Deficit in working memory and abnormal behavioral tactics in dopamine transporter knockout rats during training in the 8-arm maze

Kurzina, Natalia; Aristova, Irina; Volnova, Anna; Gainetdinov, Raul R.

doi:10.1016/j.bbr.2020.112642

Cited by 27 publications

(27 citation statements)

References 60 publications

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“…Compulsive OCD-like features include reduced spontaneous alternation in Y-maze [ 15 ], increased marble hiding [ 18 ], inflexibility in dynamic reward tasks, and compulsive destroying of objects [ 17 ]. ADHD aspects are represented by hyperactivity, antihyperkinetic responses to psychostimulants [ 15 ], and impaired working memory [ 19 ]. Schizophrenia-like features include compromised sensorimotor gating and functional hyperdopaminergia [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

et al. 2022

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Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and obsessive-compulsive disorder (OCD). Investigation of DAT silencing thus provides a transdiagnostic approach towards a systems-level understanding of common underlying pathways. Using a high-field multimodal imaging approach and a highly sensitive cryogenic coil, we integrated structural, functional and metabolic investigations in tandem with behavioral assessments on a newly developed preclinical rat model, comparing DAT homozygous knockout (DAT-KO, N = 14), heterozygous knockout (N = 8) and wild-type male rats (N = 14). We identified spatially distributed structural and functional brain alterations encompassing motor, limbic and associative loops that demonstrated strong behavioral relevance and were highly consistent across imaging modalities. DAT-KO rats manifested pronounced volume loss in the dorsal striatum, negatively correlating with cerebellar volume increase. These alterations were associated with hyperlocomotion, repetitive behavior and loss of efficient functional small-world organization. Further, prefrontal and midbrain regions manifested opposite changes in functional connectivity and local network topology. These prefrontal disturbances were corroborated by elevated myo-inositol levels and increased volume. To conclude, our imaging genetics approach provides multimodal evidence for prefrontal-midbrain decoupling and striato-cerebellar neuroplastic compensation as two key features of constitutive DAT blockade, proposing them as transdiagnostic mechanisms of hyperdopaminergia. Thus, our study connects developmental DAT blockade to systems-level brain changes, underlying impaired action inhibition control and resulting in motor hyperactivity and compulsive-like features relevant for ADHD, schizophrenia and OCD.

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Section: Introductionmentioning

confidence: 99%

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

et al. 2022

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“…Investigations in DAT knockdown (DAT-KD) mice showed that the elevated DA level did not affect instrumental learning but reduced the selectivity of the stimulus control in the Pavlovian conditional training (Yin et al, 2006). In our studies, DAT-KO rats learn and perform motor tasks easier than spatial tasks (Kurzina et al, 2020).…”

Section: Discussionmentioning

confidence: 43%

“…DAT-KO rats also demonstrated an increased perseverative pattern during the spatial task. Analysis of repeated entry sequences showed that DAT-KO rats had a sustainable statistically significant tendency to increase the arms revisits (Kurzina et al, 2020). Highly perseverative patterns of locomotor activity during eight-arm radial maze task were previously reported in DAT-KO mice (Gainetdinov et al, 2002;Efimova et al, 2016).…”

Section: Discussionmentioning

confidence: 51%

“…We have found previously that DAT-KO rats are unable to form an optimal strategy for food search in comparison with WT rats. They also have a pronounced impairment in working memory (Kurzina et al, 2020). Intriguingly, in children with ADHD, the impairment of working memory components related to attention was described (Rodríguez-Martínez et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the impairment of spatial working memory was also demonstrated in DAT-KO rats. It was shown that they can learn the behavioral task in an eightarm radial maze but perform it much less effectively than the control wild-type (WT) rats (Kurzina et al, 2020). Independently developed DAT deficient rats were also hyperactive, failed to show conditioned fear responses, were unable to learn stimulus-reward associations, and showed anhedonia and impaired cognition and social behaviors (Vengeliene et al, 2017;Sukhanov et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

Kurzina

Volnova

Aristova

et al. 2021

Front. Behav. Neurosci.

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Attention deficit hyperactivity disorder (ADHD) is believed to be connected with a high level of hyperactivity caused by alterations of the control of dopaminergic transmission in the brain. The strain of hyperdopaminergic dopamine transporter knockout (DAT-KO) rats represents an optimal model for investigating ADHD-related pathological mechanisms. The goal of this work was to study the influence of the overactivated dopamine system in the brain on a motor cognitive task fulfillment. The DAT-KO rats were trained to learn an object recognition task and store it in long-term memory. We found that DAT-KO rats can learn to move an object and retrieve food from the rewarded familiar objects and not to move the non-rewarded novel objects. However, we observed that the time of task performance and the distances traveled were significantly increased in DAT-KO rats in comparison with wild-type controls. Both groups of rats explored the novel objects longer than the familiar cubes. However, unlike controls, DAT-KO rats explored novel objects significantly longer and with fewer errors, since they preferred not to move the non-rewarded novel objects. After a 3 months’ interval that followed the training period, they were able to retain the learned skills in memory and to efficiently retrieve them. The data obtained indicate that DAT-KO rats have a deficiency in learning the cognitive task, but their hyperactivity does not prevent the ability to learn a non-spatial cognitive task under the presentation of novel stimuli. The longer exploration of novel objects during training may ensure persistent learning of the task paradigm. These findings may serve as a base for developing new ADHD learning paradigms.

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A Human‐Specific De Novo Gene Promotes Cortical Expansion and Folding

et al. 2023

Advanced Science

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Newly originated de novo genes have been linked to the formation and function of the human brain. However, how a specific gene originates from ancestral noncoding DNAs and becomes involved in the preexisting network for functional outcomes remains elusive. Here, a human‐specific de novo gene, SP0535, is identified that is preferentially expressed in the ventricular zone of the human fetal brain and plays an important role in cortical development and function. In human embryonic stem cell‐derived cortical organoids, knockout of SP0535 compromises their growth and neurogenesis. In SP0535 transgenic (TG) mice, expression of SP0535 induces fetal cortex expansion and sulci and gyri‐like structure formation. The progenitors and neurons in the SP0535 TG mouse cortex tend to proliferate and differentiate in ways that are unique to humans. SP0535 TG adult mice also exhibit improved cognitive ability and working memory. Mechanistically, SP0535 interacts with the membrane protein Na+/K+ ATPase subunit alpha‐1 (ATP1A1) and releases Src from the ATP1A1‐Src complex, allowing increased level of Src phosphorylation that promotes cell proliferation. Thus, SP0535 is the first proven human‐specific de novo gene that promotes cortical expansion and folding, and can function through incorporating into an existing conserved molecular network.

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Deficit in working memory and abnormal behavioral tactics in dopamine transporter knockout rats during training in the 8-arm maze

Cited by 27 publications

References 60 publications

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

A Human‐Specific De Novo Gene Promotes Cortical Expansion and Folding

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