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Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 March 2024) | Viewed by 8897

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Prof. Dr. Changjong Moon

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College of Veterinary Medicine, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea
Interests: behavioral neuroscience; cognitive function; emotional regulation; prefrontal cortex; hippocampus; molecular neurobiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Various animal models have played a key role in neurological disorder research. These models aim to replicate various aspects of the disorders, including the genetic basis, histopathological lesions, and clinical symptoms. They provide us with improved comprehension of the etiopathogenesis of these disorders, with the end goal of mechanistically constructing therapeutics which can eventually lead to the modification and/or prevention of neurological disorders. Despite the vast amount of knowledge previously assimilated, researchers and the general public can still benefit from novel animal models that better recapitulate the human disease, in addition to updates concerning previously established animal models, as well as new insights regarding the molecular mechanisms underlying these disorders. This Special Issue intends to present new and interesting developments in the field. Articles offering innovative insights into the multifaceted pathophysiology of neurological disorders are welcome. This Special Issue may include, but is not limited to: original research articles focusing on differential gene expression analyses of genetic models, the development of new models, further characterization of established models, therapeutic studies utilizing animal models, and review articles which summarize and highlight recent advances in the field.

Prof. Dr. Changjong Moon
Guest Editor

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Keywords

neurological disorders
animal models
developmental models
genetic models
molecular mechanisms
genetic analysis
drug efficacy testing

Published Papers (8 papers)

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Research

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14 pages, 8369 KiB

Open AccessArticle

Chicoric Acid Ameliorated Beta-Amyloid Pathology and Enhanced Expression of Synaptic-Function-Related Markers via L1CAM in Alzheimer’s Disease Models

by Ruonan Wang, Shijia Kang, Zirui Zhao, Lingling Jin, Xiaolin Cui, Lili Chen, Melitta Schachner, Sheng Li, Yanjie Guo and Jie Zhao

Int. J. Mol. Sci. 2024, 25(6), 3408; https://doi.org/10.3390/ijms25063408 - 17 Mar 2024

Viewed by 705

Abstract

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aβ) plaques is a distinctive pathological feature of AD patients. The aims of this study were to evaluate the therapeutic effect of chicoric acid (CA) on AD models and to explore its underlying mechanisms. APPswe/Ind SH-SY5Y cells and 5xFAD mice were treated with CA. Soluble Aβ1–42 and Aβ plaque levels were analyzed by ELISA and immunohistochemistry, respectively. Transcriptome sequencing was used to compare the changes in hippocampal gene expression profiles among the 5xFAD mouse groups. The specific gene expression levels were quantified by qRT-PCR and Western blot analysis. It was found that CA treatment reduced the Aβ1–42 levels in the APPswe/Ind cells and 5xFAD mice. It also reduced the Aβ plaque levels as well as the APP and BACE1 levels. Transcriptome analysis showed that CA affected the synaptic-plasticity-related genes in the 5xFAD mice. The levels of L1CAM, PSD-95 and synaptophysin were increased in the APPswe/Ind SH-SY5Y cells and 5xFAD mice treated with CA, which could be inhibited by administering siRNA-L1CAM to the CA-treated APPswe/Ind SH-SY5Y cells. In summary, CA reduced Aβ levels and increased the expression levels of synaptic-function-related markers via L1CAM in AD models. Full article

(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0)

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19 pages, 5666 KiB

Open AccessArticle

Chronic Treatment with Nigella sativa Oil Exerts Antimanic Properties and Reduces Brain Inflammation in Rats

by Sarit Uzzan, Ira-Sivan Rostevanov, Elina Rubin, Olivia Benguigui, Said Marazka, Jacob Kaplanski, Riad Agbaria and Abed N. Azab

Int. J. Mol. Sci. 2024, 25(3), 1823; https://doi.org/10.3390/ijms25031823 - 02 Feb 2024

Viewed by 922

Abstract

Nigella sativa (NS) is a native herb consumed habitually in several countries worldwide, possessing manifold therapeutic properties. Among them, anti-inflammatory features have been reported, presumably relating to mechanisms involved in the nuclear factor kappa-B pathway, among others. Given the observed association between neuroimmune factors and mental illness, the primary aim of the present study was to examine the effects of chronic NS use on manic-like behavior in rats, as well as analyze levels of brain inflammatory mediators following NS intake. Using male and female rats, baseline tests were performed; thereafter, rats were fed either regular food (control) or NS-containing food (treatment) for four weeks. Following intervention, behavioral tests were induced (an open field test, sucrose consumption test, three-chamber sociality test, and amphetamine-induced hyperactivity test). Subsequently, brain samples were extracted, and inflammatory mediators were evaluated, including interleukin-6, leukotriene B4, prostaglandin E2, tumor necrosis factor-α, and nuclear phosphorylated-p65. Our findings show NS to result in a marked antimanic-like effect, in tandem with a positive modulation of select inflammatory mediators among male and female rats. The findings reinforce the proposed therapeutic advantages relating to NS ingestion. Full article

(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0)

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14 pages, 4792 KiB

Open AccessArticle

Chemogenetics Modulation of Electroacupuncture Analgesia in Mice Spared Nerve Injury-Induced Neuropathic Pain through TRPV1 Signaling Pathway

by I-Han Hsiao, Chia-Ming Yen, Hsin-Cheng Hsu, Hsien-Yin Liao and Yi-Wen Lin

Int. J. Mol. Sci. 2024, 25(3), 1771; https://doi.org/10.3390/ijms25031771 - 01 Feb 2024

Cited by 1 | Viewed by 774

Abstract

Neuropathic pain, which is initiated by a malfunction of the somatosensory cortex system, elicits inflammation and simultaneously activates glial cells that initiate neuroinflammation. Electroacupuncture (EA) has been shown to have therapeutic effects for neuropathic pain, although with uncertain mechanisms. We suggest that EA can reliably cure neuropathic disease through anti-inflammation and transient receptor potential V1 (TRPV1) signaling pathways from the peripheral to the central nervous system. To explore this, we used EA to treat the mice spared nerve injury (SNI) model and explore the underlying molecular mechanisms through novel chemogenetics techniques. Both mechanical and thermal pain were found in SNI mice at four weeks (mechanical: 3.23 ± 0.29 g; thermal: 4.9 ± 0.14 s). Mechanical hyperalgesia was partially attenuated by 2 Hz EA (mechanical: 4.05 ± 0.19 g), and thermal hyperalgesia was fully reduced (thermal: 6.22 ± 0.26 s) but not with sham EA (mechanical: 3.13 ± 0.23 g; thermal: 4.58 ± 0.37 s), suggesting EA’s specificity. In addition, animals with Trpv1 deletion showed partial mechanical hyperalgesia and no significant induction of thermal hyperalgesia in neuropathic pain mice (mechanical: 4.43 ± 0.26 g; thermal: 6.24 ± 0.09 s). Moreover, we found increased levels of inflammatory factors such as interleukin-1 beta (IL1-β), IL-3, IL-6, IL-12, IL-17, tumor necrosis factor alpha, and interferon gamma after SNI modeling, which decreased in the EA and Trpv1^−/− groups rather than the sham group. Western blot and immunofluorescence analysis showed similar tendencies in the dorsal root ganglion, spinal cord dorsal horn, somatosensory cortex (SSC), and anterior cingulate cortex (ACC). In addition, a novel chemogenetics method was used to precisely inhibit SSC to ACC activity, which showed an analgesic effect through the TRPV1 pathway. In summary, our findings indicate a novel mechanism underlying neuropathic pain as a beneficial target for neuropathic pain. Full article

(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0)

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16 pages, 2142 KiB

Open AccessArticle

DNA Methylation Inhibition Reversibly Impairs the Long-Term Context Memory Maintenance in Helix

by Alena B. Zuzina, Aliya Kh. Vinarskaya and Pavel M. Balaban

Int. J. Mol. Sci. 2023, 24(18), 14068; https://doi.org/10.3390/ijms241814068 - 14 Sep 2023

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Abstract

This work aims to study the epigenetic mechanisms of regulating long-term context memory in the gastropod mollusk: Helix. We have shown that RG108, an inhibitor of DNA methyltransferase (DNMT), impaired long-term context memory in snails, and this impairment can be reversed within a limited time window: no more than 48 h. Research on the mechanisms through which the long-term context memory impaired by DNMT inhibition could be reinstated demonstrated that this effect depends on several biochemical mechanisms: nitric oxide synthesis, protein synthesis, and activity of the serotonergic system. Memory recovery did not occur if at least one of these mechanisms was impaired. The need for the joint synergic activity of several biochemical systems for a successful memory rescue confirms the assumption that the memory recovery process depends on the process of active reconsolidation, and is not simply a passive weakening of the effect of RG108 over time. Finally, we showed that the reactivation of the impaired memory by RG108, followed by administration of histone deacetylase inhibitor sodium butyrate, led to memory recovery only within a narrow time window: no more than 48 h after memory disruption. Full article

(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0)

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26 pages, 8112 KiB

Open AccessArticle

Survival Bias, Non-Lineal Behavioral and Cortico-Limbic Neuropathological Signatures in 3xTg-AD Mice for Alzheimer’s Disease from Premorbid to Advanced Stages and Compared to Normal Aging

by Aida Muntsant, Maria del Mar Castillo-Ruiz and Lydia Giménez-Llort

Int. J. Mol. Sci. 2023, 24(18), 13796; https://doi.org/10.3390/ijms241813796 - 07 Sep 2023

Cited by 1 | Viewed by 1084

Abstract

Pre-clinical research in aging is hampered by the scarcity of studies modeling its heterogeneity and complexity forged by pathophysiological conditions throughout the life cycle and under the sex perspective. In the case of Alzheimer’s disease, the leading cause of dementia in older adults, we recently described in female wildtype and APP23 mice a survival bias and non-linear chronology of behavioral signatures from middle age to long life. Here, we present a comprehensive and multidimensional (physical, cognitive, and neuropsychiatric-like symptoms) screening and underlying neuropathological signatures in male and female 3xTg-AD mice at 2, 4, 6, 12, and 16 months of age and compared to their non-transgenic counterparts with gold-standard C57BL/6J background. Most variables studied detected age-related differences, whereas the genotype factor was specific to horizontal and vertical activities, thigmotaxis, coping with stress strategies, working memory, and frailty index. A sex effect was predominantly observed in classical emotional variables and physical status. Sixteen-month-old mice exhibited non-linear age- and genotype-dependent behavioral signatures, with higher heterogeneity in females, and worsened in naturalistically isolated males, suggesting distinct compensatory mechanisms and survival bias. The underlying temporal and spatial progression of Aβ and tau pathologies pointed to a relevant cortico-limbic substrate roadmap: premorbid intracellular Aβ immunoreactivity and pSer202/pThr205 tau phosphorylation in the amygdala and ventral hippocampus, and the entorhinal cortex and ventral hippocampus as the areas most affected by Aβ plaques. Therefore, depicting phenotypic signatures and neuropathological correlates can be critical to unveiling preventive/therapeutic research and intervention windows and studying adaptative behaviors and maladaptive responses relevant to psychopathology. Full article

(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0)

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24 pages, 15123 KiB

Open AccessArticle

Downregulation of PACAP and the PAC1 Receptor in the Basal Ganglia, Substantia Nigra and Centrally Projecting Edinger–Westphal Nucleus in the Rotenone model of Parkinson’s Disease

by Máté Fehér, Zsombor Márton, Ákos Szabó, János Kocsa, Viktória Kormos, Ágnes Hunyady, László Ákos Kovács, Balázs Ujvári, Gergely Berta, József Farkas, Nóra Füredi, Tamás Gaszner, Bence Pytel, Dóra Reglődi and Balázs Gaszner

Int. J. Mol. Sci. 2023, 24(14), 11843; https://doi.org/10.3390/ijms241411843 - 24 Jul 2023

Viewed by 1272

Abstract

Numerous in vitro and in vivo models of Parkinson’s disease (PD) demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP) conveys its strong neuroprotective actions mainly via its specific PAC1 receptor (PAC1R) in models of PD. We recently described the decrease in PAC1R protein content in the basal ganglia of macaques in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD that was partially reversed by levodopa therapy. In this work, we tested whether these observations occur also in the rotenone model of PD in the rat. The rotarod test revealed motor skill deterioration upon rotenone administration, which was reversed by benserazide/levodopa (B/L) treatment. The sucrose preference test suggested increased depression level while the open field test showed increased anxiety in rats rendered parkinsonian, regardless of the received B/L therapy. Reduced dopaminergic cell count in the substantia nigra pars compacta (SNpc) diminished the dopaminergic fiber density in the caudate-putamen (CPu) and decreased the peptidergic cell count in the centrally projecting Edinger–Westphal nucleus (EWcp), supporting the efficacy of rotenone treatment. RNAscope in situ hybridization revealed decreased PACAP mRNA (Adcyap1) and PAC1R mRNA (Adcyap1r1) expression in the CPu, globus pallidus, dopaminergic SNpc and peptidergic EWcp of rotenone-treated rats, but no remarkable downregulation occurred in the insular cortex. In the entopeduncular nucleus, only the Adcyap1r1 mRNA was downregulated in parkinsonian animals. B/L therapy attenuated the downregulation of Adcyap1 in the CPu only. Our current results further support the evolutionarily conserved role of the PACAP/PAC1R system in neuroprotection and its recruitment in the development/progression of neurodegenerative states such as PD. Full article

(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0)

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Review

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14 pages, 692 KiB

Open AccessReview

Neurogenic Fever after Subarachnoid Hemorrhage in Animal Models: A Systematic Review

by Ernesto Migliorino, Francesco Nonino, Roberto Amici, Domenico Tupone and Raffaele Aspide

Int. J. Mol. Sci. 2023, 24(14), 11514; https://doi.org/10.3390/ijms241411514 - 15 Jul 2023

Cited by 1 | Viewed by 1428

Abstract

The observation of neurogenic fever resulting from subarachnoid hemorrhage (SAH) in animal models is a useful tool for the interpretation of its pathophysiology in humans, which is still a major challenge in the management of neurocritical patients. This systematic review aims to identify the prognostic factors and pathophysiological elements that determine the onset of neurogenic fever and its severity in animal models. In addition, our study aims to analyze which pharmacological treatments are most effective. All the articles available in Pubmed, Embase, and the Biological Science Collection until August 2021 concerning in vivo experimental studies on SAH animal models, including full texts and abstracts written in English and Italian, were considered. The risk of bias was assessed with SYRCLE’s Risk of Bias tool. In total, 81 records were retrieved; after excluding duplicates, 76 records were potentially relevant. A total of 64 articles was excluded after title and abstract screening. The remaining 12 studies were evaluated as full texts, and 6 other studies were excluded (SAH-induced animal studies without a body temperature assessment). In one study, body temperature was measured after SAH induction, but the authors did not report temperature recording. Therefore, only five studies met the search criteria. The high methodological heterogeneity (different animal species, different temperature measurement methods, and different methods of the induction of bleeding) prevented meta-analysis. Synthesis methodology without meta-analysis (SWiM) was used for data analysis. The total number of animals used as controls was 87 (23 rabbits, 32 mice, and 32 rats), while there were 130 animals used as interventions (54 rabbits, 44 mice, and 32 rats). The presence of blood in the subarachnoid space, particularly red blood cells, is responsible for neurogenic fever; the role of hemoglobin is unclear. The mechanism is apparently not mediated by prostaglandins. The autonomic nervous system innervating brown adipose tissue is undoubtedly implicated in the onset of neurogenic fever. The activation of the central adenosine-1 receptor is effective in controlling the temperature of animals with neurogenic fever (by inhibiting thermogenesis of brown adipose tissue). Full article

(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0)

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Other

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9 pages, 1613 KiB

Open AccessBrief Report

Effect Sizes of Cognitive and Locomotive Behavior Tests in the 5XFAD-J Mouse Model of Alzheimer’s Disease

by Moonseok Choi, Hyung-Sup Jang, Taekwon Son, Dongsoo Kim, Young-Jin Youn, Gyu-Bin Hwang, Young Pyo Choi and Yun Ha Jeong

Int. J. Mol. Sci. 2023, 24(20), 15064; https://doi.org/10.3390/ijms242015064 - 11 Oct 2023

Viewed by 1339

Abstract

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid β (Aβ) plaques in the brain, leading to cognitive impairment and other clinical symptoms. The 5XFAD mouse model is commonly used in AD research because it expresses five human transgenes that result in the accumulation of Aβ plaques and cognitive decline at a relatively early age. Behavioral experiments are frequently conducted using this model; however, the effect size has not yet been reported. In this study, we examined basic cognition and locomotion in 5XFAD mice with a C57BL6/J background (5XFAD-J) at 6 months of age, a period in which impairments of cognitive function and locomotion are commonly observed. We analyzed the effect sizes of cognitive and locomotive experiments in the 5XFAD mice compared with those in the wild-type mice. Our results suggest that for long-term memory analysis, the novel object recognition test (p = 0.013, effect size 1.24) required a sample size of at least 12 to obtain meaningful results. Moreover, analysis of general locomotion over total distance with the Laboratory Animal Behavior Observation, Registration and Analysis System (LABORAS) test during the dark phase (p = 0.007, effect size −1.37) needed a sample size of 10 for a statistical power (1-β) of 0.8. In conclusion, we can conduct more ethical and scientifically rigorous animal experiments using 5XFAD mice based on the effect and sample sizes suggested in this study. Full article

(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles 3.0)

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