functions such as working memory and cognitive flexibility. Progress in developing effective treatments for disorders may benefit from targeting these cognitive impairments, the success of which is predicated on the development of animal models with validated behavioural assays. Zebrafish offer a promising model for studying complex brain disorders, but tasks assessing executive function are lacking. The Free-movement pattern (FMP) Y-maze combines aspects of the common Y-maze assay, which exploits the inherent motivation of an organism to explore an unknown environment, with analysis based on a series of sequential two-choice discriminations. We validate the task as a measure of working memory and executive function by comparing task performance parameters in adult zebrafish treated with a range of glutamatergic, cholinergic and dopaminergic drugs known to impair working memory and cognitive flexibility. We demonstrate the cross-species validity of the task by assessing performance parameters in adapted versions of the task for mice and Drosophila, and finally a virtual version in humans, and identify remarkable commonalities between vertebrate species' navigation of the maze. Together, our results demonstrate that the FMP Y-maze is a sensitive assay for assessing working memory and cognitive flexibility across species from invertebrates to humans, providing a simple and widely applicable behavioural assay with exceptional translational relevance.

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Section: Discussionsupporting

confidence: 84%

The Free-movement pattern Y-maze: A cross-species measure of working memory and executive function

et al. 2020

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“…The touchscreen TUNL task of spatial working memory is a nonmatch to location task, and is sensitive to dysfunction of hippocampus and prefrontal cortex (McAllister, Saksida, & Bussey, 2013; Talpos et al, 2010). Previous studies have shown that accuracy in this task is reduced following treatment with NMDAr antagonists in rodents, including MK-801 (Davies, Hurtubise, Greba, & Howland, 2017; Hurtubise et al, 2017; Kumar et al, 2015; Sokolenko et al, 2019, 2020). Our data here are in keeping with these previous studies, showing that MK-801 impairs working memory using variable delays between the sample and choice phases.…”

Section: Discussionmentioning

confidence: 97%

“…J. Wang, 1999), so it is perhaps not surprising that this cognitive function is disrupted when antagonists of this receptor are administered. Several labs are now trying to conclusively elucidate the specific receptor subtypes (Kumar et al, 2015), and cellular (Sokolenko et al, 2020) and electrophysiological (Korotkova et al, 2010; Sokolenko et al, 2019) substrates which mediate these effects. It is also possible to assess the effects of trial difficulty, or pattern separation, in the TUNL task.…”

Section: Discussionmentioning

confidence: 99%

“…This may be mechanistically important because the same cognitive domains, notably attention and working memory, have been closely linked with gamma frequency oscillations (Basar-Eroglu et al, 2007; Jensen, Kaiser, & Lachaux, 2007). However, recent studies have suggested that different cellular mechanisms may be responsible for these various phenotypes caused by NMDAr hypofunction (Hudson et al, 2020; Sokolenko, Nithianantharajah, & Jones, 2020), and so further research is required to understand the mechanisms of how NMDA receptor antagonists can induce specific behavioral disturbances.…”

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confidence: 99%

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Acute NMDA receptor antagonism impairs working memory performance but not attention in rats—Implications for the NMDAr hypofunction theory of schizophrenia.

Lee¹,

Buuse²,

Nithianantharajah³

et al. 2020

Behavioral Neuroscience

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Cognitive deficits in schizophrenia, which include impairments in working memory and attention, represent some of the most disabling symptoms of this complex psychiatric condition, and lack effective treatments. NMDA receptor (NMDAr) hypofunction is a strong candidate mechanism underlying schizophrenia pathophysiology, and has been modeled preclinically using acute administration of NMDAr antagonists to rodents to investigate biological mechanisms underpinning cognitive dysfunction. However, whether and how NMDAr hypofunction specifically influences all affected cognitive domains is unclear. Here we studied the effects of the NMDAr antagonist MK-801 (dizocilpine) on tasks of attention and working memory in rats using automated touchscreen chambers. Adult male Wistar rats were trained to perform the trial-unique nonmatching to location (TUNL) task of spatial working memory, or the 5-choice serial reaction time task (5CSRTT) of attention. Once trained, rats received injection of vehicle (saline) or low-dose MK-801 (0.06 mg/kg sc) 10 min prior to commencing test sessions. MK-801 significantly impaired working memory, as evidenced by reduced performance accuracy on the TUNL task (p < .0001), compared with vehicle. However, we found no significant effects on attentional processing or perseveration on the 5CSRTT. Additional measures indicated that MK-801 impaired behavioral flexibility in the TUNL task, and decreased response inhibition in both tasks. Using the automated touchscreen system to measure different cognitive functions under the same testing environment, we demonstrate that spatial working memory, response inhibition, and behavioral flexibility are more vulnerable to NMDAr hypofunction than attentional processing. This may have implications for the NMDAr hypofunction hypothesis of schizophrenia.

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“…This suggests a sensitivity of the task that may be particularly important when studying manipulations more subtle than large-scale lesions or inactivations. Further characterization demonstrated that exposure to systemic NMDAr antagonist MK-801 also significantly reduces mouse TUNL performance independent of delay length ( Sokolenko et al, 2019 , 2020 ). In the current study, we demonstrate that an updated version of the mouse TUNL protocol is also dependent on the functioning of the mPFC.…”

Section: Introductionmentioning

confidence: 99%

Decision Making in Mice During an Optimized Touchscreen Spatial Working Memory Task Sensitive to Medial Prefrontal Cortex Inactivation and NMDA Receptor Hypofunction

et al. 2022

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Working memory is a fundamental cognitive process for decision-making and is a hallmark impairment in a variety of neuropsychiatric and neurodegenerative diseases. Spatial working memory paradigms are a valuable tool to assess these processes in rodents and dissect the neurobiology underlying working memory. The trial unique non-match to location (TUNL) task is an automated touchscreen paradigm used to study spatial working memory and pattern separation processes in rodents. Here, animals must remember the spatial location of a stimulus presented on the screen over a delay period; and use this representation to respond to the novel location when the two are presented together. Because stimuli can be presented in a variety of spatial configurations, TUNL offers a trial-unique paradigm, which can aid in combating the development of unwanted mediating strategies. Here, we have optimized the TUNL protocol for mice to reduce training time and further reduce the potential development of mediating strategies. As a result, mice are able to accurately perform an enhanced trial-unique paradigm, where the locations of the sample and choice stimuli can be presented in any configuration on the screen during a single session. We also aimed to pharmacologically characterize this updated protocol, by assessing the roles of the medial prefrontal cortex (mPFC) and N-methyl-D-aspartate (NMDA) receptor (NMDAr) functioning during TUNL. Temporary inactivation of the medial prefrontal cortex (mPFC) was accomplished by directly infusing a mixture of GABA agonists muscimol and baclofen into the mPFC. We found that mPFC inactivation significantly impaired TUNL performance in a delay-dependent manner. In addition, mPFC inactivation significantly increased the susceptibility of mice to proactive interference. Mice were then challenged with acute systemic injections of the NMDAr antagonist ketamine, which resulted in a dose-dependent, delay-dependent working memory impairment. Together, we describe an optimized automated touchscreen task of working memory, which is dependent on the intact functioning of the mPFC and sensitive to acute NMDAr hypofunction. With the vast genetic toolbox available for modeling disease and probing neural circuit functioning in mice, the TUNL task offers a valuable paradigm to pair with these technologies to further investigate the processes underlying spatial working memory.

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MK-801 impairs working memory on the Trial-Unique Nonmatch-to-Location test in mice, but this is not exclusively mediated by NMDA receptors on PV+ interneurons or forebrain pyramidal cells

Cited by 11 publications

References 71 publications

The Free-movement pattern Y-maze: A cross-species measure of working memory and executive function

The Free-movement pattern Y-maze: A cross-species measure of working memory and executive function

Acute NMDA receptor antagonism impairs working memory performance but not attention in rats—Implications for the NMDAr hypofunction theory of schizophrenia.

Decision Making in Mice During an Optimized Touchscreen Spatial Working Memory Task Sensitive to Medial Prefrontal Cortex Inactivation and NMDA Receptor Hypofunction

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