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Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition)

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (15 December 2024) | Viewed by 7120

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Prof. Dr. Marc Ekker

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Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada
Interests: brain development and regeneration; development of dopamine and GABA neurons; control of gene expression; transgenic models; evolution of developmental mechanisms; zebrafish models of disease including Parkinson's disease
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Dr. Sandesh Panthi

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Department of Zoology, Brain Health Research Centre, University of Otago, Dunedin 9016, New Zealand
Interests: epilepsy; seizures; chemogenetics; animal model of neurological disorder; animal model of epilepsy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Animal models are powerful tools for investigating the key principles and underlying mechanisms of diseases and disorders. The use of animal models has allowed us to conduct various types of experiments and interrogate the mechanisms underlying diseases and disorders in manners that are unfeasible and unthinkable to apply to human patients. The usefulness of any animal model depends on various parameters such as predictive validity, symptoms, similarity to human conditions, and tractability. To date, various mammalian and non-mammalian animal models of neurological disorders have been established and characterized. They reflect the genetics, behavioral, and/or electrophysiological phenotypes of human patients.

There are various neurological disorders but, in this issue, we are mainly focusing on five prominent disorders: Parkinson’s disease, Alzheimer’s disease, epilepsy, Huntington’s disease, and schizophrenia. This Special Issue will provide experimental evidence, updated views, and new treatment strategies regarding these disorders. Critical discussions on the advantages and limitations of animal models used to mirror these neurological disorders are also welcome. This Special Issue will cover original articles and reviews on every aspect of mammalian and non-mammalian animal models of Parkinson’s disease, Alzheimer’s disease, epilepsy, Huntington’s disease, and schizophrenia. This may include (but is not limited to) genetic, pharmacological, chemogenetic (such as DREADDs), and optogenetic models of neurological disorders. In this issue, we also encourage authors to submit work on rare neurological and developmental disorders which affect the brain, spinal cord, or peripheral nerves.

Moreover, we encourage submissions on novel tools and methods related to animal models of the abovementioned neurological disorders as well. Tools and methods will only be considered if they are novel, well documented, discussed, and have the potential to be useful to the scientific world.

Prof. Dr. Marc Ekker
Dr. Sandesh Panthi
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

animal model of neurological disorders
Parkinson’s disease
Alzheimer’s disease
epilepsy
seizures
Huntington’s disease
schizophrenia

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Published Papers (7 papers)

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Research

13 pages, 14711 KiB

Open AccessArticle

D-Serine May Ameliorate Hippocampal Synaptic Plasticity Impairment Induced by Patients’ Anti-N-methyl-D-aspartate Receptor Antibodies in Mice

by Hanyu Luo, Xiaoyue Yang, Jiaxin Yang, Ziyao Han, Dishu Huang, Jianxiong Gui, Ran Ding, Hengsheng Chen, Li Cheng, Jiannan Ma and Li Jiang

Biomedicines 2024, 12(12), 2882; https://doi.org/10.3390/biomedicines12122882 - 18 Dec 2024

Viewed by 260

Abstract

Objective: To establish a mouse model of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and assess the potential therapeutic benefits of D-serine supplementation in mitigating synaptic plasticity impairments induced by anti-NMDAR antibodies. Methods: Anti-NMDAR antibodies were purified from cerebrospinal fluid (CSF) samples of patients diagnosed with anti-NMDAR encephalitis and verified using a cell-based assay. CSF from patients with non-inflammatory neurological diseases served as the control. These antibodies were then injected intraventricularly into C57BL/6 mice. Forty-eight hours following the injection, mice were administered either D-serine (500 mg/kg) or sterile saline intraperitoneally for three consecutive days. Subsequent analyses included Western blotting, immunofluorescence, electrophysiological studies, and a series of behavioral tests to assess pathological changes caused by anti-NMDAR antibodies. Results: Mice injected with anti-NMDAR antibodies exhibited a significant reduction in hippocampal long-term potentiation compared to controls, which was notably ameliorated by D-serine treatment. Additionally, these mice displayed decreased levels of hippocampal membrane NMDAR1 protein and postsynaptic NMDAR1 density. However, D-serine administration did not significantly alter these conditions. Notably, no significant behavioral differences were observed between mice injected with anti-NMDAR antibodies and controls in open fields, elevated plus maze, novel object recognition, or Morris water maze tests. Conclusions: Our findings indicate that exogenous D-serine can improve hippocampal plasticity impairments caused by anti-NMDAR antibodies but does not reverse the decreased expression of NMDAR. Furthermore, a single intraventricular injection of patients’ antibodies was insufficient to induce anti-NMDAR encephalitis-related behaviors in mice. Full article

(This article belongs to the Special Issue Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition))

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17 pages, 2903 KiB

Open AccessArticle

Exploring the Impact of Semaglutide on Cognitive Function and Anxiety-Related Behaviors in a Murine Model of Alzheimer’s Disease

by Ianis Kevyn Stefan Boboc, Petrica-Daniel Dumitrelea, Andreea Daniela Meca, Liliana Mititelu-Tartau and Maria Bogdan

Biomedicines 2024, 12(12), 2689; https://doi.org/10.3390/biomedicines12122689 - 25 Nov 2024

Viewed by 513

Abstract

Background: Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive decline and behavioral disturbances, with an increasing incidence as the global population ages. This study investigates the effects of semaglutide (SEM), a glucagon-like peptide-1 analog, on cognitive function and anxiety-like behavior in a transgenic murine model of AD. Methods: 20 mice were randomly distributed into the following groups (n = 5): (WT + VEH) group: C57BL/6J + saline, (WT + SEM) group: C57BL/6J + semaglutide, (AD + VEH) group: AD + saline, (AD + SEM) group: AD + semaglutide. The animals underwent a four-week treatment, during which we monitored blood glucose levels, body weight, and responses in an open field test, novel object recognition test, social chamber test, and 0-maze test. Results: Post-treatment, SEM significantly reduced blood glucose levels in AD mice, aligning them with those of wild-type controls. Cognitive assessments indicated an improvement in the investigation index for SEM-treated mice compared to those receiving a vehicle, suggesting cognitive benefits. Although SEM did not significantly enhance motor and exploratory activities, it displayed a potential anxiolytic effect, particularly evident in the combined anxiety index, with notable differences observed before and after treatment in the AD group. Conclusions: The findings of this pilot study suggest that SEM may play a dual role in managing AD by improving glycemic control and potentially enhancing cognitive function. As the landscape of AD treatment evolves, the comprehensive approach of utilizing SEM could pave the way for innovative interventions targeting the complex interplay of metabolic and cognitive dysfunctions in this challenging neurodegenerative disorder. Full article

(This article belongs to the Special Issue Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition))

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17 pages, 3206 KiB

Open AccessArticle

Circadian Alterations in Brain Metabolism Linked to Cognitive Deficits During Hepatic Ischemia-Reperfusion Injury Using [¹H-¹³C]-NMR Metabolomics

by Yijing Li, Yanbo Liu, Zhigang He, Zhixiao Li and Hongbing Xiang

Biomedicines 2024, 12(11), 2536; https://doi.org/10.3390/biomedicines12112536 - 6 Nov 2024

Viewed by 833

Abstract

Background: Hepatic ischemia-reperfusion injury (HIRI) is known to affect cognitive functions, with particular concern for its impact on brain metabolic dynamics. Circadian rhythms, as a crucial mechanism for internal time regulation within organisms, significantly influence metabolic processes in the brain. This study aims to explore how HIRI affects hippocampal metabolism and its circadian rhythm differences in mice, and to analyze how these changes are associated with cognitive impairments. Methods: A C57BL/6 male mouse model was used, simulating HIRI through hepatic ischemia-reperfusion surgery, with a sham operation conducted for the control group. Cognitive functions were evaluated using open field tests, Y-maze tests, and novel object recognition tests. Magnetic resonance spectroscopic imaging (MRSI) technology, combined with intravenous injection of [2-¹³C]-acetate and [1-¹³C]-glucose, was utilized to analyze metabolic changes in the hippocampus of HIRI mice at different circadian time points (Zeitgeber Time ZT0, 8:00 and ZT12, 20:00). Circadian rhythms regulate behavioral, physiological, and metabolic rhythms through transcriptional feedback loops, with ZT0 at dawn (lights on) and ZT12 at dusk (lights off). Results: HIRI mice exhibited significant cognitive impairments in behavioral tests, particularly in spatial memory and learning abilities. MRSI analysis revealed significant circadian rhythm differences in the concentration of metabolites in the hippocampus, with the enrichment concentrations of lactate, alanine, glutamate, and taurine showing different trends at ZT0 compared to ZT12, highlighting the important influence of circadian rhythms on metabolic dysregulation induced by HIRI. Conclusions: This study highlights the significant impact of HIRI on brain metabolic dynamics in mice, especially in the hippocampal area, and for the first time reveals the differences in these effects within circadian rhythms. These findings not only emphasize the association between HIRI-induced cognitive impairments and changes in brain metabolism but also point out the crucial role of circadian rhythms in this process, offering new metabolic targets and timing considerations for therapeutic strategies against HIRI-related cognitive disorders. Full article

(This article belongs to the Special Issue Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition))

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19 pages, 3553 KiB

Open AccessArticle

Comparison of Malondialdehyde, Acetylcholinesterase, and Apoptosis-Related Markers in the Cortex and Hippocampus of Cognitively Dysfunctional Mice Induced by Scopolamine

by Hee-Jung Park, Myeong-Hyun Nam, Ji-Hoon Park, Ji-Min Lee, Hye-Sun Hong, Tae-Woo Kim, In-Ho Lee, Chang-Ho Shin, Soo-Hong Lee and Young-Kwon Seo

Biomedicines 2024, 12(11), 2475; https://doi.org/10.3390/biomedicines12112475 - 28 Oct 2024

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Abstract

Objectives: Until now, many researchers have conducted evaluations on hippocampi for analyses of cognitive dysfunction models using scopolamine. However, depending on the purposes of these analyses, there are differences in the experimental results for the hippocampi and cortexes. Therefore, this study intends to compare various analyses of cognitive dysfunction after scopolamine administration with each other in hippocampi and cortexes. Methods: Scopolamine was administered at three dosages in mice: 0.5, 1, and 3 mg/kg. And this study evaluates the differences in cognitive function and the expression of malondialdehyde (MDA), acetylcholinesterase (AChE), and brain-derived neurotrophic factor (BDNF) in mice’s hippocampi and cortexes based on scopolamine dosages. Results: The Morris water maze test was conducted between 1 and 3 h after scopolamine injection to assess its duration. A significant decrease in behavioral ability was evaluated at 1 h, and we observed a similar recovery to the normal group at 3 h. And the Morris water maze escape latency showed differences depending on scopolamine concentration. While the escape waiting time in the control group and scop 0.5 administration group remained similar to that seen before administration, the administration of scop 1 and 3 increased it. In the experimental group administered scop 1 and 3, cerebral MDA levels in the cerebral cortex significantly increased. In the hippocampus, the MDA level in the scopolamine-administered groups slightly increased compared to the cortex. A Western blotting assay shows that Bax and Bcl-xl showed a tendency to increase or decrease depending on the concentration, but BDNF increased in scop 0.5, and scop 1 and 3 did not show a significant decrease compared to the control at the cerebral cortex. In the hippocampus, BDNF showed a concentration-dependent decrease in expression. Conclusions: This study’s findings indicate that chemical analyses for MDA and AChE can be performed in the cerebral cortex, while the hippocampus is better suited for protein analysis of apoptosis and BDNF. Full article

(This article belongs to the Special Issue Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition))

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13 pages, 2124 KiB

Open AccessArticle

Electrophysiological and Behavioral Markers of Hyperdopaminergia in DAT-KO Rats

by Zoia Fesenko, Maria Ptukha, Marcelo M. da Silva, Raquel S. Marques de Carvalho, Vassiliy Tsytsarev, Raul R. Gainetdinov, Jean Faber and Anna B. Volnova

Biomedicines 2024, 12(9), 2114; https://doi.org/10.3390/biomedicines12092114 - 17 Sep 2024

Viewed by 1005

Abstract

Background/Objectives: Dopamine dysfunction (DA) is a hallmark of many neurological disorders. In this case, the mechanism of changes in dopamine transmission on behavior remains unclear. This study is a look into the intricate link between disrupted DA signaling, neuronal activity patterns, and behavioral abnormalities in a hyperdopaminergic animal model. Methods: To study the relationship between altered DA levels, neuronal activity, and behavioral deficits, local field potentials (LFPs) were recorded during four different behaviors in dopamine transporter knockout rats (DAT-KO). At the same time, local field potentials were recorded in the striatum and prefrontal cortex. Correlates of LFP and accompanying behavioral patterns in genetically modified (DAT-KO) and control animals were studied. Results: DAT-KO rats exhibited desynchronization between LFPs of the striatum and prefrontal cortex, particularly during exploratory behavior. A suppressive effect of high dopamine levels on the striatum was also observed. Wild-type rats showed greater variability in LFP patterns across certain behaviors, while DAT-KO rats showed more uniform patterns. Conclusions: The decisive role of the synchrony of STR and PFC neurons in the organization of motor acts has been revealed. The greater variability of control animals in certain forms of behavior probably suggests greater adaptability. More uniform patterns in DAT-KO rats, indicating a loss of striatal flexibility when adapting to specific motor tasks. It is likely that hyperdopaminergy in the DAT-KO rat reduces the efficiency of information processing due to less synchronized activity during active behavior. Full article

(This article belongs to the Special Issue Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition))

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16 pages, 1990 KiB

Open AccessArticle

Rats Lacking the Dopamine Transporter Display Inflexibility in Innate and Learned Behavior

by Anastasia Belskaya, Natalia Kurzina, Artem Savchenko, Ilya Sukhanov, Arina Gromova, Raul R. Gainetdinov and Anna Volnova

Biomedicines 2024, 12(6), 1270; https://doi.org/10.3390/biomedicines12061270 - 7 Jun 2024

Cited by 3 | Viewed by 1424

Abstract

Playing a key role in the organization of striatal motor output, the dopamine (DA)-ergic system regulates both innate and complex learned behaviors. Growing evidence clearly indicates the involvement of the DA-ergic system in different forms of repetitive (perseverative) behavior. Some of these behaviors accompany such disorders as obsessive–compulsive disorder (OCD), Tourette’s syndrome, schizophrenia, and addiction. In this study, we have traced how the inflexibility of repetitive reactions in the recently developed animal model of hyper-DA-ergia, dopamine transporter knockout rats (DAT-KO rats), affects the realization of innate behavior (grooming) and the learning of spatial (learning and reversal learning in T-maze) and non-spatial (extinction of operant reaction) tasks. We found that the microstructure of grooming in DAT-KO rats significantly differed in comparison to control rats. DAT-KO rats more often demonstrated a fixed syntactic chain, making fewer errors and very rarely missing the chain steps in comparison to control rats. DAT-KO rats’ behavior during inter-grooming intervals was completely different to the control animals. During learning and reversal learning in the T-maze, DAT-KO rats displayed pronounced patterns of hyperactivity and perseverative (stereotypical) activity, which led to worse learning and a worse performance of the task. Most of the DAT-KO rats could not properly learn the behavioral task in question. During re-learning, DAT-KO rats demonstrated rigid perseverative activity even in the absence of any reinforcement. In operant tasks, the mutant rats demonstrated poor extinction of operant lever pressing: they continued to perform lever presses despite no there being reinforcement. Our results suggest that abnormally elevated DA levels may be responsible for behavioral rigidity. It is conceivable that this phenomenon in DAT-KO rats reflects some of the behavioral traits observed in clinical conditions associated with endogenous or exogenous hyper-DA-ergia, such as schizophrenia, substance abuse, OCD, patients with Parkinson disease treated with DA mimetics, etc. Thus, DAT-KO rats may be a valuable behavioral model in the search for new pharmacological approaches to treat such illnesses. Full article

(This article belongs to the Special Issue Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition))

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16 pages, 4816 KiB

Open AccessArticle

Wireless EEG Recording of Audiogenic Seizure Activity in Freely Moving Krushinsky-Molodkina Rats

by Sergey Krivopalov, Boris Yushkov and Alexey Sarapultsev

Biomedicines 2024, 12(5), 946; https://doi.org/10.3390/biomedicines12050946 - 24 Apr 2024

Viewed by 1192

Abstract

This study investigates audiogenic epilepsy in Krushinsky-Molodkina (KM) rats, questioning the efficacy of conventional EEG techniques in capturing seizures during animal restraint. Using a wireless EEG system that allows unrestricted movement, our aim was to gather ecologically valid data. Nine male KM rats, prone to audiogenic seizures, received implants of wireless EEG transmitters that target specific seizure-related brain regions. These regions included the inferior colliculus (IC), pontine reticular nucleus, oral part (PnO), ventrolateral periaqueductal gray (VLPAG), dorsal area of the secondary auditory cortex (AuD), and motor cortex (M1), facilitating seizure observation without movement constraints. Our findings indicate that targeted neural intervention via electrode implantation significantly reduced convulsive seizures in approximately half of the subjects, suggesting therapeutic potential. Furthermore, the amplitude of brain activity in the IC, PnO, and AuD upon audiogenic stimulus onset significantly influenced seizure severity and nature, highlighting these areas as pivotal for epileptic propagation. Severe cases exhibited dual waves of seizure generalization, indicative of intricate neural network interactions. Distinctive interplay between specific brain regions, disrupted during convulsive activity, suggests neural circuit reconfiguration in response to escalating seizure intensity. These discoveries challenge conventional methodologies, opening avenues for novel approaches in epilepsy research and therapeutic interventions. Full article

(This article belongs to the Special Issue Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition))

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